EULEXIN

Eulexin™ capsules contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, ,,-trifluoro-2-methyl-4'-nitro- m -propionotoluidide. Each capsule contains 125 mg flutamide. The compound is a buff to yellow powder with a molecular weight of 276.22 and the following structural formula: C 11 H 11 F 3 N 2 O 3 In addition, each capsule contains the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate. Gelatin capsule shells may contain gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, FDA/E172 Red Iron Oxide, FDA/E172 Yellow Iron Oxide, and black ink containing pharmaceutical glaze (modified) in SD-45, synthetic black iron oxide, N-butyl alcohol, SDA-3A alcohol, FD&C Blue No.2 Aluminum Lake, FD&C Red No.40 Aluminum Lake, FD&C Blue No.1 Aluminum Lake, and D&C Yellow No.10 Aluminum Lake. Chemical Structure

Eulexin™ capsules are indicated for use in combination with LHRH-agonists for the management of locally confined Stage B 2 -C and Stage D 2 metastatic carcinoma of the prostate. Stage B 2 -C Prostatic Carcinoma Treatment with Eulexin™ capsules and the goserelin acetate implant should start eight weeks prior to initiating radiation therapy and continue during radiation therapy. Stage D 2 Metastatic Carcinoma To achieve benefit from treatment, Eulexin™ 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™ capsules are contraindicated in patients who are hypersensitive to Eulexin™ 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).

Stage B 2 -C Prostatic Carcinoma 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 Eulexin™ + goserelin acetate implant + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below: Adverse Events During Acute Radiation Therapy (within first 90 days of radiation therapy) (n=231) Goserelin Acetate Implant + Eulexin™ + Radiation (n=235) Radiation Only % All % All Rectum/Large Bowel 80 76 Bladder 58 60 Skin 37 37 Adverse Events During Late Radiation Phase (after 90 days of radiation therapy) (n=231) Goserelin Acetate Implant + Eulexin™ + Radiation (n=235) Radiation Only % All % All Diarrhea 36 40 Cystitis 16 16 Rectal Bleeding 14 20 Proctitis 8 8 Hematuria 7 12 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%). Stage D 2 Metastatic Carcinoma The following adverse experiences were reported during a multicenter clinical trial comparing Eulexin™ + 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 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) Eulexin™ + LHRH agonist (n=28) Placebo + LHRH agonist % All % All 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 Eulexin™ + 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 Eulexin™ + 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 Eulexin™: 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 Eulexin™ 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 Eulexin™. Malignant breast neoplasms have occurred rarely in male patients being treated with Eulexin™ 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 Eulexin™ 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.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).