FLUTAMIDE capsule
For Healthcare Providers >

1. Patient Information
2. What Is Flutamide Therapy?
3. Who Should Not Take The Flutamide Product?
4. Are There Important Risks I Should Know About Flutamide Therapy?
5. How Should I Take Flutamide Capsules?
6. Can I Take Other Medicines?
7. What Are The Other Possible Side Effects Of Taking Flutamide Capsules?
8. Are There Any Other Lab Tests My Doctor Will Be Performing?
9. Manufactured By:
10. Important Information For Patients Taking Flutamide Capsules:
11. What Is Flutamide Therapy?
12. Who Should Not Take The Flutamide Product?
13. Are There Important Risks I Should Know About Flutamide Therapy?
14. A Recommended Schedule For These Blood Tests Is:
15. In Addition, You Shouldcall Your Doctor Right Away If You Have Any Of The Following Signs Or Symptoms:
16. How Should I Take Flutamide Capsules?
17. If You Experience Moderate Diarrhea Due To Flutamide Capsules, The Following Advice May Help:
18. Manufactured By:
19. Distributed By:

Patient Information ⮝

Important information for patients taking flutamide capsules.

Read this information carefully each time your prescription is refilled because there may be new information available. This summary does not tell you everything you need to know about flutamide therapy. Your doctor is the best source of information about your treatment. Ask your doctor about questions you have.

What Is Flutamide Therapy? ⮝

Flutamide capsules, in combination with other therapies, is a treatment option for men with some types of prostate cancer.

Prostate cancer results from the abnormal growth of prostate cells. Medical scientists do not know exactly what causes the abnormal cells, but age, environment, and genetics are important factors. Male hormones ( androgens ) cause the cancer to grow. The cancer growth can be slowed down by blocking the effect of androgens.

The flutamide product is used together with an injection called LHRH agonist, as a combined treatment called total androgen blockade. The goal of this treatment is to reduce androgen levels and to block the effect of androgen on the tumor. The LHRH agonist reduces androgen levels. Flutamide therapy blocks the effect of androgen on the tumor.

Who Should Not Take The Flutamide Product? ⮝

You should not take flutamide capsules if you have liver problems or if you are allergic to it. Flutamide capsules are for useonlyin men, therefore women should not take flutamide capsules.

Are There Important Risks I Should Know About Flutamide Therapy? ⮝

Some men taking the flutamide product had liver injury and needed to be hospitalized. In rare cases, men died because of liver failure while they were taking flutamide capsules. In about half of these cases, the liver failure occurred in the first 3 months that they were taking flutamide capsules.

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.

How Should I Take Flutamide Capsules? ⮝

Take your flutamide capsules as your doctor has prescribed. The usual dosing is 2 capsules every 8 hours.

Your doctor will determine whether flutamide therapy is right for you based on many different factors. These include how large your tumor is, how far it has spread and your physical condition. In addition to flutamide capsules, you may be getting other treatments, including regular injections of LHRH agonist or radiation therapy. Do not stop or interrupt any treatment without consulting your healthcare professional.

If you miss a dose of flutamide capsules, simply continue therapy with your next scheduled dose. Do not try to make up for it by taking extra capsules.

Can I Take Other Medicines? ⮝

If you are taking any other medicines, especially warfarin (a blood-thinning drug), tell your doctor before beginning flutamide therapy.

What Are The Other Possible Side Effects Of Taking Flutamide Capsules? ⮝

In a medical study, when flutamide capsules were taken together with an LHRH agonist, the most common side effects were hot flashes, loss of sex drive (libido) and impotence. In addition, some men had diarrhea, nausea or vomiting, and breast enlargement.

In another medical study, when the flutamide product was taken together with goserelin acetate (an LHRH agonist) and radiation therapy, the side effects of flutamide therapy were about the same as when radiation therapy was given alone. These included hot flashes, diarrhea, nausea and skin rash.

Are There Any Other Lab Tests My Doctor Will Be Performing? ⮝

Your doctor may perform other regular tests (such as the PSA blood test) to ensure that your body is responding to treatment. Ask your doctor if you have any questions about how your flutamide therapy is being monitored.

Please ask your doctor about any questions concerning prostate cancer or flutamide therapy, or you can also ask for a more detailed leaflet that is written for healthcare professionals.

Manufactured By: ⮝

PAR PHARMACEUTICAL

Chestnut Ridge, NY 10977

Marketed/Packaged by:
GSMS, Inc.

Camarillo, CA USA 93012

Important Information For Patients Taking Flutamide Capsules: ⮝

Read this information carefully each time your prescription is refilled because there may be new information available. This summary does not tell you everything you need to know about flutamide therapy. Your doctor is the best source of information about your treatment. Ask your doctor about questions you have.

What Is Flutamide Therapy? ⮝

Flutamide, in combination with other therapies, is a treatment option for men with some types of prostate cancer.

Prostate cancer results from the abnormal growth of prostate cells. Medical scientists do not know exactly what causes the abnormal cells, but age, environment, and genetics are important factors. Male hormones ( androgens ) cause the cancer to grow. The cancer growth can be slowed down by blocking the effect of androgens.

The flutamide product is used together with an injection called LHRH agonist , as a combined treatment called total androgen blockade . The goal of this treatment is to reduce androgen levels and to block the effect of androgen on the tumor. The LHRH agonist reduces androgen levels. Flutamide therapy blocks the effect of androgen on the tumor.

Who Should Not Take The Flutamide Product? ⮝

You should not take flutamide if you have liver problems or if you are allergic to it. Flutamide capsules are for useonlyin men, therefore women should not take flutamide capsules.

Are There Important Risks I Should Know About Flutamide Therapy? ⮝

Some men taking the flutamide product 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 Shouldcall Your Doctor Right Away If You Have Any Of The Following Signs Or Symptoms: ⮝

• 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).

These may be signs of liver failure.

How Should I Take Flutamide Capsules? ⮝

Take your flutamide capsules as your doctor has prescribed. The usual dosing is 2 capsules every 8 hours.

Your doctor will determine whether flutamide therapy is right for you based on many different factors. These include how large your tumor is, how far it has spread, and your physical condition. In addition to flutamide, you may be getting other treatments, including regular injections of LHRH agonist or radiation therapy.

Do not stop or interrupt any treatment without consulting your healthcare professional.

If you miss a dose of flutamide capsules, simply continue therapy with your next scheduled dose. Do not try to make up for it by taking extra capsules.

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 nonprescription antidiarrheal medicines.

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

Manufactured By: ⮝

Actavis Laboratories FL, Inc.
Fort Lauderdale, FL 33314 USA

Distributed By: ⮝

Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Revised: July 2014 195814-2

1. No Title 1572551214
2. No Title 1572552914
3. No Title 1572452886
4. Clinical Studies
5. Principal Display Panel- 125 Mg/ 180 Capsule Container Label
6. Boxed Warning
7. Description
8. Clinical Pharmacology
9. Indications And Usage
10. Contraindications
11. Warnings
12. Precautions
13. Adverse Reactions
14. Overdosage
15. Dosage And Administration
16. How Supplied
17. Patient Medication Information Section
18. Package Label.principal Display Panel
19. No Title 1572455901
20. Rx Only
21. Description:
22. Clinical Pharmacology:
23. Indications And Usage:
24. Contraindications:
25. Warnings:
26. Precautions:
27. Adverse Reactions:
28. Overdosage:
29. Dosage And Administration:
30. How Supplied:
31. Principal Display Panel

No Title 1572551214 ⮝

WARNINGS

Hepatic Injury

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, e.g., 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.

No Title 1572552914 ⮝

Flutamide Capsules, USP

Rx only

Revised: July 2014

195814-2

No Title 1572452886 ⮝

WARNINGS

Hepatic Injury

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, e.g., 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.

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 D2prostatic carcinoma.

Stage B2-C Prostatic Carcinoma

The effects of hormonal treatment combined with radiation was 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).

Stage D2Prostatic 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.

Principal Display Panel- 125 Mg/ 180 Capsule Container Label ⮝

Flutamide 125mg Capsules 180

NDC 60429-272-18

GSMS, Inc.

FLUTAMIDE flutamide capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60429-272(NDC:49884-753) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FLUTAMIDE (UNII: 76W6J0943E) (FLUTAMIDE - UNII:76W6J0943E) FLUTAMIDE 125 mg

Product Characteristics Color brown (Beige) Score no score Shape CAPSULE Size 22mm Flavor Imprint Code 93;7120 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60429-272-18 180 in 1 BOTTLE; Type 0: Not a Combination Product 09/18/2001

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075298 09/18/2001

Labeler - Golden State Medical Supply, Inc. (603184490)

Establishment
Name	Address	ID/FEI	Business Operations
Golden State Medical Supply, Inc.		603184490	relabel(60429-272) , repack(60429-272)

Revised: 10/2019 Document Id: 92d7d335-977d-d55e-e053-2995a90a82b9 34391-3 Set id: 82bb75cc-0d36-44ab-9ea6-2bd26998ce0f Version: 4 Effective Time: 20191024 Golden State Medical Supply, Inc.

Boxed Warning ⮝

WARNINGS

Hepatic Injury

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, e.g., 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.

Description ⮝

Flutamide capsules contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, , , -trifluoro-2-methyl-4'-nitrom-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 11H 11F 3N 2O 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.

Clinical Pharmacology ⮝

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

Absorption

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.

Distribution

In male rats administered an oral 5 mg/kg dose of 14C-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 six 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-5nitro-4-(trifluoromethyl)phenol.

Excretion

Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours.

Plasma Pharmacokinetics of Flutamide and Hydroxyflutamide in Geriatric Volunteers (mean SD)

	Single Dose Flutamide	Hydroxyflutamide	Steady-State Flutamide	Hydroxyflutamide
C max (ng/mL)	25.2 34.2	894 406	113 213	1629 586
Elimination half-life (hr)	---	8.1 1.3	7.8	9.6 2.5
T max (hr)	1.9 0.7	2.7 1.0	1.3 0.7	1.9 0.6
C min (ng/mL)	---	---	---	673 316

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 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 maxor AUC of flutamide. Renal impairment did not have an effect on the C maxor 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 WARNING, Hepatic Injury).

Women, Pediatrics Flutamide has not been studied in women or pediatric subjects.

Drug-Drug Interactions

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

Indications And Usage ⮝

Flutamide capsules are indicated for use in combination with LHRH-agonists for the management of locally confined Stage B 2-C and Stage D 2metastatic carcinoma of the prostate.

Stage B 2-C Prostatic Carcinoma

Treatment with flutamide capsules and the goserelin acetate implant should start eight weeks prior to initiating radiation therapy and continue during radiation therapy.

Stage D 2Metastatic Carcinoma

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

Contraindications ⮝

Flutamide capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation.

Flutamide capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).

Warnings ⮝

Hepatic Injury

SEE BOXED WARNING

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 nonlife-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.

Precautions ⮝

General

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

Information for Patients

Patients should be informed that flutamide 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.

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 flutamide therapy the patient 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.

Drug Interactions

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 flutamide capsules are administered concomitantly with warfarin.

Carcinogenesis and Mutagenesis and 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 doses of 10, 30, and 50 mg/kg/day were administered). These produced plasma C maxvalues 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 flutamide capsules (see ADVERSE REACTIONSsection).

Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/microsome -- 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 to 4 years. These 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.

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).

Adverse Reactions ⮝

Stage B 2-C Prostatic Carcinoma

Treatment with flutamide 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 listed below:

Adverse Events During Acute Radiation Therapy

(within first 90 days of radiation therapy)

	(n=231) Goserelin Acetate Implant + Flutamide + 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 + Flutamide + Radiation	(n=235) Radiation Only
	% All	% All
Diarrhea	36	40
Cystitis	16	16
Rectal Bleeding	14	20
Proclitis	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 2Metastatic Carcinoma

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 flutamide 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) Flutamide + 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 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 flutamide capsules.

Abnormal Laboratory Test Values: Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.

Overdosage ⮝

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.

Dosage And Administration ⮝

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

How Supplied ⮝

Flutamide capsules USP, 125 mg, are available as opaque, beige/beige capsules, imprinted par/753 on the cap and body. They are available in bottle of 180 (NDC 60429-272-18).

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).

Patient Medication Information Section ⮝

Rx only

Important information for patients taking flutamide capsules

Read this information carefully each time your prescription is refilled because there may be new information available. This summary does not tell you everything you need to know about flutamide therapy. Your doctor is the best source of information about your treatment. Ask your doctor about questions you have.

What is flutamide therapy?

Flutamide, in combination with other therapies, is a treatment option for men with some types of prostate cancer.

Prostate cancer results from the abnormal growth of prostate cells. Medical scientists do not know exactly what causes the abnormal cells, but age, environment and genetics are important factors. Male hormones ("androgens") cause the cancer to grow. The cancer growth can be slowed down by blocking the effect of androgens.

The flutamide product is used together with an injection called "LHRH agonist," as a combined treatment called "total androgen blockade." The goal of this treatment is to reduce androgen levels and to block the effect of androgen on the tumor. The LHRH agonist reduces androgen levels. Flutamide therapy blocks the effect of androgen on the tumor.

Who should not take the flutamide product?

You should not take flutamide if you have liver problems or if you are allergic to it. Flutamide is for use only in men; therefore women should not take flutamide.

Are there important risks I should know about flutamide therapy?

Some men taking the flutamide product 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:

• 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)

• 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.

Are there any other lab tests my doctor will be performing?

Your doctor may perform other regular tests (such as the PSA blood test) to ensure that your body is responding to treatment. Ask your doctor if you have any questions about how your flutamide therapy is being monitored.

Where can I get further support?

Please ask your doctor about any questions concerning prostate cancer or flutamide therapy, or you can also ask for a more detailed leaflet that is written for healthcare professionals.

Manufactured by:

CIPLA Verna.

Goa, India

Manufactured for:

Cipla USA, Inc.

1560 Sawgrass Corporate Parkway.

Suite 130 Miami, FL 33323

Issued: 05/2017

Package Label.principal Display Panel ⮝

RX only

NDC 69097-915-91

Flutamide

Capsules, USP

125mg

Each capsule contains 125 mg flutamide, USP.

180 tablets

Cipla

RX only

NDC 69097-915-12

Flutamide

Capsules, USP

125mg

Each capsule contains 125 mg flutamide, USP.

500 tablets

Cipla

FLUTAMIDE flutamide capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:69097-915 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FLUTAMIDE (UNII: 76W6J0943E) (FLUTAMIDE - UNII:76W6J0943E) FLUTAMIDE 125 mg

Inactive Ingredients Ingredient Name Strength FERROSOFERRIC OXIDE (UNII: XM0M87F357) STARCH, CORN (UNII: O8232NY3SJ) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) ALUMINUM OXIDE (UNII: LMI26O6933) GELATIN (UNII: 2G86QN327L) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color BROWN (LIGHT) Score no score Shape CAPSULE Size 22mm Flavor Imprint Code CIPLA;915;125 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:69097-915-91 180 in 1 BOTTLE; Type 0: Not a Combination Product 09/21/2016 2 NDC:69097-915-12 500 in 1 BOTTLE; Type 0: Not a Combination Product 09/21/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075780 09/21/2016

Labeler - Cipla USA Inc. (078719707)

Registrant - Cipla USA Inc. (078719707)

Establishment
Name	Address	ID/FEI	Business Operations
Cipla Ltd.- Goa		650072015	MANUFACTURE(69097-915)

Establishment
Name	Address	ID/FEI	Business Operations
Cipla Limited, Bangalore		915154892	ANALYSIS(69097-915) , API MANUFACTURE(69097-915)

Revised: 11/2018 Document Id: b002fcb1-d247-4333-b38a-6b1de5a05a2c 34391-3 Set id: 328910be-4d0e-4d7b-a062-e3ce0cf793b9 Version: 2 Effective Time: 20181129 Cipla USA Inc.

No Title 1572455901 ⮝

Flutamide Capsules, USP

Rx only

Revised: July 2014

195814-2

Rx Only ⮝

WARNINGS:
Hepatic Injury:
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, e.g., 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.

Description: ⮝

Flutamide Capsules contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, 2-methyl-N-[4-nitro-3-(tri fluoro methyl)phenyl] propanamide. The compound is a buff to Yellow powder and has the following structural formula:

Each capsule, for oral administration, contains 125 mg flutamide and has the following inactive ingredients: lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, and sodium lauryl sulfate.

The ingredients in the capsule shell are black iron oxide, gelatin, red iron oxide, yellow iron oxide, and titanium dioxide.

The ingredients in the imprinting ink are D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Red No. 40, n-butyl alcohol, pharmaceutical glaze, propylene glycol, SDA-3A alcohol, and synthetic black iron oxide.

Clinical Pharmacology: ⮝

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:

Absorption: 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.

Distribution: In male rats administered an oral 5 mg/kg dose of 14C-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 six 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 a single dose excreted in the feces over 72 hours.

Plasma Pharmacokinetics of Flutamide and Hydroxyflutamide in Geriatric Volunteers (mean SD)

	Single Dose		Steady State
	Flutamide	Hydroxyflutamide	Flutamide	Hydroxyflutamide
Cmax (ng/mL)	25.2 34.2	894 406	113 213	1629 586
Elimination half-life (hr)		8.1 1.3	7.8	9.6 2.5
Tmax (hr)	1.9 0.7	2.7 1.0	1.3 0.7	1.9 0.6
Cmin (ng/mL)				679 316

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 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 Cmaxor 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.

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

Women, Pediatrics: Flutamide has not been studied in women or pediatric subjects.

Drug-Drug Interactions: Interactions between flutamide capsules and LHRH-agonists have not occurred. Increases in prothrombin time 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 carcin o ma and the other study evaluated flutamide and an LHRH-agonist as the sole therapy in stage D2 prostatic carcinoma.

Stage B2-C Prostatic Carcinoma: The effects of hormonal treatment combined with radiation was 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).

Stage D2 Prostatic 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.

Indications And Usage: ⮝

Flutamide 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 flutamide capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.

Stage D2 Metastatic Carcinoma:

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

Contraindications: ⮝

Flutamide capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation.

Flutamide capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).

Warnings: ⮝

Hepatic Injury: See BOXED WARNING.

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 non-serious 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-fluoromethylaniline. 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.

Precautions: ⮝

General:

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

Information for Patients:

Patients should be informed that flutamide 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.

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 flutamide therapy the patient 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.

Drug Interactions:

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 flutamide capsules are administered concomitantly with warfarin.

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 doses of 10, 30, and 50 mg/kg/day were administered). These produced plasma Cmax 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, 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 flutamide 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, intra-atrial fibrosis, myocardial acid ophilic 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 1.4 times the human dose).

Adverse Reactions: ⮝

Stage B2-C Prostatic Carcinoma:

Treatment with flutamide 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 listed 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%).

	Adverse Events During Acute Radiation Therapy (within first 90 days of radiation therapy)
	(n = 231)	(n = 235)
	Goserelin Acetate Implant + Flutamide + Radiation % All	Radiation Only % 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)	(n = 235)
	Goserelin Acetate Implant + Flutamide + Radiation % All	Radiation Only % All
Diarrhea	36	40
Cystitis	16	16
Rectal Bleeding	14	20
Proctitis	8	8
Hematuria	7	12

Stage D2 Metastatic Carcinoma:

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 flutamide 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) Flutamide + LHRH agonist % All	(n=285) Placebo + LHRH agonist % 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 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 enceph alopathy, 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 flutamide.

Abnormal Laboratory Test Values: Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.

Overdosage: ⮝

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.

Dosage And Administration: ⮝

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

How Supplied: ⮝

Flutamide Capsules, USP are available as:

125 mg: Brown opaque cap and white opaque body filled with yellow powder.
Imprinted in black ink with WPI 2227 .

Available in bottles of:

180 NDC-0591-2466-18

Dispense with a child-resistant closure in a tight, light-resistant container as defined in the USP/NF.

Store at 25 C (77 F); excursions permitted to 15 -30 C (59 -86 F).

Manufactured by:
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL 33314 USA

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Revised: July 2014

195814-2

Principal Display Panel ⮝

NDC 0591-2466-18

Flutamide
Capsules, USP
125 mg

Actavis 180 Capsules Rx only

Each Capsule Contains:
125 mg flutamide.

Dispense with a child-resistant closure in
a tight, light-resistant container as defined
in the USP/NF.

Usual dose: Two 125 mg capsules (250 mg)
3 times a day, at 8-hour intervals.
See package brochure.

Store at 25 C (77 F); excursions
permitted to 15 to 30 C (59 - 86 F).

Manufactured by:
Actavis Laboratories, FL, Inc.
Fort Lauderdale, FL 33314 USA
Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Rev. 07/14
195813-2

FLUTAMIDE flutamide capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0591-2466 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FLUTAMIDE (UNII: 76W6J0943E) (FLUTAMIDE - UNII:76W6J0943E) FLUTAMIDE 125 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) FERROSOFERRIC OXIDE (UNII: XM0M87F357) GELATIN (UNII: 2G86QN327L) FERRIC OXIDE RED (UNII: 1K09F3G675) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3)

Product Characteristics Color BROWN (Brown Opaque Cap) , WHITE (White Opaque Body) Score no score Shape CAPSULE Size 22mm Flavor Imprint Code WPI;2227 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0591-2466-18 180 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 07/28/2011 02/29/2020

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075820 07/28/2011 02/29/2020

Labeler - Actavis Pharma, Inc. (119723554)

Revised: 7/2014 Document Id: d9eff529-e9e5-4dae-9be4-e3e63a4c00ae 34391-3 Set id: d037fb0c-881f-43d2-8693-aa1342d0130a Version: 9 Effective Time: 20140720 Actavis Pharma, Inc.