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Eulexin®
(flutamide) Capsules
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, eg, 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.
EULEXIN Capsules contain flutamide, an acetanilid, nonsteroidal, orally active anti-androgen having the chemical name, 2-methyl-N-[4-nitro-3 (trifluoromethyl) phenyl] propanamide.
Each capsule contains 125 mg flutamide. The compound is a buff to yellow powder with a molecular weight of 276.2 and the following structual formula:
The inactive ingredients for EULEXIN (flutamide) Capsules include: corn starch, lactose, magnesium stearate, povidone, and sodium lauryl sulfate. Gelatin capsule shells may contain methylparaben, propylparaben, butylparaben, and the following dye systems: FD&C Blue 1, FD&C Yellow 6, and either FD&C Red 3 or FD&C Red 40 plus D&C Yellow 10, with titanium dioxide and other inactive ingredients.
EULEXIN (flutamide) Capsules are indicated for use in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate.
Stage B2-C Prostatic Carcinoma
Treatment with EULEXIN (flutamide) Capsules and the LHRH agonist should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.
Stage D2 Metastatic Carcinoma
To achieve benefit from treatment, EULEXIN (flutamide) Capsules should be initiated with the LHRH agonist and continued until progression.
The recommended dosage is 2 capsules 3 times a day at 8-hour intervals for a total daily dose of 750 mg.
EULEXIN (flutamide) Capsules, 125 mg, are available as opaque, two- toned brown capsules, imprinted with "Schering 525†. They are supplied as follows:
NDC 0085-0525-05 - Bottles of 500
NDC 0085-0525-03 - Unit Dose packages of 100 (10 x 10†s)
NDC 0085-0525-06 - Bottles of 180
Store between 2o and 30o C (36o and 86o F). Protect the Unit Dose packages from excessive moisture.
Stage B2-C Prostatic Carcinoma
Treatment with EULEXIN (flutamide) Capsules and the LHRH agonist did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing EULEXIN (flutamide) Capsules + LHRH-A +radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below.
|
Adverse Events During Acute Radiation Therapy | ||
|
|
(n= 231) |
(n= 235) |
| Rectum/Large Bowel |
80 |
76 |
| Bladder |
58 |
60 |
| Skin |
37 |
37 |
|
Adverse Events During Late Radiation Phase | ||
|
|
(n= 231) |
(n= 235) |
| Diarrhea |
36 |
40 |
| Cystitis |
16 |
16 |
| Rectal Bleeding |
14 |
20 |
| Proctitis |
8 |
8 |
| Hematuria |
7 |
12 |
Additional adverse event data was 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 D2 Metastatic Carcinoma
The following adverse experiences were reported during a multi-center clinical trial comparing EULEXIN (flutamide) Capsules + LHRH agonist versus placebo + LHRH agonist.
The most frequently reported (greater than 5%) adverse experiences during treatment with EULEXIN (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) |
(n= 285) |
| 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 |
As 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 than1%.
In addition, the following adverse reactions were reported during treatment with flutamide + LHRH agonist. No causal relatedness of these reactions to drug treatment has been made, and some of the adverse experiences reported are those that commonly occur in elderly patients.
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, 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 usually reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide.
Malignant breast neoplasms have occured in male patients being treated with EULEXIN (flutamide) Capsules.
Abnormal Laboratory Test Values: Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.
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 EULEXIN (flutamide) Capsules are administered concomitantly with warfarin.
Gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.
Flutamide may cause fetal harm when administered to a pregnant woman. There was decreased 24-hour survival in the offspring of rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose) during pregnancy. A slight increase in minor variations in the development of the stemebrae and vertebrae was seen in fetuses of rats at the two higher doses. Feminization of the males also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day; equal to 1.4 times the human dose).
Preclinical data from rats, cats, dogs, and monkeys, as well as clinical data in men, demonstrate that one metabolite of flutamide is 4-nitro-3-fluoromethylaniline. Several toxicities consistent with aniline exposure including methemoglobinemia, hemolytic anemia, and cholestatic jaundice have been observed in animals and humans after flutamide administration. Methemoglobin levels should be monitored in patients susceptible to aniline toxicity (e.g. persons with glucose-6-phosphate dehydrogenase deficiency or hemoglobin M disease as well as patients who smoke).
Serious 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 2-4 years. The 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 1 to 12-fold greater than those observed in humans at therapeutic levels.
Hepatic Injury
Since transaminase abnormalities, cholestatic jaundice, hepatic necrosis, and hepatic encephalopathy have been reported with the use of flutamide, periodic liver function tests should be considered. (See ADVERSE REACTIONS section.) Appropriate laboratory testing should be done at the first symptom/ sign of liver dysfunction (eg, pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, or unexplained "flu-like† symptoms). If the patient has clinically evident jaundice, in the absence of biopsy-confirmed liver metastases, EULEXIN (flutamide) therapy should be discontinued. In clinically asymptomatic patients, if transaminases increase over 2-3 times the upper limit of normal, treatment should be discontinued. The hepatic injury is usually reversible after discontinuation of therapy, and in some patients, after dosage reduction. However, there have been reports of death following severe hepatic injury associated with use of flutamide.
General:
In clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.
Information for Patients
See PATIENT INFORMATION section.
Laboratory Tests
Regular assessment of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise significantly and consistently during EULEXIN (flutamide) therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated P.A. a treatment- free period of antiandrogen while continuing the LHRH analogue may be considered.
Drug Interactions
See DRUG INTERACTIONS section.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 1-year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily oral doses of 10, 30, and 50 mg/kg/day were administered). These produce plasma Cmax values that are 1, 2-3, and 4-fold, respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for 1 year, tumors were still present after 1 year of a drug-free period, but the incidences were 43% to 47%. In a 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 1- to 4- fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with EULEXIN Capsules (see ADVERSE REACTIONS section).
Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/ microsome Mutagenesis Assay. Dominant lethal tests in rats were negative.
Reduced sperm counts were observed during a 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 Toxicology:
Serious 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 2-4 years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intraatrial fibrosis, myocardial acidophilic degeneration, vasculitis, and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were 1- to 12-fold greater than those observed in humans at therapeutic levels.
Pregnancy: Pregnancy Category D. There 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, 9, and 19 times the human dose). A 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 a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose).
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 to1500mg 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 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.
EULEXIN (flutamide) Capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation.
EULEXIN (flutamide) Capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment.
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.
Pharmacokinetlcs
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)
| Single Dose | Steady State | |||
|
Flutamide |
Hydroxy-flutamide |
Flutamide |
Hydroxy-flutamide | |
| 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. 0± 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, 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 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
