Flutamide

Flutamide comes as a capsule to take by mouth. It is usually taken with or without food every 8 hours (three times a day.) Take flutamide at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take flutamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Continue to take flutamide along with the LHRH agonist treatment even if you feel well. Do not stop taking either medication without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Flutamide may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• diarrhea
• nausea
• vomiting
• loss of appetite
• hot flashes
• decrease in sexual ability or desire
• breast enlargement in men
• drowsiness
• confusion
• depression
• anxiety
• swelling of the hands, feet, ankles, or lower legs
• blue-green or orange-colored urine

Some side effects can be serious. If you experience any of the symptoms listed in the IMPORTANT WARNING section, call your doctor immediately.

Although it is rare, some men taking flutamide have developed breast cancer. Talk to your doctor about the risks of taking this medication.

Flutamide may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Pregnancy Category: D

Lactation: Excretion in milk unknown; not recommended

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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.

Serious side effects have been reported with flutamide. 

Some men taking flutamide had liver injury and needed to be hospitalized. In rare cases, men died because of liver failure while they were taking flutamide. In about half of these cases, the liver failure occurred in the first 3 months that they were taking flutamide. Because the flutamide product may cause liver failure, it is very important that you have all blood tests recommended by your doctor. These tests help identify whether you are having liver problems. A recommended schedule for these blood tests is:

• before starting flutamide treatment
• every month for the first 4 months of therapy
• periodically after the first 4 months

In addition, you should call your doctor right away if you have any of the following signs or symptoms: (These may be signs of liver failure.)

• loss of appetite
• nausea and vomiting
• stomach or abdominal pain
• fatigue (feeling extremely tired)
• flu-like symptoms (muscle aches, soreness)
• brown urine
• jaundice (yellowing of the skin or whites of the eyes)

If you experience moderate diarrhea due to flutamide capsules, the following advice may help:

• drink plenty of fluids
• reduce your intake of dairy products (for example, milk, cheese, yogurt)
• increase your intake of whole grains, fruits, and vegetables
• stop laxative use
• take non-prescription anti-diarrheal medicines

If your diarrhea continues or it becomes severe, contact your doctor right away.

Periodic liver function tests and sperm count determinations must be performed in patients on long-term treatment with flutamide.

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.

Flutamide is not to be used by women. It is only indicated for men. 

Flutamide can cause harm to your unborn baby if given to a pregnant woman. 

Flutamide has a metabolite that can cause methemoglobinemia, hemolytic anemia and cholestatic jaundice. If you have glucose-6-phosphate dehydrogenase deficiency, have hemoglobin M disease and/or smoke, you are at increased risk for toxicity from the metabolite. In these cases, your doctor may monitoring methemoglobin levels. 

Do not take flutamide if you:

• are allergic to flutamide or any of its ingredients
• have severe liver impairment (patients whose liver does not really work)
• are a woman

You should not use this medicine if you are allergic to flutamide.

Flutamide should never be taken by a woman or a child.

Although flutamide is not for use by women, this medicine can cause birth defects if a woman is exposed to it during pregnancy.

To make sure flutamide is safe for you, tell your doctor if you have:

• liver disease;

• a genetic enzyme deficiency called glucose-6-phosphate dehydrogenase (G6PD) deficiency

• hemoglobin M disease;

• if you smoke; or

• if you also take a blood thinner (warfarin, Coumadin, Jantoven).

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Other drugs may interact with flutamide, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration, with peak plasma concentrations of active metabolite (2-hydroxyflutamide) attained within about 2 hours.1 27

Food

Food does not affect bioavailability.1

Special Populations

In patients with chronic renal impairment, there appears to be no correlation between creatinine clearance and maximum plasma concentrations or AUC of flutamide; renal impairment did not affect maximum plasma concentrations or AUC of active metabolite.1

Distribution

Plasma Protein Binding

Flutamide: 94–96%; 2-hydroxyflutamide: 92–94%.1 27

Elimination

Metabolism

Rapidly and extensively metabolized to ≥6 metabolites, including an active α-hydroxylated derivative, 2-hydroxyflutamide.1 27

Elimination Route

Excreted principally in urine and to lesser extent in feces (4.2%) as unchanged drug and metabolites.1

Half-life

2-Hydroxyflutamide: about 6 hours after a single 250-mg dose.1

Special Populations

In patients with renal impairment (Clcr <29 mL/minute), half-life of active metabolite was slightly prolonged; no dosage adjustment necessary in chronic renal impairment.1

In geriatric patients, half-life of active metabolite is about 8 hours after a single 250-mg dose.1

Pharmacokinetics not studied in patients with hepatic impairment, women, or pediatric patients.1

It is very important that your doctor check your progress at regular visits to make sure that flutamide is working properly. Blood tests may be needed to check for unwanted effects.

Liver problems may occur while you are using flutamide. Stop using flutamide and check with your doctor right away if you are having more than one of these symptoms: clay-colored stools; dark urine; fever; headache; loss of appetite; nausea and vomiting; pain or tenderness in the upper right side of the stomach; unusual tiredness or weakness; or yellow eyes or skin.

flutamide may cause gynecomastia (swelling of the breasts and breast soreness) in some patients. If you have questions on this, ask your doctor.

Do not take other medicines unless they have been discussed with your doctor. Your doctor may adjust the doses of your medications or monitor you carefully for side effects.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• If you have loose stools (diarrhea) with flutamide, drink lots of noncaffeine liquids unless your doctor told you not to. Lower how much dairy you eat. Eat more fruit, grains, and veggies, and stop taking any laxatives. There may be other ways for you to treat loose stools (diarrhea). Talk with your doctor.
• If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Blood in the urine.
• Bleeding from rectum or rectal pain.
• Feeling very tired or weak.
• Shortness of breath.
• Blue or gray skin color.
• Very loose stools (diarrhea).

Flutamide Capsules USP contain Flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, α,α,α-Trifluoro-2-methyl-4’-nitro-m-propionotoluidide and has the following structural formula:

C11H11F3N2O3 M.W. 276.21

Flutamide is a buff to yellow powder. Each capsule, for oral administration, contains 125 mg Flutamide and has the following inactive ingredients: black iron oxide, corn starch, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.

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.

Pharmacokinetics

Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled 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 alpha-hydroxylated 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.

In male rats neither Flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-Flutamide. 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 levels of Flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of Flutamide is about 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.

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.

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

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.

There are no known alterations in Flutamide absorption, distribution, metabolism, or excretion due to race.

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 Cmax or AUC of Flutamide. Renal impairment did not have an effect on the Cmax 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.

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

Flutamide has not been studied in women or pediatric patients.

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

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.

The effects of hormonal treatment combined with radiation were studied in 466 patients (231 Flutamide capsules + goserelin acetate implant + 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 Flutamide 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).

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.

Hepatic Injury

See BOXED WARNINGS.

Use in Women

Flutamide 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 non-life threatening conditions.

Fetal Toxicity

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

Aniline Toxicity

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 (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered.

Nonsteroidal antiandrogen that inhibits androgen uptake and/or inhibits binding of androgen in target tissues.

Absorption

Oral: Rapid and complete

Metabolism

Extensively hepatic to ≥6 metabolites, primarily 2-hydroxyflutamide (active)

Excretion

Primarily urine (as metabolites); feces (~4%)

Time to Peak

~2 hours (2-hydroxyflutamide)

Half-Life Elimination

~6 hours (2-hydroxyflutamide)

Protein Binding

Parent drug: 94% to 96%; 2-hydroxyflutamide: 92% to 94%

May be administered with or without food. Administer orally in 3 divided doses (every 8 hours).

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense with a child-resistant closure in a tight, light-resistant container.

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, 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.

Applies to flutamide: oral capsule

General

In general, flutamide has been used concomitantly with LHRH agonists or after bilateral orchiectomy. Therefore, little data are available on the side effects of flutamide alone.[Ref]

Hepatic

Nineteen cases of severe flutamide related hepatotoxicity were reported by the FDA in 1993. The flutamide related hepatitis developed 56 to 80 days after the beginning of therapy and was mainly cytolytic. Four of the cases involved massive hepatic necrosis with fatal outcomes. The mechanism of action was believed to be direct hepatotoxicity.

In a study of 1,091 patients with prostate cancer treated with flutamide and an LHRH agonist, four patients (0.36%) developed severe hepatotoxicity in the first four weeks of therapy. Serum aminotransferases increased more than four times normal values. Alkaline phosphatase increased more than six times normal values in one patient. Total bilirubin was elevated in two patients. Only two patients developed clinical manifestations, including fatigue, anorexia, weight loss, nausea, and vomiting. None of the remaining 1,089 patients had significant elevations in liver function tests although transient, mild elevations in AST and ALT occasionally occurred.

In most cases, discontinuation of flutamide results in resolution of symptoms.

A case of fatal liver complications has been reported where the drug was prescribed for an 18 year old woman for the treatment of minor acne and hirsutism. The risk of lethal hepatic complications makes the risk-benefit ratio unacceptable when flutamide is being considered to treat disorders such as polycystic ovaries, and especially for benign complaints such as alopecia, hirsutism, and acne.[Ref]

Hepatic side effects have included elevations in serum transaminases as well as cases of cholestatic jaundice, hepatic necrosis, hepatic encephalopathy, and fatal hepatotoxicity.[Ref]

Hematologic

Hematologic side effects have included anemia (6%), leukopenia (3%), and thrombocytopenia (1%). Flutamide has also been implicated in cases of methemoglobinemia, sulphemoglobinemia and neutropenia. In addition, eosinophilia has been reported in association with some cases of hepatotoxicity.[Ref]

Nervous system

Nervous system side effects have been reported in less than 1% of patients and include drowsiness, dizziness, sedation, and confusion.[Ref]

Renal

Renal side effects including renal failure (in association with severe hepatotoxicity) have been reported.[Ref]

Cardiovascular

Cardiovascular side effects reported include hypertension (1%), thromboembolism, and edema.[Ref]

Dermatologic

Pseudoporphyria (blisters, increased skin fragility, and erosions in sun-exposed areas) was reported in a 68-year-old man being treated for prostate cancer with appropriate doses of flutamide and goserelin. The patient presented with skin fragility and blisters on the back of the hands. After replacing the flutamide with bicalutamide, the lesions healed.[Ref]

Dermatologic side effects including rash (3%), alopecia, sweating, and cases of photosensitivity/photoallergy have been reported. One case of flutamide-induced pseudoporphyria has also been reported.[Ref]

Endocrine

Endocrine side effects including hot flashes (29% to 63%), gynecomastia (up to 19%), fever, and breast tenderness (7%) have been reported.[Ref]

Gastrointestinal

Two female patients receiving flutamide for the treatment of bulimia nervosa noted decreased symptoms within a week after initiation of therapy. Both patients relapsed after the drug was later withdrawn.[Ref]

Gastrointestinal side effects including mucositis, diarrhea, nausea, vomiting, abdominal pain, anorexia, and either weight loss or gain have been reported.[Ref]

Musculoskeletal

Musculoskeletal side effects including muscle cramps in up to 15% of patients have been reported.[Ref]

Psychiatric

Psychiatric side effects including depression, anxiety, and nervousness have been reported. One case report of mania has also been reported.[Ref]

Genitourinary

Genitourinary side effects including impotence and loss of libido have been reported.[Ref]

Other

Several studies have described a flutamide withdrawal syndrome in which significant reductions in prostate-specific antigen (PSA) levels are noted following the discontinuation of flutamide therapy in patients with hormone-refractory prostate cancer.

Several studies have evaluated the effect of concurrent discontinuation of flutamide and initiation of aminoglutethimide therapy in patients with hormone-refractory prostate cancer. In one study, serum PSA levels declined by more than 80% for more than four weeks in 14 out of 29 (48%) patients. Clinical improvement was also noted. Some authors propose prolonged flutamide therapy may result in the selective proliferation of cancer cell lines with androgen receptors which recognize hydroxyflutamide as an androgenic agonist. Additional research is needed to fully evaluate this phenomenon.[Ref]

Other side effects have included flutamide withdrawal syndrome.[Ref]

Respiratory

Respiratory side effects including one case of pneumonitis have been reported.[Ref]

Some side effects of flutamide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.