Euflex (Flutamide)

EUFLEX®

Schering

Flutamide

Nonsteroidal Antiandrogen

Action And Clinical Pharmacology: Flutamide demonstrates potent antiandrogenic effects by inhibiting androgen uptake and/or inhibiting nuclear binding of androgen in target tissues. In adult male rats, ventral prostate weights and seminal vesicle weights were markedly reduced by daily administration of flutamide.

Indications And Clinical Uses: For use in combination with LHRH agonistic analogues (such as leuprolide acetate) for the treatment of metastatic prostatic carcinoma (Stage D2). To achieve the benefit of the adjunctive therapy with flutamide, treatment must be started simultaneously using both drugs. Also as an adjunctive therapy to orchiectomy, in order to achieve complete androgen blockade.

Flutamide in combination with LHRH agonists are also indicated prior to and during definitive external beam radiotherapy for patients with bulky locally advanced Stage B2 and Stage C prostatic carcinoma (see Dosage).

Contra-Indications: Patients who have shown hypersensitivity to flutamide or any component of this preparation.

Manufacturers’ Warnings In Clinical States: Gynecomastia occurred in 9% of patients receiving flutamide together with medical castration. Physicians must familiarize themselves with the proper use of LHRH before combination medication is contemplated.

Pregnancy and Lactation: Flutamide is indicated only for use in male patients. No studies have been conducted in pregnant or lactating women. Therefore, the possibility that flutamide may cause fetal harm if administered to a pregnant woman, or may be present in the breast milk of lactating women must be considered.

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 sternebra and vertebra 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).

Precautions: Periodic liver function tests and sperm count determinations must be performed in patients on long-term treatment with flutamide. After long-term administration in rats, flutamide produced testicular interstitial cell adenomas and dose-related increases in mammary gland adenomas or carcinomas. The relevance of these findings to humans is unknown. It should be noted that few cases of malignant breast neoplasms have been reported in male patients receiving flutamide; causality has not been established.

Since flutamide tends to elevate plasma testosterone and estradiol levels, fluid retention may occur. Accordingly, flutamide should be used with caution in those patients with cardiac disease.

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. Appropriate laboratory testing should be done at the first symptom/sign of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained “flu-like” symptoms). If the patient has laboratory evidence of liver injury or jaundice, in the absence of biopsy-confirmed liver metastases, flutamide therapy should be discontinued or the dosage reduced. 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 the use of flutamide.

Drug Interactions: Interactions between flutamide and leuprolide have not occurred. In patients receiving long-term warfarin therapy, increases in prothrombin time have been reported after flutamide monotherapy was initiated. Therefore, close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide is administered concomitantly with warfarin.

Information for the Patient: Patients should be informed that flutamide 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.

Adverse Reactions: The most frequently reported adverse reactions to flutamide monotherapy are gynecomastia and/or breast tenderness, sometimes accompanied by galactorrhea. These reactions disappear upon discontinuation of treatment or reduction in dosage. The incidence of gynecomastia is reduced greatly when flutamide is administered concomitantly with an LHRH agonist.

As shown in Table I, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, loss of libido, impotence) were those known to be associated with low serum androgen levels and known to occur with LHRH-agonists alone.

The only notable difference between these treatment groups was the higher incidence of diarrhea in the flutamide + LHRH-agonist group (12%) as compared to the placebo + LHRH-agonist group (4%). The cases of diarrhea reported were severe in less than 1% of the patients. 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: hypertension in 1% of patients. Rarely thrombophlebitis, pulmonary embolism, myocardial infarction.

CNS: CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients. Rarely insomnia, tiredness, headache, dizziness, weakness, malaise, blurred vision and decreased libido have been reported.

Endocrine: gynecomastia in 9% of patients. Rarely breast tenderness sometimes accompanied by galactorrhea.

Gastrointestinal: Nausea/vomiting occurred in 11%; diarrhea 12%, anorexia 4%, and other GI disorders occurred in 6% of patients. Increased appetite, indigestion and constipation have also been reported.

Hematopoietic: Anemia occurred in 6% of patients, leukopenia 3%, thrombocytopenia 1%.

Skin: Irritation at the injection site and rash occurred in 3% of patients. Photosensitivity reactions have been reported.

Other: Pruritus, ecchymosis, herpes zoster, thirst, lymphedema, lupus-like syndrome, hematuria, reduced sperm counts have been reported rarely in long-term treatment. Edema occurred in 4% of patients; neuromuscular, genitourinary symptoms occurred in 2% of patients.

Additional Adverse Experiences: In addition, the following adverse experiences have been reported during worldwide marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, photosensitivity reactions including erythema, ulcerations, bullous eruptions, and epidermal necrolysis and change in urine color to an amber or yellow-green appearance, which can be attributed to flutamide and/or its metabolites. Also observed 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.

Two reports of malignant male breast neoplasms in patients being dosed with flutamide have been reported. One involved aggravation of a preexisting nodule which was first detected 3 to 4 months before initiation of flutamide monotherapy in a patient with benign prostatic hypertrophy. After excision, this was diagnosed as a poorly differentiated ductal carcinoma. The other report involved gynecomastia and a nodule noted 2 and 6 months respectively, after initiation of flutamide monotherapy for treatment of advanced prostatic carcinoma. Nine months after the initiation of therapy, the nodule was excised and diagnosed as a moderately differentiated invasive ductal tumor staged T4N0M0, G3, no metastases had advanced.

Laboratory Values: Reported abnormal laboratory test results include elevated AST, ALT; elevated blood urea nitrogen (BUN) and bilirubin levels; less frequently, elevated serum creatinine levels and elevated gamma-glutamyl transferase levels have been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquillization, emesis and methemoglobinemia.

Clinical trials have been conducted with flutamide in doses up to 1 500 mg/day for periods up to 36 weeks with no serious effects reported. Those adverse reactions reported included gynecomastia, breast tenderness and some increases in AST. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established.

Since flutamide is highly protein bound, dialysis may not be of any use as treatment for overdose. 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.

Dosage And Administration: The recommended dosage of flutamide in combination with orchiectomy or in combination with an LHRH agonist is one 250 mg tablet 3 times a day at 8-hour intervals. In combination with an LHRH agonist, either the 2 agents may be initiated simultaneously, or flutamide therapy may be started 24 hours prior to initiation of the LHRH agonist.

In the management of bulky locally advanced Stage B2 and Stage C prostatic carcinoma, the recommended dosage is one 250 mg tablet, 3 times a day at 8-hour intervals. Flutamide should be started simultaneously or 24 hours prior to initiation of the LHRH agonist. Administration of flutamide should begin 8 weeks prior to external beam radiation therapy and continue through the course of radiation therapy.

Availability And Storage: Each round, biconvex, pale yellow, compressed tablet, engraved with “EUFLEX” on one face, and a single score on the other with the “SP” logo engraved on each side of the score line, contains: flutamide 250 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium stearate, pregelatinized starch, silica gel and sodium lauryl sulfate. Tartrazine-free. Bottles of 100. Store at 2 to 30°C.

EUFLEX® Schering Flutamide Nonsteroidal Antiandrogen

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