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Eulexin

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Eulexin

Warnings
Precautions

WARNINGS

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.

PRECAUTIONS

General:

In clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.

Information for Patients

See PATIENT INFORMAION 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).

Last reviewed on RxList: 12/28/2004
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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