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 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 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 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 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, 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 2^o and 30^o C (36^o and 86^o F). Protect the Unit Dose packages from excessive moisture.

Stage B₂-C Prostatic Carcinoma

Treatment with EULEXIN 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 Capsules + LHRH-A +radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below.

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 Capsules + 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.

 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 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 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 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 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 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 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.

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.

 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 C_max, or AUC of flutamide. Renal impairment did not have an effect on the C_max or AUC of the biologically active alpha-hydroxylated metabolite of flutamide. In subjects with creatinine clearance of <29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted.

Hepatic Impairment

No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury).

Women, Pediatrics

Flutamide has not been studied in women or pediatric patients.

Drug- Drug Interactions

Interactions between EULEXIN Capsules and LHRH agonists have not occurred. Increases in prothrombin have been noted in patients receiving warfarin therapy (see PRECAUTIONS).

Clinical Studies

Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion.

The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH agonist as neoadjuvant therapy to radiation in stage B₂-C prostatic carcinoma and the other study evaluated flutamide and an LHRH agonist as the sole therapy in stage D₂ metastatic carcinoma.

Stage B₂-C Prostatic Carcinoma: The effects of hormonal treatment combined with radiation were studied in 466 patients (231 EULEXIN Capsules + LHRH- A + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B₂) or extending beyond the capsule (stage C), with or without pelvic node involvement.

In this multicentered, controlled trial, administration of EULEXIN Capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs 33% at 4 years, P< 0. 001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs 36% at 4 years, P = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs 2. 6 years, P< 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs 1.5 years, P< 0.001).

Stage D₂ Metastatic Carcinoma: To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + flutamide, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial.

Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9, months for patients treated with leuprolide alone. This 7-month increment represents a 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo.

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.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FLUTAMIDE - ORAL

(FLEW-tuh-mide)

COMMON BRAND NAME(S): Eulexin

WARNING: Rarely, flutamide has caused severe (sometimes fatal) liver problems. Immediately tell your doctor if you develop symptoms of liver problems (appetite loss, persistent nausea, vomiting, stomach/abdominal pain, severe tiredness, dark urine, yellowing eyes/skin, aching muscles, joint pain). Liver problems can happen at any time while taking flutamide, but they occur most often during the first 3 months of treatment. Your doctor will tell you whether to stop or continue flutamide. Your doctor will be monitoring your liver function with blood tests while you are taking flutamide. Keep all medical and laboratory appointments. Avoid alcohol while taking flutamide.

USES: This medication is used in men with other medications and sometimes with radiation treatments to treat prostate cancer. Flutamide belongs to a class of drugs known as anti-androgens (anti-testosterone). Testosterone, a natural hormone in men, helps prostate cancer to grow and spread. Flutamide works by blocking the effects of testosterone, thereby slowing the growth and spread of prostate cancer.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using flutamide and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually 3 times daily or as directed by your doctor.

Dosage is based on your medical condition and response to therapy.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. Do not stop any medications for your prostate cancer unless told to do so by your doctor. Stopping your medications could allow the cancer to spread more rapidly.

Inform your doctor if your condition persists or worsens (e.g., urination becomes more difficult, bone pain increases).

SIDE EFFECTS: See also Warning section.

Because flutamide is usually used with other medications, the side effects may be due to either one medicine or the combination of medications. Hot flashes, loss of sexual interest/ability, diarrhea, nausea, vomiting, and enlargement of male breasts may occur. Less common side effects include drowsiness. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

If you develop diarrhea: drink plenty of fluids, decrease dairy products (e.g., milk, cheese, yogurt), increase whole grains/vegetables/fruit, stop any laxatives.

Consult your pharmacist for appropriate over-the-counter medication for diarrhea.

Flutamide may change the color of your urine to light orange-brown or yellow-green. This is not harmful.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: depression, mental/mood changes (e.g., anxiety, nervousness), swelling of legs/hands, lung problems.

Tell your doctor immediately if any of these rare but very serious side effects occur: breast lump, confusion, sudden severe tiredness, weakness, pale skin, bluish fingernails/lips/skin, fast heartbeat at rest, feeling short of breath at rest, new fever, chills, cough, breathing problems, loss of appetite, weight loss, new diarrhea, sore throat, easy bruising/bleeding.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking flutamide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: serious liver problems, a certain enzyme deficiency (glucose-6-phosphate dehydrogenase-G6PD).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: smoking, hemoglobin M disease, mild liver problems.

This drug may rarely make you dizzy or drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness until you know how this medication affects you. Avoid alcoholic beverages.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially drowsiness.

Flutamide should not be used in women. Women who are pregnant should avoid touching or accidentally taking this medication. It may harm an unborn baby. Consult your doctor for more information.

It is not known whether this drug passes into breast milk. Women who are breastfeeding should avoid touching or accidentally taking this medication. Consult your doctor for more information.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: testosterone (patch, gel, injection), illegal anabolic steroids, over-the-counter androgens/anabolics/testosterone precursors, DHEA.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting flutamide.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: warfarin.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., liver blood tests, blood PSA test) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is within 4 hours of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.