EULEXIN^®
brand of flutamide
Capsules, USP

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.

PRODUCT
INFORMATION

EULEXIN Capsules contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide.

Each capsule contains 125 mg flutamide, USP. The compound is a buff to yellow powder with a molecular weight of 276.2 and the following structural formula:

The inactive ingredients for EULEXIN Capsules include: corn starch, lactose, magnesium stearate, povidone, and sodium lauryl sulfate. Gelatin capsule shells may also contain benzyl alcohol, butylparaben, colloidal silicon dioxide, edetate calcium disodium, methylparaben, propylparaben, and sodium propionate, and the following dye systems: FD&C Blue No. 1, FD&C Red No. 3, FD&C Yellow No. 6, titanium dioxide, black ink, and other inactive ingredients.

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, eg, castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.

EULEXIN 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.

Treatment with EULEXIN Capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.

To achieve benefit from treatment, EULEXIN Capsules should be initiated with the LHRH-agonist and continued until progression.

EULEXIN Capsules are contraindicated in patients who are hypersensitive to flutamide 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).

SEE BOXED WARNING.

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.

Flutamide may cause fetal harm when administered to a pregnant woman (see Pregnancy).

One metabolite of flutamide 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 flutamide administration. In patients susceptible to aniline toxicity (eg, persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease, and smokers), monitoring of methemoglobin levels should be considered.

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

Patients should be informed that EULEXIN Capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.

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 therapy the patients should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment period free of antiandrogen while continuing the LHRH analogue may be considered.

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 Capsules are administered concomitantly with warfarin.

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 doses of 10, 30, and 50 mg/kg/day were administered). These produced plasma C_max values that are 1-, 2- to 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, adeno carcinomas, 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.

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.

Treatment with EULEXIN Capsules and the goserelin acetate implant did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing flutamide + goserelin acetate implant + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are uled below.

Additional adverse event data were 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%).

The following adverse experiences were reported during a multicenter clinical trial comparing flutamide + LHRH agonist versus placebo + LHRH agonist.

The most frequently reported (greater than 5%) adverse experiences during treatment with EULEXIN Capsules in combination with an LHRH agonist are uled in the table below. For comparison, adverse experiences seen with an LHRH agonist and placebo are also uled in the following table.

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 than 1%.

In addition, the following adverse reactions were reported during treatment with flutamide + LHRH agonist.

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, sulfhemoglobinemia, 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 often reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide.

Malignant breast neoplasms have occurred rarely in male patients being treated with EULEXIN Capsules.

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 to 1500 mg 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 the 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.

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

EULEXIN 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 × 10's)
NDC 0085-0525-06 - Bottles of 180

Store between 2° and 30°C (36° and 86°F).

Protect the Unit Dose packages from excessive moisture.

Rev. 12/00

18822440T
B-16887692

Copyright © 1989, 1996, 1999, Schering Corporation. All rights reserved.