BICALUTAMIDE tablet, film coated
For Healthcare Providers >

1. What Are Bicalutamide Tablets, Usp?
2. Do Not Take Bicalutamide Tablets, Usp If:
3. Before You Take Bicalutamide Tablets, Usp, Tell Your Healthcare Provider About All Your Medical Conditions Including If You:
4. What Should I Avoid While Taking Bicalutamide Tablets, Usp?
5. What Are The Possible Side Effects Of Bicalutamide Tablets, Usp?
6. Get Medical Help Right Away, If You Have:
7. The Most Common Side Effects Of Bicalutamide Tablets, Usp Include:
8. How Should I Store Bicalutamide Tablets, Usp?
9. What Are The Ingredients In Bicalutamide Tablets, Usp?
10. What Are Bicalutamide Tablets?
11. Do Not Take Bicalutamide Tablets If You Are:
12. Bicalutamide Tablets May Cause Serious Side Effects, Including:
13. Bicalutamide Tablets Include:
14. Bicalutamide Tablets?
15. Dose And Schedule:
16. Hepatitis:
17. Hemorrhage With Concomitant Use Of Coumarin Anticoagulant:
18. Glucose Tolerance:
19. Somnolence:
20. Photosensitivity:
21. Contraception And Fertility:
22. Manufactured In Israel By:
23. Manufactured For:
24. Patient Information

What Are Bicalutamide Tablets, Usp? ⮝

Bicalutamide Tablets, USP are a prescription medicine called an androgen receptor inhibitor, used in combination with lutenizing hormone-releasing hormone (LHRH) medicines to treat stage D2 metatastic prostate cancer. It is not known if Bicalutamide Tablets, USP are safe and effective in children.

Do Not Take Bicalutamide Tablets, Usp If: ⮝

• you are a woman.
• you are allergic to any of the ingredients in Bicalutamide Tablets, USP.

Before You Take Bicalutamide Tablets, Usp, Tell Your Healthcare Provider About All Your Medical Conditions Including If You: ⮝

• are a woman (
  • Take Bicalutamide Tablets, USP exactly as prescribed.
  • Take Bicalutamide Tablets, USP at the same time everyday.
  • Your treatment with Bicalutamide Tablets, USP should start at the same time as your treatment with the LHRH medicine
  • If you miss a dose do not take an extra dose, take the next dose at your regular time. Do not take 2 doses at the same time.
  • Bicalutamide Tablets, USP can be taken with or without food.
  • If you take too much Bicalutamide Tablets, USP, call your healthcare provider or Poison Control Center or go to the nearest hospital emergency room right away.
  • Do not stop taking Bicalutamide Tablets, USP unless your healthcare provider tells you.
  • Your healthcare provider may do blood tests while you take Bicalutamide Tablets, USP
  • Your prostate cancer may get worse while taking Bicalutamide Tablets, USP in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.

What Should I Avoid While Taking Bicalutamide Tablets, Usp? ⮝

Driving and operating machinery. Do not drive, operate machinery, or do other dangerous activities until you know how Bicalutamide Tablets, USP affects you.

What Are The Possible Side Effects Of Bicalutamide Tablets, Usp? ⮝

Bicalutamide Tablets, USP can cause serious side effects.

Get Medical Help Right Away, If You Have: ⮝

• trouble breathing with or without a cough or fever. Some people who take Bicalutamide Tablets, USP get an inflammation in the lungs called interstitial lung disease.
• An allergic reaction.Symptoms of an allergic reaction include:itching of the skin, hives (raised bumps), swelling of the face, lips, tongue, throat, or trouble swallowing.
• Yellowing of the skin and eyes (jaundice), dark urine, right upper stomach pain, nausea, vomiting, tiredness, loss of appetite, chills, fever, whole body pain. These may be symptoms of liver damage.
• Poor blood sugar control can happen in people who take Bicalutamide Tablets, USP in combination with LHRH medicines.
• enlargement of breast (gynecomastia) and breast pain

The Most Common Side Effects Of Bicalutamide Tablets, Usp Include: ⮝

• hot flashes, or short periods of feeling warm and sweating
• whole body pain in your back, pelvis, stomach
• feeling weak
• constipation
• infection
• nausea
• swelling in your ankles, legs or feet
• diarrhea
• blood in your urine
• waking from sleep to urinate at night
• a decrease in red blood cells (anemia)
• feeling dizzy

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Bicalutamide Tablets, USP. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at

1-800-FDA-1088.

How Should I Store Bicalutamide Tablets, Usp? ⮝

Store Bicalutamide Tablets, USP between 20 C to 25 C (68 F to 77 F).

Keep Bicalutamide Tablets, USP and all medicines out of the reach of children.

General information about the safe and effective use of Bicalutamide Tablets, USP.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Bicalutamide Tablets, USP for a condition for which it was not prescribed. Do not give Bicalutamide Tablets, USP to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about Bicalutamide Tablets, USP. If you would like more information about Bicalutamide Tablets, USP talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Bicalutamide Tablets, USP that is written for health professionals. For more information call 1-866-947-3282.

What Are The Ingredients In Bicalutamide Tablets, Usp? ⮝

Active ingredients include: bicalutamide

Inactive ingredients include: lactose monohydrate, magnesium stearate, povidone, crospovidone, sodium lauryl sulfate, polyethylene glycol, hypromellose, titanium dioxide.

Manufactured for:
DAVA Pharmaceuticals, Inc.
Fort Lee, NJ 07024, USA

Manufactured by:
Synthon Hispania S.L.
Barcelona, Spain
Made in Spain

Revised: 06/2009

PPI-5003-1

What Are Bicalutamide Tablets? ⮝

Bicalutamide tablets are a prescription medicine called an androgen receptor inhibitor, used in combination with luteinizing hormone-releasing hormone (LHRH) medicines to treat Stage D2metastatic prostate cancer

Bicalutamide 150 mg daily is not approved for use alone or with other treatments.

It is not known if bicalutamide is safe and effective in children.

Do Not Take Bicalutamide Tablets If You Are: ⮝

• allergic to bicalutamide or any of the ingredients in bicalutamide tablets.
  • Take bicalutamide tablets exactly as your healthcare provider tells you to take it.
  • Do not stop taking bicalutamide tablets unless your healthcare provider tells you to.
  • Bicalutamide tablets can be taken either in the morning or in the evening, but you should take it at the same time every day.
  • Your treatment with bicalutamide tablets should start at the same time as your treatment with the LHRH medicine.
  • If you miss a bicalutamide tablets dose do not take the missed dose, take the next dose at your next scheduled time. Do not take 2 doses at the same time.
  • Bicalutamide tablets can be taken with or without food.
  • If you take too many bicalutamide tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

  What should I avoid during treatment with

Bicalutamide Tablets May Cause Serious Side Effects, Including: ⮝

• Liver problems.Severe liver problems, including liver failure that may need to be treated in a hospital or that may lead to death have happened in people who take bicalutamide tablets. Your healthcare provider should do blood tests to check your liver function before and during treatment with bicalutamide tablets. Tell your healthcare provider right away if you develop any of these symptoms of liver problems during treatment:

yellowing of the skin and eyes (jaundice)	dark urine
right upper stomach pain	nausea
vomiting	tiredness
loss of appetite	chills
fever

• Bleeding problems.Serious bleeding problems have happened in people who take bicalutamide tablets in combination with a blood thinner medicine (coumarin anticoagulants). Bleeding problems have happened days to weeks after starting bicalutamide tablets treatment. If you take a blood thinner medicine during treatment with bicalutamide tablets, tell your healthcare provider if you develop any bleeding or unexplained bruising.
• Breast enlargement (gynecomastia) and breast pain.
• Blood sugar problems.Poor blood sugar control can happen in people who take bicalutamide tablets in combination with LHRH medicines.

Your healthcare provider may do blood tests during treatment with bicalutamide tablets to check for side effects.

Your prostate cancer may get worse during treatment with bicalutamide tablets in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.

Tell your healthcare provider if you have trouble breathing with or without a cough or fever. Some people taking bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.

The most common side effects of

Bicalutamide Tablets Include: ⮝

hot flashes (short periods of feeling warm and sweating)	infection	diarrhea
body pain (including back, pelvis, stomach)	nausea	blood in your urine
feeling weak	swelling in your arms, ankles, legs or feet	frequent urination at night
constipation	shortness of breath (dyspnea)	a decrease in red blood cells (anemia)
	dizziness

Bicalutamide may have an effect on male fertility which could be reversible. Talk to your healthcare provider if this is a concern for you.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of bicalutamide tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store

Bicalutamide Tablets? ⮝

Store bicalutamide tablets at room temperature between 68 F to 77 F (20 C to 25 C).
Keepbicalutamide tablets and all medicines out of the reach of children.

General information about the safe and effective use ofbicalutamide tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use bicalutamide tablets for a condition for which they were not prescribed. Do not give bicalutamide tablets to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about bicalutamide tablets. If you would like more information about bicalutamide tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for health professionals.

What are the ingredients in

Dose And Schedule: ⮝

Inform patients that therapy with bicalutamide tablets and the LHRH analog should be started at the same time and that they should not interrupt or stop taking these medications without consulting their healthcare provider[see Dosage and Administration (2.1)].

Hepatitis: ⮝

Inform patients that bicalutamide tablets can cause hepatitis, which may result in hepatic failure and death. Advise patients that liver function tests should be monitored regularly during treatment and to report signs and symptoms of hepatitis[see Warnings and Precautions (5.1)].

Hemorrhage With Concomitant Use Of Coumarin Anticoagulant: ⮝

Inform patients that serious bleeding has occurred with reported increased anticoagulant effects while taking bicalutamide tablets. Advise patients to notify their healthcare provider of any bleeding or spontaneous bruising while on bicalutamide tablets and taking anticoagulants[see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Glucose Tolerance: ⮝

Inform patients that diabetes or loss of glycemic control in patients with preexisting diabetes has been reported during treatment with LHRH agonists. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide tablets in combination with LHRH agonists[see Warnings and Precautions (5.4)].

Somnolence: ⮝

During treatment with bicalutamide tablets, somnolence has been reported. Advise patients who experience this symptom to observe caution when driving or operating machines[see Adverse Reactions (6.1)].

Photosensitivity: ⮝

Inform patients that cases of photosensitivity have been reported during treatment with bicalutamide tablets and that they should avoid direct exposure to excessive sunlight or UV-light exposure. Consideration should be given to the use of sunscreen[see Adverse Reactions (6.2)].

Contraception And Fertility: ⮝

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 130 days after the last dose of bicalutamide tablets therapy. Advise male patients that bicalutamide tablets may impair fertility[see Use in Specific Populations (8.3)].

Manufactured In Israel By: ⮝

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For: ⮝

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. H 12/2017

Patient Information ⮝

Patients should be informed that therapy with Bicalutamide Tablets, USP and the LHRH analog should be started at the same time and that they should not interrupt or stop taking these medications without consulting their physician.

During treatment with Bicalutamide Tablets, USP, somnolence has been reported, and those patients who experience this symptom should observe caution when driving or operating machines.

Patients should be informed that diabetes, or loss of glycemic control in patients with pre-existing diabetes has been reported during treatment with LHRH agonists. Consideration should therefore be given to monitoring blood glucose in patients receiving Bicalutamide Tablets, USP in combination with LHRH agonists.

Manufactured for:
DAVA Pharmaceuticals, Inc.
Fort Lee, NJ 07024, USA

Manufactured by:
Synthon Hispania S.L.
Barcelona, Spain
Made in Spain

Revised: 06/2009

PI-5002-1

1. No Title 1572554824
2. No Title 1572555535
3. No Title 1572555740
4. 3. Dosage Forms & Strengths
5. 16. How Supplied/storage And Handling
6. Principal Display Panel - 50 Mg 30 Tablets
7. Principal Display Panel - 50 Mg 100 Tablets
8. 1 Indications And Usage
9. 2 Dosage And Administration
10. 3 Dosage Forms And Strengths
11. 4 Contraindications
12. 5 Warnings And Precautions
13. 6 Adverse Reactions
14. 7 Drug Interactions
15. 8 Use In Specific Populations
16. 10 Overdosage
17. 11 Description
18. 12 Clinical Pharmacology
19. 13 Nonclinical Toxicology
20. 14 Clinical Studies
21. 16 How Supplied/storage And Handling
22. Package Label.principal Display Panel
23. No Title 1572451126
24. Package/label Display Panel
25. No Title 1572451319
26. Container Label
27. 1 Indications And Usage
28. 2 Dosage And Administration
29. 3 Dosage Forms And Strengths
30. 4 Contraindications
31. 5 Warnings And Precautions
32. 6 Adverse Reactions
33. 7 Drug Interactions
34. 8 Use In Specific Populations
35. 10 Overdosage
36. 11 Description
37. 12 Clinical Pharmacology
38. 13 Nonclinical Toxicology
39. 14 Clinical Studies
40. 16 How Supplied/storage And Handling
41. Principal Display Panel
42. Highlights Of Prescribing Information
43. Indications And Usage
44. Dosage And Administration
45. Dosage Forms And Strengths
46. Contraindications
47. Warnings And Precautions
48. Adverse Reactions
49. Drug Interactions
50. Use In Specific Populations
51. 1. Indications And Usage
52. 2. Dosage And Administration
53. 3. Dosage Forms And Strengths
54. 4. Contraindications
55. 5. Warnings And Precautions
56. 6. Adverse Reactions
57. 7. Drug Interactions
58. 8. Use In Specific Populations
59. 10. Overdosage
60. 11. Description
61. 12. Clinical Pharmacology
62. 13. Nonclinical Toxicology
63. 14. Clinical Studies
64. 16. How Supplied/storage And Handling
65. Principal Display Panel
66. No Title 1572456491
67. Bicalutamide 50mg Tablet

No Title 1572554824 ⮝

PRINCIPAL DISPLAY PANEL - 50000 Tablet Label

Work Order: 210294
Drum: *

Item: 125436
Bicalutamide 50mg t blk

Lot: 06E29IM
Coating1: 1
Coating2: 0

Quantity: 100 E3
Print Date:
08-10-10

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63672-0005 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Bicalutamide (UNII: A0Z3NAU9DP) (Bicalutamide - UNII:A0Z3NAU9DP) Bicalutamide 50 mg

Inactive Ingredients Ingredient Name Strength lactose monohydrate (UNII: EWQ57Q8I5X) magnesium stearate (UNII: 70097M6I30) povidone (UNII: FZ989GH94E) crospovidone (UNII: 68401960MK) sodium lauryl sulfate (UNII: 368GB5141J) polyethylene glycol (UNII: 3WJQ0SDW1A) hypromelloses (UNII: 3NXW29V3WO) titanium dioxide (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code BCM;50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63672-0005-0 50000 in 1 DRUM

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077973 07/06/2009

Labeler - Synthon Pharmaceuticals, Inc. (013502302)

Revised: 10/2010 Document Id: 65ee30e3-b0ed-4150-b590-95387ed3a991 34391-3 Set id: c267f783-1d39-4f27-83ed-8288577bf66d Version: 1 Effective Time: 20101014 Synthon Pharmaceuticals, Inc.

No Title 1572555535 ⮝

PATIENT INFORMATION

Bicalutamide (BYE-ka-LOO-ta-mide) Tablets

What are bicalutamide tablets?

Bicalutamide tablets are a prescription medicine called an androgen receptor inhibitor, used in combination with luteinizing hormone-releasing hormone (LHRH) medicines to treat Stage D2 metastatic prostate cancer.

Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments.

It is not known if bicalutamide tablets are safe and effective in children.

Do not take bicalutamide tablets if you are:

• allergic to bicalutamide or any of the ingredients in bicalutamide tablets. See the end of this Patient Information leaflet for a complete list of ingredients in bicalutamide tablets. Get medical help right away if you develop any of the following symptoms of an allergic reaction:
• itching
• swelling of the face, lips or tongue
• hives (raised bumps)
• trouble breathing or swallowing

• female. Bicalutamide tablets are not for use by women.
• pregnant or may become pregnant. Bicalutamide tablets may harm your unborn baby.

Before taking bicalutamide tablets, tell your healthcare provider about all your medical conditions, including if you:

• have liver problems.
• take a medicine to thin your blood. Ask your healthcare provider or pharmacist if you are not sure if your medicine is a blood thinner.
• have diabetes.
• have a female partner who can become pregnant. Males who have a female partner who can become pregnant should use effective birth control during treatment with bicalutamide tablets and for 130 days after the final dose. Talk to your healthcare provider if you have any questions about birth control.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Bicalutamide tablets may affect the way other medicines work and other medicines may affect how bicalutamide tablets work, causing side effects.

Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers when you get a new medicine.

How should I take bicalutamide tablets?

• Take bicalutamide tablets exactly as your healthcare provider tells you to take them.
• Do not stop taking bicalutamide tablets unless your healthcare provider tells you to.
• Bicalutamide tablets can be taken either in the morning or in the evening, but you should take them at the same time every day.
• Your treatment with bicalutamide tablets should start at the same time as your treatment with the LHRH medicine.
• If you miss a bicalutamide tablet dose do not take the missed dose, take the next dose at your next scheduled time. Do not take 2 doses at the same time.
• Bicalutamide tablets can be taken with or without food.
• If you take too many bicalutamide tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid during treatment with bicalutamide tablets?

• Do not drive, operate machinery, or do other dangerous activities until you know how bicalutamide tablets affect you. Bicalutamide tablets can make you sleepy.

• Avoid sunlight, sunlamps, and tanning beds, and consider using sunscreen during treatment with bicalutamide tablets. Some people have had skin sensitivity to sunlight during treatment with bicalutamide tablets.

What are the possible side effects of bicalutamide tablets?

Bicalutamide tablets may cause serious side effects, including:

• Liver problems. Severe liver problems, including liver failure that may need to be treated in a hospital or that may lead to death have happened in people who take bicalutamide tablets. Your healthcare provider should do blood tests to check your liver function before and during treatment with bicalutamide tablets. Tell your healthcare provider right away if you develop any of these symptoms of liver problems during treatment:

yellowing of the skin and eyes (jaundice) right upper stomach pain vomiting loss of appetite fever

dark urine nausea tiredness chills

• Bleeding problems. Serious bleeding problems have happened in people who take bicalutamide tablets in combination with a blood thinner medicine (coumarin anticoagulants). Bleeding problems have happened days to weeks after starting bicalutamide tablet treatment. If you take a blood thinner medicine during treatment with bicalutamide tablets, tell your healthcare provider if you develop any bleeding or unexplained bruising.
• Breast enlargement (gynecomastia) and breast pain.
• Blood sugar problems. Poor blood sugar control can happen in people who take bicalutamide tablets in combination with LHRH medicines.

Your healthcare provider may do blood tests during treatment with bicalutamide tablets to check for side effects.

Your prostate cancer may get worse during treatment with bicalutamide tablets in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.

Tell your healthcare provider if you have trouble breathing with or without a cough or fever. Some people taking bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.

The most common side effects of bicalutamide tablets include:

hot flashes, (short periods of feeling warm and sweating) body pain (including back, pelvis, stomach) feeling weak constipation infection

nausea swelling in your arms, ankles, legs or feet shortness of breath (dyspnea) dizziness diarrhea blood in your urine frequent urination at night a decrease in red blood cells (anemia)

Bicalutamide tablets may have an effect on male fertility which could be reversible. Talk to your healthcare provider if this is a concern for you.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of bicalutamide tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store bicalutamide tablets?

Store bicalutamide tablets at room temperature between 68 to 77 F (20 to 25 C).

Keep bicalutamide tablets and all medicines out of the reach of children.

General information about the safe and effective use of bicalutamide tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use bicalutamide tablets for a condition for which they were not prescribed. Do not give bicalutamide tablets to other people, even if they have the same symptoms that you have. They may harm them. This Patient Information leaflet summarizes the most important information about bicalutamide tablets. If you would like more information about bicalutamide tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for health professionals.

What are the ingredients in bicalutamide tablets?

Active ingredient: bicalutamide, USP

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol 4000, povidone, sodium lauryl sulfate, and titanium dioxide.

For more information call 1-888-838-2872.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. F 12/2017

No Title 1572555740 ⮝

PATIENT INFORMATION

Bicalutamide (BYE-ka-LOO-ta-mide) Tablets

What are bicalutamide tablets?

Bicalutamide tablets are a prescription medicine called an androgen receptor inhibitor, used in combination with luteinizing hormone-releasing hormone (LHRH) medicines to treat Stage D2 metastatic prostate cancer.

Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments.

It is not known if bicalutamide tablets are safe and effective in children.

Do not take bicalutamide tablets if you are:

• allergic to bicalutamide or any of the ingredients in bicalutamide tablets. See the end of this Patient Information leaflet for a complete list of ingredients in bicalutamide tablets. Get medical help right away if you develop any of the following symptoms of an allergic reaction:
• itching
• swelling of the face, lips or tongue
• hives (raised bumps)
• trouble breathing or swallowing

• female. Bicalutamide tablets are not for use by women.
• pregnant or may become pregnant. Bicalutamide tablets may harm your unborn baby.

Before taking bicalutamide tablets, tell your healthcare provider about all your medical conditions, including if you:

• have liver problems.
• take a medicine to thin your blood. Ask your healthcare provider or pharmacist if you are not sure if your medicine is a blood thinner.
• have diabetes.
• have a female partner who can become pregnant. Males who have a female partner who can become pregnant should use effective birth control during treatment with bicalutamide tablets and for 130 days after the final dose. Talk to your healthcare provider if you have any questions about birth control.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Bicalutamide tablets may affect the way other medicines work and other medicines may affect how bicalutamide tablets work, causing side effects.

Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers when you get a new medicine.

How should I take bicalutamide tablets?

• Take bicalutamide tablets exactly as your healthcare provider tells you to take them.
• Do not stop taking bicalutamide tablets unless your healthcare provider tells you to.
• Bicalutamide tablets can be taken either in the morning or in the evening, but you should take them at the same time every day.
• Your treatment with bicalutamide tablets should start at the same time as your treatment with the LHRH medicine.
• If you miss a bicalutamide tablet dose do not take the missed dose, take the next dose at your next scheduled time. Do not take 2 doses at the same time.
• Bicalutamide tablets can be taken with or without food.
• If you take too many bicalutamide tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid during treatment with bicalutamide tablets?

• Do not drive, operate machinery, or do other dangerous activities until you know how bicalutamide tablets affect you. Bicalutamide tablets can make you sleepy.

• Avoid sunlight, sunlamps, and tanning beds, and consider using sunscreen during treatment with bicalutamide tablets. Some people have had skin sensitivity to sunlight during treatment with bicalutamide tablets.

What are the possible side effects of bicalutamide tablets?

Bicalutamide tablets may cause serious side effects, including:

• Liver problems. Severe liver problems, including liver failure that may need to be treated in a hospital or that may lead to death have happened in people who take bicalutamide tablets. Your healthcare provider should do blood tests to check your liver function before and during treatment with bicalutamide tablets. Tell your healthcare provider right away if you develop any of these symptoms of liver problems during treatment:

yellowing of the skin and eyes (jaundice) right upper stomach pain vomiting loss of appetite fever

dark urine nausea tiredness chills

• Bleeding problems. Serious bleeding problems have happened in people who take bicalutamide tablets in combination with a blood thinner medicine (coumarin anticoagulants). Bleeding problems have happened days to weeks after starting bicalutamide tablet treatment. If you take a blood thinner medicine during treatment with bicalutamide tablets, tell your healthcare provider if you develop any bleeding or unexplained bruising.
• Breast enlargement (gynecomastia) and breast pain.
• Blood sugar problems. Poor blood sugar control can happen in people who take bicalutamide tablets in combination with LHRH medicines.

Your healthcare provider may do blood tests during treatment with bicalutamide tablets to check for side effects.

Your prostate cancer may get worse during treatment with bicalutamide tablets in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.

Tell your healthcare provider if you have trouble breathing with or without a cough or fever. Some people taking bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.

The most common side effects of bicalutamide tablets include:

hot flashes, (short periods of feeling warm and sweating) body pain (including back, pelvis, stomach) feeling weak constipation infection

nausea swelling in your arms, ankles, legs or feet shortness of breath (dyspnea) dizziness diarrhea blood in your urine frequent urination at night a decrease in red blood cells (anemia)

Bicalutamide tablets may have an effect on male fertility which could be reversible. Talk to your healthcare provider if this is a concern for you.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of bicalutamide tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store bicalutamide tablets?

Store bicalutamide tablets at room temperature between 68 to 77 F (20 to 25 C).

Keep bicalutamide tablets and all medicines out of the reach of children.

General information about the safe and effective use of bicalutamide tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use bicalutamide tablets for a condition for which they were not prescribed. Do not give bicalutamide tablets to other people, even if they have the same symptoms that you have. They may harm them. This Patient Information leaflet summarizes the most important information about bicalutamide tablets. If you would like more information about bicalutamide tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for health professionals.

What are the ingredients in bicalutamide tablets?

Active ingredient: bicalutamide, USP

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol 4000, povidone, sodium lauryl sulfate, and titanium dioxide.

For more information call 1-888-838-2872.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. F 12/2017

3. Dosage Forms & Strengths ⮝

Bicalutamide Tablets, USP 50 mg Tablets for oral administration.

16. How Supplied/storage And Handling ⮝

Bicalutamide Tablets, USP, 50 mg are white, round, biconvex, film-coated tablets with "BCM 50" debossed on one side. They are supplied as follows:

NDC 67253-191-03, Bottles of 30

NDC 67253-191-10, Bottles of 100

16.1. Storage and Handling

Store at controlled room temperature, 20 to 25 C (68 to 77 F). Excursions permitted to 15 to 30 C (59 to 86 F). See USP Controlled Room Temperature.

Principal Display Panel - 50 Mg 30 Tablets ⮝

NDC 67253-191-03

BICALUTAMIDE
TABLETS, USP

50 mg

30 tablets
Rx only

DAVA

Principal Display Panel - 50 Mg 100 Tablets ⮝

NDC 67253-191-10

BICALUTAMIDE
TABLETS, USP

50 mg

100 tablets
Rx only

DAVA

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67253-191 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength bicalutamide (UNII: A0Z3NAU9DP) (bicalutamide - UNII:A0Z3NAU9DP) bicalutamide 50 mg

Inactive Ingredients Ingredient Name Strength crospovidone (UNII: 68401960MK) povidone (UNII: FZ989GH94E) lactose monohydrate (UNII: EWQ57Q8I5X) magnesium stearate (UNII: 70097M6I30) sodium lauryl sulfate (UNII: 368GB5141J) polyethylene glycol (UNII: 3WJQ0SDW1A) hypromellose (UNII: 3NXW29V3WO) titanium dioxide (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape ROUND (bi-convex) Size 7mm Flavor Imprint Code BCM;50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67253-191-03 30 in 1 BOTTLE, PLASTIC 2 NDC:67253-191-10 100 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077973 07/06/2009

Labeler - Dava Pharmaceuticals, Inc. (172202025)

Registrant - Synthon Pharmaceuticals, Inc. (013502302)

Establishment
Name	Address	ID/FEI	Business Operations
Synthon Hispania S.L.		460486264	MANUFACTURE

Revised: 7/2009 Document Id: 0353c7a7-53e1-4628-8585-049afbc48c1b 34391-3 Set id: 59df7b06-81d0-423c-9e80-9014d424b64c Version: 1 Effective Time: 20090717 Dava Pharmaceuticals, Inc.

1 Indications And Usage ⮝

Bicalutamide tablets 50 mg daily are indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.

Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments [see Clinical Studies (14.2)].

2 Dosage And Administration ⮝

2.1 Recommended Dose and Schedule

The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide tablets be taken at the same time each day. Treatment with bicalutamide tablets should be started at the same time as treatment with an LHRH analog. If a dose of bicalutamide tablets is missed, take the next dose at the scheduled time. Do not take the missed dose and do not double the next dose.

2.2 Dosage Adjustment in Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].

2.3 Dosage Adjustment in Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n = 4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide, no dosage adjustment is necessary [see Use in Specific Populations (8.6)].

3 Dosage Forms And Strengths ⮝

Bicalutamide tablets USP 50 mg for oral administration.

4 Contraindications ⮝

Bicalutamide tablets are contraindicated in:

• Hypersensitivity
  Bicalutamide tablets are contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported.
• Women
  Bicalutamide tablets have no indication for women, and should not be used in this population.
• Pregnancy
  Bicalutamide tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

5 Warnings And Precautions ⮝

5.1 Hepatitis

Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported postmarketing in association with the use of bicalutamide tablets. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of bicalutamide tablet patients in controlled clinical trials.

Serum transaminase levels should be measured prior to starting treatment with bicalutamide tablets, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, bicalutamide tablets should be immediately discontinued with close follow-up of liver function.

5.2 Hemorrhage with Concomitant Use of Coumarin Anticoagulant

In the postmarketing setting, there have been reports of excessive prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) days to weeks after the introduction of bicalutamide in patients who were previously stable on coumarin anticoagulants. Some patients had serious bleeding including intracranial, retroperitoneal, and gastrointestinal requiring blood transfusion and/or administration of vitamin K. Closely monitor the PT/INR, and adjust the anticoagulant dose as needed [see Drug Interactions (7) and Adverse Reactions (6.2)].

5.3 Gynecomastia and Breast Pain

In clinical trials with bicalutamide 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively.

5.4 Glucose Tolerance

A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with preexisting diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.

5.5 Laboratory Tests

Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient s response. If PSA levels rise during bicalutamide therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.

6 Adverse Reactions ⮝

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience

In patients with advanced prostate cancer treated with bicalutamide in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).

In the multi-center, double-blind, controlled clinical trial comparing bicalutamide 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported.

Table 1: Incidence of Adverse Reactions ( 5% in Either Treatment Group) Regardless of Causality

Body System Adverse Reaction	Treatment Group Number of Patients (%)
	Bicalutamide Plus LHRH Analog	Flutamide Plus LHRH Analog
	(n = 401)	(n = 407)
Body as a Whole
Pain (General)	142 (35)	127 (31)
Back Pain	102 (25)	105 (26)
Asthenia	89 (22)	87 (21)
Pelvic Pain	85 (21)	70 (17)
Infection	71 (18)	57 (14)
Abdominal Pain	46 (11)	46 (11)
Chest Pain	34 (8)	34 (8)
Headache	29 (7)	27 (7)
Flu Syndrome	28 (7)	30 (7)
Cardiovascular
Hot Flashes	211 (53)	217 (53)
Hypertension	34 (8)	29 (7)
Digestive
Constipation	87 (22)	69 (17)
Nausea	62 (15)	58 (14)
Diarrhea	49 (12)	107 (26)
Increased Liver Enzyme Test	30 (7)	46 (11)
Dyspepsia	30 (7)	23 (6)
Flatulence	26 (6)	22 (5)
Anorexia	25 (6)	29 (7)
Vomiting	24 (6)	32 (8)
Hemic and Lymphatic
Anemia	45 (11)	53 (13)
Metabolic and Nutritional
Peripheral Edema	53 (13)	42 (10)
Weight Loss	30 (7)	39 (10)
Hyperglycemia	26 (6)	27 (7)
Alkaline Phosphatase Increased	22 (5)	24 (6)
Weight Gain	22 (5)	18 (4)
Musculoskeletal
Bone Pain	37 (9)	43 (11)
Myasthenia	27 (7)	19 (5)
Arthritis	21 (5)	29 (7)
Pathological Fracture	17 (4)	32 (8)
Nervous System
Dizziness	41 (10)	35 (9)
Paresthesia	31 (8)	40 (10)
Insomnia	27 (7)	39 (10)
Anxiety	20 (5)	9 (2)
Depression	16 (4)	33 (8)
Respiratory System
Dyspnea	51 (13)	32 (8)
Cough Increased	33 (8)	24 (6)
Pharyngitis	32 (8)	23 (6)
Bronchitis	24 (6)	22 (3)
Pneumonia	18 (4)	19 (5)
Rhinitis	15 (4)	22 (5)
Skin and Appendages
Rash	35 (9)	30 (7)
Sweating	25 (6)	20 (5)
Urogenital
Nocturia	49 (12)	55 (14)
Hematuria	48 (12)	26 (6)
Urinary Tract Infection	35 (9)	36 (9)
Gynecomastia	36 (9)	30 (7)
Impotence	27 (7)	35 (9)
Breast Pain	23 (6)	15 (4)
Urinary Frequency	23 (6)	29 (7)
Urinary Retention	20 (5)	14 (3)
Urinary Impaired	19 (5)	15 (4)
Urinary Incontinence	15 (4)	32 (8)

Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality.

Body as a Whole: Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst

Cardiovascular: Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope

Digestive: Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal Abscess; Gastrointestinal Carcinoma

Metabolic and Nutritional: Edema; BUN Increased; Creatinine Increased; Dehydration; Gout; Hypercholesteremia

Musculoskeletal: Myalgia; Leg Cramps

Nervous: Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness

Respiratory: Lung Disorder; Asthma; Epistaxis; Sinusitis

Skin and Appendages: Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder

Special Senses: Cataract Specified

Urogenital: Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder

Abnormal Laboratory Test Values:

Laboratory abnormalities including: elevated AST, ALT, bilirubin, BUN, and creatinine; and decreased hemoglobin and white cell count, have been reported in both bicalutamide-LHRH analog treated and flutamide-LHRH analog treated patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bicalutamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory disorders: Interstitial lung disease (some fatal) including interstitial pneumonitis and pulmonary fibrosis, most often at doses greater than 50 mg

Hemorrhage: Increased PT/INR due to interaction between coumarin anticoagulants and bicalutamide. Serious bleeding reported [see Warnings and Precautions (5.2)].

Skin and subcutaneous tissue disorders: Photosensitivity

7 Drug Interactions ⮝

Clinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic enzymes.

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4 with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Clinical studies have shown that with coadministration of bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5-fold (for Cmax) and 1.9-fold (for AUC). Hence, caution should be exercised when bicalutamide is coadministered with CYP 3A4 substrates.

In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. PT/INR should be closely monitored in patients concomitantly receiving coumarin anticoagulants and bicalutamide. Adjustment of the anticoagulant dose may be necessary [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

Bicalutamide is contraindicated for use in pregnant women because it can cause fetal harm. Bicalutamide is not indicated for use in females. There are no human data on the use of bicalutamide in pregnant women. In animal reproduction studies, oral administration of bicalutamide to pregnant rats during organogenesis caused abnormal development of reproductive organs in male fetuses at exposures approximately 0.7 to 2 times the human exposure at the recommended dose (see Data).

Data

Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 15, male fetuses had reduced anogenital distance at doses of 10 mg/kg/day and above (approximately 0.7 to 2 times the human exposure at the recommended dose).

In a pre- and post-natal development study, female rats were dosed from gestation day 7 to 16 and allowed to litter and rear their offspring to weaning. Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance.

In a peri- and post-natal development study, female rats were dosed from gestation day 16 to lactation day 22 and allowed to litter and rear their offspring to weaning. Survival and weights of offspring during lactation were reduced for litters from maternal rats receiving doses of 250 mg/kg/day (approximately 2 times the human exposure at the recommended dose). Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance, smaller secondary sex organs, cryptorchidism and hypospadias resulting in an inability to mate and impregnate their female partners. Female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above had reduced pregnancy rates.

8.2 Lactation

Risk Summary

Bicalutamide is not indicated for use in pregnant women. There is no information available on the presence of bicalutamide in human milk, or on the effects on the breastfed infant or on milk production. Bicalutamide has been detected in rat milk.

8.3 Females and Males of Reproductive Potential

Contraception

Males

Antiandrogen therapy may cause morphological changes in spermatozoa [see Nonclinical Toxicology (13.1)]. Based on findings in animal reproduction studies and its mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 130 days after the final dose of bicalutamide [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

Infertility

Males

Based on animal studies, bicalutamide can lead to inhibition of spermatogenesis and may impair fertility in males of reproductive potential. The long-term effects of bicalutamide on male fertility have not been studied [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of bicalutamide in pediatric patients have not been established.

Bicalutamide orodispersible tablet was studied in combination with anastrozole orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin-independent precocious puberty in boys with familial male-limited precocious puberty, also known as testotoxicosis. Patients were enrolled in the study if they had a baseline age 2 years and a diagnosis of testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed, an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12 month study and received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months and received treatment subsequently. Mean SD characteristics at baseline were as follows: chronological age: 3.9 1.9 years; bone age 8.8 2.5; bone age/chronological age ratio: 2.06 0.51; growth rate (cm/yr): 10.81 4.22; growth rate standard deviation score (SDS): 0.41 1.36.

The starting bicalutamide dose was 12.5 mg. Bicalutamide was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5 to 15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved bicalutamide dose of 50 mg. The starting daily dose of anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at steady-state a serum estradiol concentration of < 10 pmol/L (2.7 pg/mL). The following ascending doses were used for bicalutamide: 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two ascending doses: 0.5 mg and 1 mg. At the end of the titration phase, 1 patient was on 12.5 mg bicalutamide, 8 patients were on 50 mg bicalutamide, and 4 patients were on 100 mg bicalutamide; 10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by Day 8.

The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior to entering the study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced during treatment. During bicalutamide/anastrozole treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p = 0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI ( 1.2 to 1.0) p = 0.88. Table 2 shows descriptive data for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.

Table 2: Growth Rates

* Change compared to pre-study growth rate. PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors. Median calculated as midpoint of 3rd and 4th ranked observations. NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole, or other aromatase inhibitors.
Endpoint	Analysis population	Pre-study Mean	Change from pre-study to 12 months			% patients with growth reduction*
			Mean	Median	(Min, Max)
Growth rate (cm/yr)	All treated (n = 13)	10.8	-1.6	-2.8	(-7.4, 8.4)	9/13 (69%)
	PT (n = 6)	10.3	-0.2	-2.6	(-7.2, 8.4)	4/6 (67%)
	NPT (n = 7)	11.2	-2.8	-2.8	(-7.4, 1.1)	5/7 (71%)
Growth rate (SD units)	All treated (n = 13)	0.4	-0.1	-0.4	(-2.7, 3.5)	9/13 (69%)
	PT (n = 6)	-0.1	+0.7	-0.2	(-1.6, 3.5)	4/6 (67%)
	NPT (n = 7)	0.8	-0.7	-0.4	(-2.7, 0.5)	5/7 (71%)

Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification.

There were no deaths, serious adverse events, or discontinuations due to adverse events during the study. Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported (> 3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%), and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase [ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrozole by investigators. For the patient who developed elevated ALT and AST, the elevation was < 3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.

8.5 Geriatric Use

In two studies in patients given 50 or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.

8.6 Hepatic Impairment

Bicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of bicalutamide may be delayed and could lead to further accumulation. Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].

No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n = 4).

8.7 Renal Impairment

Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.

10 Overdosage ⮝

Long-term clinical trials have been conducted with dosages up to 200 mg of bicalutamide daily and these dosages have been well tolerated. A single dose of bicalutamide that results in symptoms of an overdose considered to be life threatening has not been established.

There is no specific antidote; treatment of an overdose should be symptomatic.

In the management of an overdose with bicalutamide, vomiting may be induced if the patient is alert. It should be remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not likely to be helpful since bicalutamide is highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

11 Description ⮝

Bicalutamide tablets USP contain 50 mg of bicalutamide, USP, a non-steroidal androgen receptor inhibitor with no other known endocrine activity. The chemical name is propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural formula is:

C18H14N2O4F4S M.W. 430.37

The pKa', is approximately 12. Bicalutamide, USP is a fine white to off-white powder which is practically insoluble in water at 37 C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.

Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide, USP; the S-enantiomer is essentially inactive.

The inactive ingredients of bicalutamide tablets USP are: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol 4000, povidone, sodium lauryl sulfate, and titanium dioxide.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Bicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. 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.

When bicalutamide is combined with LHRH analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.

In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.

12.3 Pharmacokinetics

Absorption

Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Coadministration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.

Distribution

Bicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].

Metabolism/Elimination

Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.

Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients with prostate cancer are presented in Table 3.

Table 3: Pharmacokinetics of Bicalutamide Active Enantiomer

Parameter	Mean	Standard Deviation
Normal Males (n = 30)
Apparent Oral Clearance (L/hr)	0.320	0.103
Single Dose Peak Concentration (mcg/mL)	0.768	0.178
Single Dose Time to Peak Concentration (hours)	31.3	14.6
Half-life (days)	5.8	2.29
Patients with Prostate Cancer (n = 40)
Css (mcg/mL)	8.939	3.504

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of 5, 15, or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is approximately 0.7 times the human exposure at the recommended dose) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1.5 times the human exposure at the recommended dose). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient population.

A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times the human exposure at the recommended dose) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man. There were no tumorigenic effects suggestive of genotoxic carcinogenesis.

A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E. coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that bicalutamide does not have genotoxic activity.

In repeat-dose toxicology studies, atrophy of seminiferous tubules of the testes has been observed for all species examined, which is a predicted class effect with antiandrogens. In the 6- and 12-month rat study, testicular atrophy was seen at approximately 2 times the human exposure at the recommended dose. In the 12-month dog study, the incidence of testicular atrophy was seen at approximately 7 times the human exposure at the recommended dose. In male rats administered 250 mg/kg/day (approximately 2 times human exposure at the recommended dose), the precoital interval and time to successful mating were increased in the first pairing, but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11-week period of dosing.

Female rats dosed at 1, 10 and 250 mg/kg/day (less than to 2 times the human exposure at the recommended dose) had increased estrous cycle irregularity but there was no effect on fertility.

In a peri- and post-natal development study, female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended clinical dose) and above had reduced pregnancy rates. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above. Affected male offspring were also impotent.

14 Clinical Studies ⮝

14.1 Bicalutamide 50 mg Daily in Combination With an LHRH-A

In a multi-center, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).

In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with bicalutamide-LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).

Figure 1 - The Kaplan-Meier Probability of Death for Both Antiandrogen Treatment Groups.

There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2). Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).

Figure 2 - Kaplan-Meier Curve for Time to Progression for Both Antiandrogen Treatment Groups.

Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well-being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.

14.2 Safety Data From Clinical Studies Using Bicalutamide 150 mg

Bicalutamide 150 mg is not approved for use either alone or with other treatments.

Two identical multi-center, randomized, open-label trials comparing bicalutamide 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, M0) or metastatic (M1) prostate cancer.

Monotherapy M1 Group

Bicalutamide 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that bicalutamide treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the bicalutamide treated group compared to that in the castrated group, respectively.

Locally Advanced (T3-4, NX, M0) Group

Bicalutamide 150 mg daily is not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, M0 patients until study completion. In the larger trial (N = 352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the bicalutamide group and in the smaller trial (N = 140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the bicalutamide group.

In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for bicalutamide 150 mg, a dose that is not approved for use. These are three multi-center, randomized, double-blind, parallel group trials comparing bicalutamide 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.

Bicalutamide 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the bicalutamide arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the bicalutamide treated patients versus 279 (32.9%) deaths in the placebo-treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).

16 How Supplied/storage And Handling ⮝

Bicalutamide tablets USP are available as follows:

50 mg - white, film-coated, round tablets, debossed with 93 on one side and 220 on the other side, in bottles of 30 (NDC 0093-0220-56) and 100 (NDC 0093-0220-01).

16.1 Storage and Handling

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).

Package Label.principal Display Panel ⮝

NDC 16714-816-01 in bottle of 30 tablets

Bicalutamide Tablets USP, 50 mg

R x only

30 tablets

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16714-816 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP) BICALUTAMIDE 50 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A) POVIDONE K30 (UNII: U725QWY32X) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color white (WHITE TO OFF- WHITE) Score no score Shape ROUND Size 7mm Flavor Imprint Code B50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:16714-816-01 30 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/2018 2 NDC:16714-816-02 100 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078917 06/01/2018

Labeler - Northstar RxLLC (830546433)

Establishment
Name	Address	ID/FEI	Business Operations
Intas Pharmaceuticals Limited		725927649	analysis(16714-816) , manufacture(16714-816)

Revised: 6/2018 Document Id: 6e8aa29d-3cf6-0793-e053-2a91aa0ac080 34391-3 Set id: ad46d58b-3f81-4bcf-bf5f-de70c8b6c930 Version: 1 Effective Time: 20180613 Northstar RxLLC

No Title 1572451126 ⮝

PATIENT INFORMATION

Bicalutamide (BYE-ka-LOO-ta-mide) Tablets

What are bicalutamide tablets?

Bicalutamide tablets are a prescription medicine called an androgen receptor inhibitor, used in combination with luteinizing hormone-releasing hormone (LHRH) medicines to treat Stage D2 metastatic prostate cancer.

Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments.

It is not known if bicalutamide tablets are safe and effective in children.

Do not take bicalutamide tablets if you are:

• allergic to bicalutamide or any of the ingredients in bicalutamide tablets. See the end of this Patient Information leaflet for a complete list of ingredients in bicalutamide tablets. Get medical help right away if you develop any of the following symptoms of an allergic reaction:
• itching
• swelling of the face, lips or tongue
• hives (raised bumps)
• trouble breathing or swallowing

• female. Bicalutamide tablets are not for use by women.
• pregnant or may become pregnant. Bicalutamide tablets may harm your unborn baby.

Before taking bicalutamide tablets, tell your healthcare provider about all your medical conditions, including if you:

• have liver problems.
• take a medicine to thin your blood. Ask your healthcare provider or pharmacist if you are not sure if your medicine is a blood thinner.
• have diabetes.
• have a female partner who can become pregnant. Males who have a female partner who can become pregnant should use effective birth control during treatment with bicalutamide tablets and for 130 days after the final dose. Talk to your healthcare provider if you have any questions about birth control.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Bicalutamide tablets may affect the way other medicines work and other medicines may affect how bicalutamide tablets work, causing side effects.

Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers when you get a new medicine.

How should I take bicalutamide tablets?

• Take bicalutamide tablets exactly as your healthcare provider tells you to take them.
• Do not stop taking bicalutamide tablets unless your healthcare provider tells you to.
• Bicalutamide tablets can be taken either in the morning or in the evening, but you should take them at the same time every day.
• Your treatment with bicalutamide tablets should start at the same time as your treatment with the LHRH medicine.
• If you miss a bicalutamide tablet dose do not take the missed dose, take the next dose at your next scheduled time. Do not take 2 doses at the same time.
• Bicalutamide tablets can be taken with or without food.
• If you take too many bicalutamide tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid during treatment with bicalutamide tablets?

• Do not drive, operate machinery, or do other dangerous activities until you know how bicalutamide tablets affect you. Bicalutamide tablets can make you sleepy.

• Avoid sunlight, sunlamps, and tanning beds, and consider using sunscreen during treatment with bicalutamide tablets. Some people have had skin sensitivity to sunlight during treatment with bicalutamide tablets.

What are the possible side effects of bicalutamide tablets?

Bicalutamide tablets may cause serious side effects, including:

• Liver problems. Severe liver problems, including liver failure that may need to be treated in a hospital or that may lead to death have happened in people who take bicalutamide tablets. Your healthcare provider should do blood tests to check your liver function before and during treatment with bicalutamide tablets. Tell your healthcare provider right away if you develop any of these symptoms of liver problems during treatment:

yellowing of the skin and eyes (jaundice) right upper stomach pain vomiting loss of appetite fever

dark urine nausea tiredness chills

• Bleeding problems. Serious bleeding problems have happened in people who take bicalutamide tablets in combination with a blood thinner medicine (coumarin anticoagulants). Bleeding problems have happened days to weeks after starting bicalutamide tablet treatment. If you take a blood thinner medicine during treatment with bicalutamide tablets, tell your healthcare provider if you develop any bleeding or unexplained bruising.
• Breast enlargement (gynecomastia) and breast pain.
• Blood sugar problems. Poor blood sugar control can happen in people who take bicalutamide tablets in combination with LHRH medicines.

Your healthcare provider may do blood tests during treatment with bicalutamide tablets to check for side effects.

Your prostate cancer may get worse during treatment with bicalutamide tablets in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.

Tell your healthcare provider if you have trouble breathing with or without a cough or fever. Some people taking bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.

The most common side effects of bicalutamide tablets include:

hot flashes, (short periods of feeling warm and sweating) body pain (including back, pelvis, stomach) feeling weak constipation infection

nausea swelling in your arms, ankles, legs or feet shortness of breath (dyspnea) dizziness diarrhea blood in your urine frequent urination at night a decrease in red blood cells (anemia)

Bicalutamide tablets may have an effect on male fertility which could be reversible. Talk to your healthcare provider if this is a concern for you.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of bicalutamide tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store bicalutamide tablets?

Store bicalutamide tablets at room temperature between 68 to 77 F (20 to 25 C).

Keep bicalutamide tablets and all medicines out of the reach of children.

General information about the safe and effective use of bicalutamide tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use bicalutamide tablets for a condition for which they were not prescribed. Do not give bicalutamide tablets to other people, even if they have the same symptoms that you have. They may harm them. This Patient Information leaflet summarizes the most important information about bicalutamide tablets. If you would like more information about bicalutamide tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for health professionals.

What are the ingredients in bicalutamide tablets?

Active ingredient: bicalutamide, USP

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol 4000, povidone, sodium lauryl sulfate, and titanium dioxide.

For more information call 1-888-838-2872.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. F 12/2017

Package/label Display Panel ⮝

Bicalutamide Tablets USP 50 mg 100s Label Text

NDC 0093-0220-01

Bicalutamide

Tablets USP

50 mg

PHARMACIST: PLEASE DISPENSE WITH

ATTACHED PATIENT INFORMATION

LEAFLET

Rx only

100 TABLETS

TEVA

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0093-0220 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP) BICALUTAMIDE 50 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYDEXTROSE (UNII: VH2XOU12IE) POLYETHYLENE GLYCOL 4000 (UNII: 4R4HFI6D95) POVIDONE K30 (UNII: U725QWY32X) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code 93;220 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0093-0220-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 07/06/2009 10/31/2019 2 NDC:0093-0220-56 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/06/2009 10/31/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076932 07/06/2009 10/31/2019

Labeler - Teva Pharmaceuticals USA, Inc. (001627975)

Revised: 1/2018 Document Id: 2975092d-62bd-4e74-ba3a-d20bd47a1b7a 34391-3 Set id: 89c24844-4d2a-4ec6-bc28-adce7b82d0c0 Version: 11 Effective Time: 20180109 Teva Pharmaceuticals USA, Inc.

No Title 1572451319 ⮝

PRINCIPAL DISPLAY PANEL - 50000 Tablet Label

Work Order: 210294
Drum: *

Item: 125436
Bicalutamide 50mg t blk

Lot: 06E29IM
Coating1: 1
Coating2: 0

Quantity: 100 E3
Print Date:
08-10-10

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63672-0005 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Bicalutamide (UNII: A0Z3NAU9DP) (Bicalutamide - UNII:A0Z3NAU9DP) Bicalutamide 50 mg

Inactive Ingredients Ingredient Name Strength lactose monohydrate (UNII: EWQ57Q8I5X) magnesium stearate (UNII: 70097M6I30) povidone (UNII: FZ989GH94E) crospovidone (UNII: 68401960MK) sodium lauryl sulfate (UNII: 368GB5141J) polyethylene glycol (UNII: 3WJQ0SDW1A) hypromelloses (UNII: 3NXW29V3WO) titanium dioxide (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code BCM;50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63672-0005-0 50000 in 1 DRUM

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077973 07/06/2009

Labeler - Synthon Pharmaceuticals, Inc. (013502302)

Revised: 10/2010 Document Id: 65ee30e3-b0ed-4150-b590-95387ed3a991 34391-3 Set id: c267f783-1d39-4f27-83ed-8288577bf66d Version: 1 Effective Time: 20101014 Synthon Pharmaceuticals, Inc.

Container Label ⮝

50 MG BOTTLE TEXT

BICALUTAMIDE

Tablets USP

50 mg

PHARMACIST: PLEASE DISPENSE WITH

ATTACHED PATIENT INFORMATION

LEAFLET

Rx only

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-6133(NDC:0093-0220) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP) BICALUTAMIDE 50 mg

Inactive Ingredients Ingredient Name Strength COLLOIDAL SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSE (UNII: 3NXW29V3WO) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYDEXTROSE (UNII: VH2XOU12IE) POLYETHYLENE GLYCOL 4000 (UNII: 4R4HFI6D95) POVIDONE (UNII: FZ989GH94E) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE (white to off-white) Score no score Shape ROUND Size 7mm Flavor Imprint Code 93;220 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-6133-0 30 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076932 08/09/2010

Labeler - Physicians Total Care, Inc. (194123980)

Establishment
Name	Address	ID/FEI	Business Operations
Physicians Total Care, Inc.		194123980	relabel

Revised: 7/2009 Document Id: 2ba7e0fa-a7ca-4cc9-a6e8-5929d5dfe73c 34391-3 Set id: 020d34eb-9560-4218-9d87-dfdeff705c3a Version: 1 Effective Time: 20090706 Physicians Total Care, Inc.

1 Indications And Usage  ⮝

Bicalutamide 50 mg daily is indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.

Bicalutamide 150 mg daily is not approved for use alone or with other treatments [see Clinical Studies (14.2)].

2 Dosage And Administration  ⮝

2.1 Recommended Dose and Schedule

The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide be taken at the same time each day. Treatment with bicalutamide should be started at the same time as treatment with an LHRH analog. If a dose of bicalutamide is missed, take the next dose at the scheduled time. Do not take the missed dose and do not double the next dose.

2.2 Dosage Adjustment in Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].

2.3 Dosage Adjustment in Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide, no dosage adjustment is necessary [see Use in Specific Populations (8.6)].

3 Dosage Forms And Strengths  ⮝

Bicalutamide 50 mg tablets for oral administration.

4 Contraindications  ⮝

Bicalutamide is contraindicated in:

• Hypersensitivity

Bicalutamide is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported.

• Women

Bicalutamide has no indication for women, and should not be used in this population.

• Pregnancy

Bicalutamide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

5 Warnings And Precautions  ⮝

5.1 Hepatitis

Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported postmarketing in association with the use of bicalutamide. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of bicalutamide patients in controlled clinical trials.

Serum transaminase levels should be measured prior to starting treatment with bicalutamide, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, bicalutamide should be immediately discontinued with close follow-up of liver function.

5.2 Hemorrhage with Concomitant Use of Coumarin Anticoagulant

In the postmarketing setting, there have been reports of excessive prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) days to weeks after the introduction of bicalutamide in patients who were previously stable on coumarin anticoagulants. Some patients had serious bleeding including intracranial, retroperitoneal, and gastrointestinal requiring blood transfusion and/or administration of vitamin K. Closely monitor the PT/INR, and adjust the anticoagulant dose as needed [see Drug Interactions (7) and Adverse Reactions (6.2)].

5.3 Gynecomastia and Breast Pain

In clinical trials with bicalutamide 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively.

5.4 Glucose Tolerance

A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.

5.5 Laboratory Tests

Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient s response. If PSA levels rise during bicalutamide therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a
treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.

6 Adverse Reactions  ⮝

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience

In patients with advanced prostate cancer treated with bicalutamide in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).

In the multi-center, double-blind, controlled clinical trial comparing bicalutamide 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported.

Table 1. Incidence of Adverse Reactions ( 5% in Either Treatment Group) Regardless of Causality

	Treatment Group Number of Patients (%)
	Bicalutamide Plus	Flutamide Plus
	LHRH Analog	LHRH Analog
Body System Adverse Reaction	(n=401)	(n=407)
Body as a Whole
Pain (General)	142 (35)	127 (31)
Back Pain	102 (25)	105 (26)
Asthenia	89 (22)	87 (21)
Pelvic Pain	85 (21)	70 (17)
Infection	71 (18)	57 (14)
Abdominal Pain	46 (11)	46 (11)
Chest Pain	34 (8)	34 (8)
Headache	29 (7)	27 (7)
Flu Syndrome	28 (7)	30 (7)
Cardiovascular
Hot Flashes	211 (53)	217 (53)
Hypertension	34 (8)	29 (7)
Digestive
Constipation	87 (22)	69 (17)
Nausea	62 (15)	58 (14)
Diarrhea	49 (12)	107 (26)
Increased Liver Enzyme Test	30 (7)	46 (11)
Dyspepsia	30 (7)	23 (6)
Flatulence	26 (6)	22 (5)
Anorexia	25 (6)	29 (7)
Vomiting	24 (6)	32 (8)
Hemic and Lymphatic
Anemia	45 (11)	53 (13)
Metabolic and Nutritional
Peripheral Edema	53 (13)	42 (10)
Weight Loss	30 (7)	39 (10)
Hyperglycemia	26 (6)	27 (7)
Alkaline Phosphatase Increased	22 (5)	24 (6)
Weight Gain	22 (5)	18 (4)
Musculoskeletal
Bone Pain	37 (9)	43 (11)
Myasthenia	27 (7)	19 (5)
Arthritis	21 (5)	29 (7)
Pathological Fracture	17 (4)	32 (8)
Nervous System
Dizziness	41 (10)	35 (9)
Paresthesia	31 (8)	40 (10)
Insomnia	27 (7)	39 (10)
Anxiety	20 (5)	9 (2)
Depression	16 (4)	33 (8)
Respiratory System
Dyspnea	51 (13)	32 (8)
Cough Increased	33 (8)	24 (6)
Pharyngitis	32 (8)	23 (6)
Bronchitis	24 (6)	22 (3)
Pneumonia	18 (4)	19 (5)
Rhinitis	15 (4)	22 (5)
Skin and Appendages
Rash	35 (9)	30 (7)
Sweating	25 (6)	20 (5)
Urogenital
Nocturia	49 (12)	55 (14)
Hematuria	48 (12)	26 (6)
Urinary Tract Infection	35 (9)	36 (9)
Gynecomastia	36 (9)	30 (7)
Impotence	27 (7)	35 (9)
Breast Pain	23 (6)	15 (4)
Urinary Frequency	23 (6)	29 (7)
Urinary Retention	20 (5)	14 (3)
Urinary Impaired	19 (5)	15 (4)
Urinary Incontinence	15 (4)	32 (8)

Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality.

Body as a Whole: Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst

Cardiovascular: Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope

Digestive: Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal Abscess; Gastrointestinal Carcinoma

Metabolic and Nutritional: Edema; BUN Increased; Creatinine Increased; Dehydration; Gout; Hypercholesterolemia

Musculoskeletal: Myalgia; Leg Cramps

Nervous: Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness

Respiratory: Lung Disorder; Asthma; Epistaxis; Sinusitis

Skin and Appendages: Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder

Special Senses: Cataract Specified

Urogenital: Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder

Abnormal Laboratory Test Values:

Laboratory abnormalities including: elevated AST, ALT, bilirubin, BUN, and creatinine; and decreased hemoglobin and white cell count, have been reported in both bicalutamide-LHRH analog treated and flutamide-LHRH analog treated patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bicalutamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory disorders: Interstitial lung disease (some fatal) including interstitial pneumonitis and pulmonary fibrosis, most often at doses greater than 50 mg.

Hemorrhage: Increased PT/INR due to interaction between coumarin anticoagulants and bicalutamide. Serious bleeding reported [see Warnings and Precautions (5.2)].

Skin and subcutaneous tissue disorders: Photosensitivity.

7 Drug Interactions  ⮝

Clinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic enzymes.

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4 with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Clinical studies have shown that with coadministration of bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5-fold (for Cmax) and 1.9-fold (for AUC). Hence, caution should be exercised when bicalutamide is coadministered with CYP 3A4 substrates.

In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. PT/INR should be closely monitored in patients concomitantly receiving coumarin anticoagulants and bicalutamide. Adjustment of the anticoagulant dose may be necessary [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

8 Use In Specific Populations  ⮝

8.1 Pregnancy

Risk Summary

Bicalutamide is contraindicated for use in pregnant women because it can cause fetal harm. Bicalutamide is not indicated for use in females. There are no human data on the use of bicalutamide in pregnant women. In animal reproduction studies, oral administration of bicalutamide to pregnant rats during organogenesis caused abnormal development of reproductive organs in male fetuses at exposures approximately 0.7 to 2 times the human exposure at the recommended dose (see Data).

Data

Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, male fetuses had reduced anogenital distance at doses of 10 mg/kg/day and above (approximately 0.7 to 2 times the human exposure at the recommended dose).

In a pre- and post-natal development study, female rats were dosed from gestation day 7-16 and allowed to litter and rear their offspring to weaning. Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance.

In a peri- and post-natal development study, female rats were dosed from gestation day 16 to lactation day 22 and allowed to litter and rear their offspring to weaning. Survival and weights of offspring during lactation were reduced for litters from maternal rats receiving doses of 250 mg/kg/day (approximately 2 times the human exposure at the recommended dose). Male offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were observed to have reduced anogenital distance, smaller secondary sex organs, cryptorchidism and hypospadias resulting in an inability to mate and impregnate their female partners. Female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above had reduced pregnancy rates.

8.2 Lactation

Risk Summary

Bicalutamide is not indicated for use in pregnant women. There is no information available on the presence of bicalutamide in human milk, or on the effects on the breastfed infant or on milk production. Bicalutamide has been detected in rat milk.

8.3 Females and Males of Reproductive Potential

Contraception

Males

Antiandrogen therapy may cause morphological changes in spermatozoa [see Nonclinical Toxicology (13.1)]. Based on findings in animal reproduction studies and its mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 130 days after the final dose of bicalutamide [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

Infertility

Males

Based on animal studies, bicalutamide can lead to inhibition of spermatogenesis and may impair fertility in males of reproductive potential. The long-term effects of bicalutamide on male fertility have not been studied [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of bicalutamide in pediatric patients have not been established.

Bicalutamide orodispersible tablet was studied in combination with anastrozole orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin-independent precocious puberty in boys with familial male-limited precocious puberty, also known as testotoxicosis. Patients were enrolled in the study if they had a baseline age greater than or equal to 2 years and a diagnosis of testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed, an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12-month study and received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months and received treatment subsequently. Mean SD characteristics at baseline were as follows: chronological age: 3.9 1.9 years; bone age 8.8 2.5; bone age/chronological age ratio: 2.06 0.51; growth rate (cm/yr): 10.81 4.22; growth rate standard deviation score (SDS): 0.41 1.36.

The starting bicalutamide dose was 12.5 mg. Bicalutamide was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5 mcg/mL to 15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved bicalutamide dose of 50 mg. The starting daily dose of anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at steady-state a serum estradiol concentration of less than 10 pmol/L (2.7 pg/mL). The following ascending doses were used for bicalutamide: 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two ascending doses: 0.5 mg and 1 mg. At the end of the titration phase, 1 patient was on 12.5 mg bicalutamide, 8 patients were on 50 mg bicalutamide, and 4 patients were on 100 mg bicalutamide; 10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by Day 8.

The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of treatment, relative to the growth rate during the greater than or equal to 6 months prior to entering the study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced during treatment. During bicalutamide/anastrozole treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p=0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI ( 1.2 to 1.0) p=0.88. Table 2 shows descriptive data for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.

Table 2. Growth Rates

Endpoint	Analysis population	Pre-study Mean	Change from pre-study to 12 months			% patients with growth reduction1
			Mean	Median	(Min, Max)
Growth rate (cm/yr)	All treated (n=13)	10.8	-1.6	-2.8	(-7.4, 8.4)	9/13 (69%)
	PT2 (n=6)	10.3	-0.2	-2.63	(-7.2, 8.4)	4/6 (67%)
	NPT4 (n=7)	11.2	-2.8	-2.8	(-7.4, 1.1)	5/7 (71%)
Growth rate (SD units)	All treated (n=13)	0.4	-0.1	-0.4	(-2.7, 3.5)	9/13 (69%)
	PT2 (n=6)	-0.1	+0.7	-0.23	(-1.6, 3.5)	4/6 (67%)
	NPT4 (n=7)	0.8	-0.7	-0.4	(-2.7, 0.5)	5/7 (71%)

1Change compared to pre-study growth rate.
2PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors
3NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors
4Median calculated as midpoint of 3rd and 4th ranked observations

Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification.

There were no deaths, serious adverse events, or discontinuations due to adverse events during the study. Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported (greater than 3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%), and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase [ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrozole by investigators. For the patient who developed elevated ALT and AST, the elevation was less than 3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.

8.5 Geriatric Use

In two studies in patients given 50 mg or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.

8.6 Hepatic Impairment

Bicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of bicalutamide may be delayed and could lead to further accumulation. Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].

No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n=4).

8.7 Renal Impairment

Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.

10 Overdosage  ⮝

Long-term clinical trials have been conducted with dosages up to 200 mg of bicalutamide daily and these dosages have been well tolerated. A single dose of bicalutamide that results in symptoms of an overdose considered to be life threatening has not been established.

There is no specific antidote; treatment of an overdose should be symptomatic.

In the management of an overdose with bicalutamide, vomiting may be induced if the patient is alert. It should be remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not likely to be helpful since bicalutamide is highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

11 Description  ⮝

Bicalutamide tablets, USP contain 50 mg of bicalutamide, a non-steroidal androgen receptor inhibitor with no other known endocrine activity. The chemical name is propanamide, N [4 cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural and molecular formulas are:

Bicalutamide, USP has a molecular weight of 430.37. The pKa is approximately 12. Bicalutamide is a fine white to off-white powder which is practically insoluble in water at 37 C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.

Bicalutamide, USP is a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.

The inactive ingredients of bicalutamide tablets are lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, sodium starch glycolate (type A), talc and titanium dioxide.

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

Bicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. 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.

When bicalutamide is combined with LHRH analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.

In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.

12.3 Pharmacokinetics

Absorption

Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Coadministration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.

Distribution

Bicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].

Metabolism/Elimination

Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.

Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients with prostate cancer are presented in Table 3.

Table 3. Pharmacokinetics of Bicalutamide Active Enantiomer

Parameter	Mean	Standard Deviation
Normal Males (n=30)
Apparent Oral Clearance (L/hr)	0.320	0.103
Single Dose Peak Concentration (mcg/mL)	0.768	0.178
Single Dose Time to Peak Concentration (hours)	31.3	14.6
Half-life (days)	5.8	2.29
Patients with Prostate Cancer (n=40)
Css (mcg/mL)	8.939	3.504

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of 5, 15, or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is approximately 0.7 times the human exposure at the recommended dose) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1.5 times the human exposure at the recommended dose). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient population.

A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times the human exposure at the recommended dose) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man. There were no tumorigenic effects suggestive of genotoxic carcinogenesis.

A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E. coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that bicalutamide does not have genotoxic activity.

In repeat-dose toxicology studies, atrophy of seminiferous tubules of the testes has been observed for all species examined, which is a predicted class effect with antiandrogens. In the 6- and 12-month rat study, testicular atrophy was seen at approximately 2 times the human exposure at the recommended dose. In the 12- month dog study, the incidence of testicular atrophy was seen at approximately 7 times the human exposure at the recommended dose. In male rats administered 250 mg/kg/day (approximately 2 times human exposure at the recommended dose), the precoital interval and time to successful mating were increased in the first pairing, but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11-week period of dosing.

Female rats dosed at 1, 10 and 250 mg/kg/day (less than to 2 times the human exposure at the recommended dose) had increased estrous cycle irregularity but there was no effect on fertility.

In a peri- and post-natal development study, female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended clinical dose) and above had reduced pregnancy rates. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above. Affected male offspring were also impotent.

14 Clinical Studies  ⮝

14.1 Bicalutamide 50 mg Daily in Combination with an LHRH-A

In a multi-center, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).

In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with bicalutamide-LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).

Figure 1 - The Kaplan-Meier probability of death for both antiandrogen treatment groups.

There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2). Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).

Figure 2 - Kaplan-Meier curve for time to progression for both antiandrogen treatment groups.

Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well-being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.

14.2 Safety Data from Clinical Studies Using Bicalutamide 150 mg

Bicalutamide 150 mg is not approved for use either alone or with other treatments.

Two identical multi-center, randomized, open-label trials comparing bicalutamide 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, M0) or metastatic (M1) prostate cancer.

Monotherapy M1 Group

Bicalutamide 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that bicalutamide treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the bicalutamide treated group compared to that in the castrated group, respectively.

Locally Advanced (T3-4, NX, M0) Group

Bicalutamide 150 mg daily is not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, M0 patients until study completion. In the larger trial (N=352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the bicalutamide group and in the smaller trial (N=140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the bicalutamide group.

In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for bicalutamide 150 mg, a dose that is not approved for use. These are three multi-center, randomized, double-blind, parallel group trials comparing bicalutamide 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.

Bicalutamide 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the bicalutamide arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the bicalutamide treated patients versus 279 (32.9%) deaths in the placebo-treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).

16 How Supplied/storage And Handling ⮝

Bicalutamide tablets, USP are available as follows:

50 mg White, round, film-coated, biconvex tablets marked with B 50 on one side with on the other side are supplied in bottles of 30 tablets (NDC 16714-571-01), 100 tablets (NDC 16714-571-02), and 500 tablets (NDC 16714-571-03).

16.1 Storage and Handling

Store at controlled room temperature 20 to 25 C (68 to 77 F) [see USP].

Dispense in a tight, light-resistant container as defined in the USP.

Principal Display Panel ⮝

NDC 16714-571-01
Rx Only
Bicalutamide Tablets, USP
50 mg
PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET.
30 Tablets
NORTHSTAR

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16714-571 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP) BICALUTAMIDE 50 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) POVIDONE K30 (UNII: U725QWY32X) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TALC (UNII: 7SEV7J4R1U) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape ROUND (biconvex) Size 7mm Flavor Imprint Code B;50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:16714-571-01 30 in 1 BOTTLE; Type 0: Not a Combination Product 08/28/2009 2 NDC:16714-571-02 100 in 1 BOTTLE; Type 0: Not a Combination Product 08/28/2009 3 NDC:16714-571-03 500 in 1 BOTTLE; Type 0: Not a Combination Product 08/28/2009

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078634 08/28/2009

Labeler - Northstar RxLLC (830546433)

Revised: 12/2017 Document Id: 963fe7a5-8c45-4071-8017-96f033a17d48 34391-3 Set id: f03d7e7a-cbe9-4788-894c-d30739f7e733 Version: 8 Effective Time: 20171228 Northstar RxLLC

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use BICALUTAMIDE TABLETS safely and effectively. See full prescribing information for BICALUTAMIDE TABLETS.

BICALUTAMIDE tablets, for oral use
Initial U.S. Approval: 1995

Indications And Usage ⮝

• Bicalutamide tablets 50 mg are an androgen receptor inhibitor indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate. (1)
• Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments. (1)

Dosage And Administration ⮝

The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening). (2)

Dosage Forms And Strengths ⮝

50 mg tablets (3)

Contraindications ⮝

• Hypersensitivity (4)
• Women (4)
• Pregnancy (4, 8.1)

Warnings And Precautions ⮝

• Severe hepatic injury and fatal hepatic failure have been observed. Monitor serum transaminase levels prior to starting treatment with bicalutamide, at regular intervals for the first four months of treatment and periodically thereafter, and for symptoms or signs suggestive of hepatic dysfunction. Use bicalutamide with caution in patients with hepatic impairment. (5.1)
• Hemorrhage with Concomitant Use of Coumarin Anticoagulant. Closely monitor the Prothrombin Time (PT) and International Normalized Ratio (INR), and adjust the anticoagulant dose as needed. (5.2)
• Gynecomastia and breast pain have been reported during treatment with bicalutamide 150 mg when used as a single agent. (5.3)
• Bicalutamide is used in combination with an LHRH agonist. LHRH agonists have been shown to cause a reduction in glucose tolerance in males. Consideration should be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists. (5.4)
• Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if PSA increases. (5.5)

Adverse Reactions ⮝

Adverse reactions that occurred in more than 10% of patients receiving bicalutamide plus an LHRH-A were: hot flashes, pain (including general, back, pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea, diarrhea, hematuria, nocturia, and anemia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• R-bicalutamide is an inhibitor of CYP 3A4; therefore, caution should be used when bicalutamide is coadministered with CYP 3A4 substrates. (7)
• PT/INR should be closely monitored in patients already receiving coumarin anticoagulants who are started on bicalutamide. (7)

Use In Specific Populations ⮝

• Females and Males of Reproductive Potential: Advise males with female partners of reproductive potential to use effective contraception. (8.3)
• Pediatric patients: Efficacy has not been demonstrated for the treatment of familial male-limited precocious puberty (testotoxicosis). (8.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 1/2018

1. Indications And Usage ⮝

Bicalutamide Tablets, USP 50 mg daily are indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.

Bicalutamide Tablets, USP 150 mg daily are not approved for use alone or with other treatments [see Clinical Studies (14.2)].

2. Dosage And Administration ⮝

The recommended dose for Bicalutamide Tablets, USP therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that Bicalutamide Tablets, USP be taken at the same time each day. Treatment with Bicalutamide Tablets, USP should be started at the same time as treatment with an LHRH analog.

2.1. Dosage Adjustment in Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].

2.2. Dosage Adjustment in Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide no dosage adjustment is necessary [see Use in Specific Populations (8.6)].

3. Dosage Forms And Strengths  ⮝

Bicalutamide tablets, USP 50 mg for oral administration are white to off-white, round, biconvex, film coated tablets, debossed B 50 on one side and plain on other side.

4. Contraindications ⮝

4.1. Hypersensitivity

Bicalutamide Tablets, USP are contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet's components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported [see Adverse Reactions (6.2)].

4.2. Women

Bicalutamide Tablets, USP have no indication for women, and should not be used in this population.

4.3. Pregnancy

Bicalutamide Tablets, USP may cause fetal harm when administered to a pregnant woman. Bicalutamide Tablets, USP are contraindicated in women, including those who are or may become pregnant. There are no studies in pregnant women using Bicalutamide Tablets, USP. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1)].

5. Warnings And Precautions ⮝

5.1. Hepatitis

Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of Bicalutamide Tablets, USP. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of Bicalutamide Tablets, USP patients in controlled clinical trials.

Serum transaminase levels should be measured prior to starting treatment with Bicalutamide Tablets, USP, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, Bicalutamide Tablets, USP should be immediately discontinued with close follow-up of liver function.

5.2. Gynecomastia and Breast Pain

In clinical trials with Bicalutamide Tablets, USP 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively.

5.3. Glucose Tolerance

A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving Bicalutamide Tablets, USP in combination with LHRH agonists.

5.4. Laboratory Tests

Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise during Bicalutamide Tablets, USP therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.

6. Adverse Reactions ⮝

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1. Clinical Trials Experience

In patients with advanced prostate cancer treated with Bicalutamide Tablets, USP in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).

In the multicenter, double-blind, controlled clinical trial comparing Bicalutamide Tablets, USP 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported.

Table 1. Incidence of Adverse Reactions ( 5% in Either Treatment Group) Regardless of Causality

Body System Adverse Reaction	Treatment Group Number of Patients (%)
	Bicalutamide Tablets, USP Plus LHRH Analog (n=401)	Flutamide Plus LHRH Analog (n=407)
* Increased liver enzyme test includes increases in AST, ALT or both. Anemia includes anemia, hypochronic-and iron deficiency anemia.
Body as a Whole
Pain (General)	142 (35)	127 (31)
Back Pain	102 (25)	105 (26)
Asthenia	89 (22)	87 (21)
Pelvic Pain	85 (21)	70 (17)
Infection	71 (18)	57 (14)
Abdominal Pain	46 (11)	46 (11)
Chest Pain	34 (8)	34 (8)
Headache	29 (7)	27 (7)
Flu Syndrome	28 (7)	30 (7)
Cardiovascular
Hot Flashes	211 (53)	217 (53)
Hypertension	34 (8)	29 (7)
Digestive
Constipation	87 (22)	69 (17)
Nausea	62 (15)	58 (14)
Diarrhea	49 (12)	107 (26)
Increased Liver Enzyme Test *	30 (7)	46 (11)
Dyspepsia	30 (7)	23 (6)
Flatulence	26 (6)	22 (5)
Anorexia	25 (6)	29 (7)
Vomiting	24 (6)	32 (8)
Hemic and Lymphatic
Anemia	45 (11)	53 (13)
Metabolic and Nutritional
Peripheral Edema	53 (13)	42 (10)
Weight Loss	30 (7)	39 (10)
Hyperglycemia	26 (6)	27 (7)
Alkaline Phosphatase Increased	22 (5)	24 (6)
Weight Gain	22 (5)	18 (4)
Muscoloskeletal
Bone Pain	37 (9)	43 (11)
Myasthenia	27 (7)	19 (5)
Arthritis	21 (5)	29 (7)
Pathological Fracture	17 (4)	32 (8)
Nervous System
Dizziness	41 (10)	35 (9)
Paresthesia	31 (8)	40 (10)
Insomnia	27 (7)	39 (10)
Anxiety	20 (5)	9 (2)
Depression	16 (4)	33 (8)
Respiratory System
Dyspnea	51 (13)	32 (8)
Cough Increased	33 (8)	24 (6)
Pharyngitis	32 (8)	23 (6)
Bronchitis	24 (6)	22 (3)
Pneumonia	18 (4)	19 (5)
Rhinitis	15 (4)	22 (5)
Skin and Appendages
Rash	35 (9)	30 (7)
Sweating	25 (6)	20 (5)
Urogenital
Nocturia	49 (12)	55 (14)
Hematuria	48 (12)	26 (6)
Urinary Tract Infection	35 (9)	36 (9)
Gynecomastia	36 (9)	30 (7)
Impotence	27 (7)	35 (9)
Breast Pain	23 (6)	15 (4)
Urinary Frequency	23 (6)	29 (7)
Urinary Retention	20 (5)	14 (3)
Urinary Impaired	19 (5)	15 (4)
Urinary Incontinence	15 (4)	32 (8)

Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the Bicalutamide Tablets, USP-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality.

Body as a Whole: Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst

Cardiovascular: Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope

Digestive: Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal Abscess; Gastrointestinal Carcinoma

Metabolic and Nutritional: Edema; BUN Increased; Creatinine Increased; Dehydration; Gout; Hypercholesteremia

Musculoskeletal: Myalgia; Leg Cramps

Nervous: Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness

Respiratory: Lung Disorder; Asthma; Epistaxis; Sinusitis

Skin and Appendages: Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder

Special Senses: Cataract specified

Urogenital: Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder

Abnormal Laboratory Test Values:

Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, and creatinine and decreased hemoglobin and white cell count have been reported in both Bicalutamide Tablets, USP-LHRH analog treated and flutamide-LHRH analog treated patients.

6.2. Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Bicalutamide Tablets, USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Uncommon cases of hypersensitivity reactions, including angioneurotic edema and urticaria [see Contraindications (4.1)], and uncommon cases of interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, have been reported with Bicalutamide Tablets, USP.

Reduction in glucose tolerance, manifesting as diabetes or a loss of glycemic control in those with pre-existing diabetes, has been reported during treatment with LHRH agonists.

7. Drug Interactions ⮝

Clinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic enzymes.

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4 with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Clinical studies have shown that with co-administration of Bicalutamide Tablets, USP, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5 fold (for Cmax) and 1.9 fold (for AUC). Hence, caution should be exercised when Bicalutamide Tablets, USP are co-administered with CYP 3A4 substrates.

In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. Prothrombin times should be closely monitored in patients already receiving coumarin anticoagulants who are started on Bicalutamide Tablets, USP and adjustment of the anticoagulant dose may be necessary.

8. Use In Specific Populations ⮝

8.1. Pregnancy

PREGNANCY CATEGORY X [see Contraindications (4.3)]. Based on its mechanism of action, Bicalutamide Tablets, USP may cause fetal harm when administered to a pregnant woman. Bicalutamide Tablets, USP are contraindicated in women, including those who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

While there are no human data on the use of Bicalutamide Tablets, USP in pregnancy and Bicalutamide Tablets, USP are not for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus.

In animal reproduction studies, male offspring of rats receiving doses of 10 mg/kg/day (approximately 2/3 of clinical exposure at the recommended dose) and above, were observed to have reduced anogenital distance and hypospadias. These pharmacological effects have been observed with other antiandrogens. No other teratogenic effects were observed in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 of clinical exposure at the recommended dose) or rats receiving doses up to 250 mg/kg/day (approximately 2 times the clinical exposure at the recommended dose).

8.3. Nursing Mothers

Bicalutamide Tablets, USP are not indicated for use in women.

8.4. Pediatric Use

The safety and effectiveness of Bicalutamide Tablets, USP in pediatric patients have not been established.

Labeling describing pediatric clinical studies for bicalutamide is approved for AstraZeneca Pharmaceuticals LP's bicalutamide tablet. However, due to AstraZeneca Pharmaceuticals LP's marketing exclusivity rights, a description of those clinical studies is not approved for this bicalutamide labeling.

8.5. Geriatric Use

In two studies in patients given 50 or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.

8.6. Hepatic Impairment

Bicalutamide Tablets, USP should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide Tablets, USP are extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of Bicalutamide Tablets, USP may be delayed and could lead to further accumulation. Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].

No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n=4).

8.7. Renal Impairment

Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.

8.8. Women

Bicalutamide has not been studied in women.

10. Overdosage ⮝

Long-term clinical trials have been conducted with dosages up to 200 mg of Bicalutamide Tablets, USP daily and these dosages have been well tolerated. A single dose of Bicalutamide Tablets, USP that results in symptoms of an overdose considered to be life threatening has not been established.

There is no specific antidote; treatment of an overdose should be symptomatic.

In the management of an overdose with Bicalutamide Tablets, USP, vomiting may be induced if the patient is alert. It should be remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not likely to be helpful since Bicalutamide Tablets, USP are highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

11. Description ⮝

Bicalutamide Tablets, USP contain 50 mg of bicalutamide, a non-steroidal androgen receptor inhibitor with no other known endocrine activity. The chemical name is propanamide, N [4 cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural and empirical formulas are:

Bicalutamide has a molecular weight of 430.37. The pKa' is approximately 12. Bicalutamide is a fine white to off white powder which is practically insoluble in water at 37 C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.

Bicalutamide Tablets, USP are a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.

The inactive ingredients of Bicalutamide Tablets, USP are lactose monohydrate, magnesium stearate, povidone, crospovidone, sodium lauryl sulfate, polyethylene glycol, hypromellose, and titanium dioxide.

12. Clinical Pharmacology ⮝

12.1. Mechanism of Action

Bicalutamide Tablets, USP are a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. 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.

When Bicalutamide Tablets, USP are combined with luteinizing hormone releasing hormone (LHRH) analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with Bicalutamide Tablets, USP as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.

In a subset of patients who have been treated with Bicalutamide Tablets, USP and an LHRH agonist, and who discontinue Bicalutamide Tablets, USP therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.

12.3. Pharmacokinetics

Absorption

Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Co-administration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.

Distribution

Bicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].

Metabolism/Elimination

Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.

Pharmacokinetics of the active enantiomer of Bicalutamide Tablets, USP in normal males and patients with prostate cancer are presented in Table 3.

Table 3.

Parameter	Mean	Standard Deviation
Normal Males (n=30)
Apparent Oral Clearance (L/hr)	0.320	0.103
Single Dose Peak Concentration ( g/mL)	0.768	0.178
Single Dose Time to Peak Concentration (hours)	31.3	14.6
Half-life (days)	5.8	2.29
Patients with Prostate Cancer (n=40)
Css ( g/mL)	8.939	3.504

13. Nonclinical Toxicology ⮝

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is approximately 2/3 human therapeutic concentrations1) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1 1/2 times the human therapeutic concentrations1). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient population.

A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times human therapeutic concentrations1) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 2/3 human therapeutic concentrations1) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man. There were no tumorigenic effects suggestive of genotoxic carcinogenesis.

A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E. coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that Bicalutamide Tablets, USP does not have genotoxic activity.

Administration of Bicalutamide Tablets, USP may lead to inhibition of spermatogenesis. The long-term effects of Bicalutamide Tablets, USP on male fertility have not been studied.

In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations1), the precoital interval and time to successful mating were increased in the first pairing but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11-week period of dosing.

No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and 2 times human therapeutic concentrations, respectively1) or their female offspring were observed. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at all dose levels. Affected male offspring were also impotent.

---

1

Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.

14. Clinical Studies ⮝

14.1. Bicalutamide Tablets, USP 50 mg Daily in Combination with an LHRH-A

In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive Bicalutamide Tablets, USP 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).

In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with Bicalutamide Tablets, USP -LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).

Figure 1 - The Kaplan-Meier probability of death for both antiandrogen treatment groups.

There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2).

Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of Bicalutamide Tablets, USP plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).

Figure 2 - Kaplan-Meier curve for time to progression for both antiandrogen treatment groups.

Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.

14.2 Safety Data from Clinical Studies using Bicalutamide Tablets, USP 150 mg

Bicalutamide Tablets, USP 150 mg are not approved for use either alone or with other treatments.

Two identical multicenter, randomized, open-label trials comparing Bicalutamide Tablets, USP 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer.

Monotherapy M1 Group

Bicalutamide Tablets, USP 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that Bicalutamide Tablets, USP treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the Bicalutamide Tablets, USP treated group compared to that in the castrated group, respectively.

Locally Advanced (T3-4, NX, MO) Group

Bicalutamide Tablets, USP 150 mg daily are not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, MO patients until study completion. In the larger trial (N=352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the Bicalutamide Tablets, USP group and in the smaller trial (N=140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the Bicalutamide Tablets, USP group.

In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for Bicalutamide Tablets, USP 150 mg, a dose that is not approved for use. These are three multicenter, randomized, double-blind, parallel group trials comparing Bicalutamide Tablets, USP 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.

Bicalutamide Tablets, USP 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the Bicalutamide Tablets, USP arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the Bicalutamide Tablets, USP treated patients versus 279 (32.9%) deaths in the placebo treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).

16. How Supplied/storage And Handling  ⮝

1. Bicalutamide tablets 50 mg are white to off-white, round, biconvex, film-coated tablets debossed "B 50" on one side and plain on other side and supplied in bottles of 30 tablets (NDC 60429-177-30), and bottles of 100 tablets (60429-177-01) and bottles of 500 tablets (NDC 60429-177-05)

16.1. Storage and Handling

Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature]

Principal Display Panel ⮝

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62175-132 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP) BICALUTAMIDE 50 mg

Product Characteristics Color WHITE Score no score Shape ROUND Size 8mm Flavor Imprint Code KU;132 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:62175-132-32 30 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077995 07/01/2050

Labeler - Kremers Urban (015411751)

Revised: 2/2010 Document Id: 6182ae5f-a9a9-4011-a186-4c8921671ece 34391-3 Set id: c6e9ca46-4552-4978-9d24-83ef7cadeebe Version: 3 Effective Time: 20100209 Kremers Urban

No Title 1572456491 ⮝

PATIENT INFORMATION

Bicalutamide (BYE-ka-LOO-ta-mide) Tablets

What are bicalutamide tablets?

Bicalutamide tablets are a prescription medicine called an androgen receptor inhibitor, used in combination with luteinizing hormone-releasing hormone (LHRH) medicines to treat Stage D2 metastatic prostate cancer.

Bicalutamide tablets 150 mg daily are not approved for use alone or with other treatments.

It is not known if bicalutamide tablets are safe and effective in children.

Do not take bicalutamide tablets if you are:

• allergic to bicalutamide or any of the ingredients in bicalutamide tablets. See the end of this Patient Information leaflet for a complete list of ingredients in bicalutamide tablets. Get medical help right away if you develop any of the following symptoms of an allergic reaction:
• itching
• swelling of the face, lips or tongue
• hives (raised bumps)
• trouble breathing or swallowing

• female. Bicalutamide tablets are not for use by women.
• pregnant or may become pregnant. Bicalutamide tablets may harm your unborn baby.

Before taking bicalutamide tablets, tell your healthcare provider about all your medical conditions, including if you:

• have liver problems.
• take a medicine to thin your blood. Ask your healthcare provider or pharmacist if you are not sure if your medicine is a blood thinner.
• have diabetes.
• have a female partner who can become pregnant. Males who have a female partner who can become pregnant should use effective birth control during treatment with bicalutamide tablets and for 130 days after the final dose. Talk to your healthcare provider if you have any questions about birth control.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Bicalutamide tablets may affect the way other medicines work and other medicines may affect how bicalutamide tablets work, causing side effects.

Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers when you get a new medicine.

How should I take bicalutamide tablets?

• Take bicalutamide tablets exactly as your healthcare provider tells you to take them.
• Do not stop taking bicalutamide tablets unless your healthcare provider tells you to.
• Bicalutamide tablets can be taken either in the morning or in the evening, but you should take them at the same time every day.
• Your treatment with bicalutamide tablets should start at the same time as your treatment with the LHRH medicine.
• If you miss a bicalutamide tablet dose do not take the missed dose, take the next dose at your next scheduled time. Do not take 2 doses at the same time.
• Bicalutamide tablets can be taken with or without food.
• If you take too many bicalutamide tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid during treatment with bicalutamide tablets?

• Do not drive, operate machinery, or do other dangerous activities until you know how bicalutamide tablets affect you. Bicalutamide tablets can make you sleepy.

• Avoid sunlight, sunlamps, and tanning beds, and consider using sunscreen during treatment with bicalutamide tablets. Some people have had skin sensitivity to sunlight during treatment with bicalutamide tablets.

What are the possible side effects of bicalutamide tablets?

Bicalutamide tablets may cause serious side effects, including:

• Liver problems. Severe liver problems, including liver failure that may need to be treated in a hospital or that may lead to death have happened in people who take bicalutamide tablets. Your healthcare provider should do blood tests to check your liver function before and during treatment with bicalutamide tablets. Tell your healthcare provider right away if you develop any of these symptoms of liver problems during treatment:

yellowing of the skin and eyes (jaundice) right upper stomach pain vomiting loss of appetite fever

dark urine nausea tiredness chills

• Bleeding problems. Serious bleeding problems have happened in people who take bicalutamide tablets in combination with a blood thinner medicine (coumarin anticoagulants). Bleeding problems have happened days to weeks after starting bicalutamide tablet treatment. If you take a blood thinner medicine during treatment with bicalutamide tablets, tell your healthcare provider if you develop any bleeding or unexplained bruising.
• Breast enlargement (gynecomastia) and breast pain.
• Blood sugar problems. Poor blood sugar control can happen in people who take bicalutamide tablets in combination with LHRH medicines.

Your healthcare provider may do blood tests during treatment with bicalutamide tablets to check for side effects.

Your prostate cancer may get worse during treatment with bicalutamide tablets in combination with LHRH medicines. Regular monitoring of your prostate cancer with your healthcare provider is important to determine if your disease is worse.

Tell your healthcare provider if you have trouble breathing with or without a cough or fever. Some people taking bicalutamide tablets get an inflammation in the lungs called interstitial lung disease.

The most common side effects of bicalutamide tablets include:

hot flashes, (short periods of feeling warm and sweating) body pain (including back, pelvis, stomach) feeling weak constipation infection

nausea swelling in your arms, ankles, legs or feet shortness of breath (dyspnea) dizziness diarrhea blood in your urine frequent urination at night a decrease in red blood cells (anemia)

Bicalutamide tablets may have an effect on male fertility which could be reversible. Talk to your healthcare provider if this is a concern for you.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of bicalutamide tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store bicalutamide tablets?

Store bicalutamide tablets at room temperature between 68 to 77 F (20 to 25 C).

Keep bicalutamide tablets and all medicines out of the reach of children.

General information about the safe and effective use of bicalutamide tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use bicalutamide tablets for a condition for which they were not prescribed. Do not give bicalutamide tablets to other people, even if they have the same symptoms that you have. They may harm them. This Patient Information leaflet summarizes the most important information about bicalutamide tablets. If you would like more information about bicalutamide tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bicalutamide tablets that is written for health professionals.

What are the ingredients in bicalutamide tablets?

Active ingredient: bicalutamide, USP

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol 4000, povidone, sodium lauryl sulfate, and titanium dioxide.

For more information call 1-888-838-2872.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. F 12/2017

Bicalutamide 50mg Tablet ⮝

BICALUTAMIDE bicalutamide tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-0765(NDC:0093-0220) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BICALUTAMIDE (UNII: A0Z3NAU9DP) (BICALUTAMIDE - UNII:A0Z3NAU9DP) BICALUTAMIDE 50 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYDEXTROSE (UNII: VH2XOU12IE) POLYETHYLENE GLYCOL 4000 (UNII: 4R4HFI6D95) POVIDONE K30 (UNII: U725QWY32X) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code 93;220 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-0765-1 30 in 1 BOTTLE; Type 0: Not a Combination Product 03/02/2016 2 NDC:71335-0765-2 100 in 1 BOTTLE; Type 0: Not a Combination Product 03/02/2016 3 NDC:71335-0765-3 90 in 1 BOTTLE; Type 0: Not a Combination Product 03/02/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076932 07/06/2009

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(71335-0765) , RELABEL(71335-0765)

Revised: 12/2018 Document Id: 3e1622b3-c323-44ac-ba08-2ef16997f5c3 34391-3 Set id: a420376b-d5c9-4e18-bf1f-1dbf7f5e7baa Version: 3 Effective Time: 20181205 Bryant Ranch Prepack