1 INDICATIONS AND USAGE Abiraterone acetate tablets are indicated in combination with prednisone for the treatment of patients with • Metastatic castration-resistant prostate cancer (CRPC) • Metastatic high-risk castration-sensitive prostate cancer (CSPC) Abiraterone acetate tablets are a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with • metastatic castration-resistant prostate cancer (CRPC).

( 1 ) • metastatic high-risk castration-sensitive prostate cancer (CSPC).

( 1 )

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess [see Warnings and Precautions (5.1) ] .

• Adrenocortical Insufficiency [see Warnings and Precautions (5.2) ] .

• Hepatotoxicity [see Warnings and Precautions (5.3) ] .

• Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride [see Warnings and Precautions (5.4) ] .

The most common adverse reactions (≥ 10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache.

( 6.1 ) The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience 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 clinical practice.

Two randomized placebo-controlled, multicenter clinical trials (COU-AA-301 and COU-AA¬302) enrolled patients who had metastatic CRPC in which abiraterone acetate tablets were administered orally at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms.

Placebo plus prednisone 5 mg twice daily was given to patients on the control arm.

A third randomized placebo-controlled, multicenter clinical trial (LATITUDE) enrolled patients who had metastatic high-risk CSPC in which abiraterone acetate tablets were administered at a dose of 1,000 mg daily in combination with prednisone 5 mg once daily.

Placebos were administered to patients in the control arm.

Additionally, two other randomized, placebo-controlled trials were conducted in patients with metastatic CRPC.

The safety data pooled from 2230 patients in the 5 randomized controlled trials constitute the basis for the data presented in the Warnings and Precautions, Grade 1-4 adverse reactions, and Grade 1-4 laboratory abnormalities.

In all trials, a gonadotropin-releasing hormone (GnRH) analog or prior orchiectomy was required in both arms.

In the pooled data, median treatment duration was 11 months (0.1, 43) for abiraterone acetate tablets-treated patients and 7.2 months (0.1, 43) for placebo-treated patients.

The most common adverse reactions (≥ 10%) that occurred more commonly (> 2%) in the abiraterone acetate tablets arm were fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache.

The most common laboratory abnormalities (> 20%) that occurred more commonly (≥ 2%) in the abiraterone acetate tablets arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.

Grades 3-4 adverse events were reported for 53% of patients in the abiraterone acetate tablets arm and 46% of patients in the placebo arm.

Treatment discontinuation was reported in 14% of patients in the abiraterone acetate tablets arm and 13% of patients in the placebo arm.

The common adverse events (≥ 1%) resulting in discontinuation of abiraterone acetate tablets and prednisone were hepatotoxicity and cardiac disorders.

Deaths associated with treatment-emergent adverse events were reported for 7.5% of patients in the abiraterone acetate tablets arm and 6.6% of patients in the placebo arm.

Of the patients in the abiraterone acetate tablets arm, the most common cause of death was disease progression (3.3%).

Other reported causes of death in ≥ 5 patients included pneumonia, cardio-respiratory arrest, death (no additional information), and general physical health deterioration.

COU-AA-301 Metastatic CRPC Following Chemotherapy COU-AA-301 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy.

Patients were not eligible if AST and/or ALT ≥ 2.5 x ULN in the absence of liver metastases.

Patients with liver metastases were excluded if AST and/or ALT > 5 x ULN.

Table 1 shows adverse reactions on the abiraterone acetate tablets arm in COU-AA-301 that occurred with a ≥ 2% absolute increase in frequency compared to placebo or were events of special interest.

The median duration of treatment with abiraterone acetate tablets with prednisone was 8 months.

Table 1: Adverse Reactions due to Abiraterone Acetate Tablets in COU-AA-301 System/Organ Class Abiraterone Acetate Tablets with Prednisone (N = 791) Placebo with Prednisone (N = 394) All Grades Adverse events graded according to CTCAE version 3.0.

Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.

30 4.2 23 4.1 Muscle discomfort Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness.

26 3.0 23 2.3 General disorders Edema Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema.

27 1.9 18 0.8 Vascular disorders Hot flush 19 0.3 17 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 18 0.6 14 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 12 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 11 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures Includes all fractures with the exception of pathological fracture.

5.9 1.4 2.3 0 Cardiac disorders Arrhythmia Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia.

7.2 1.1 4.6 1.0 Chest pain or chest discomfort Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the abiraterone acetate tablets arm (1.3% vs.

1.1% respectively).

3.8 0.5 2.8 0 Cardiac failure Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased.

2.3 1.9 1.0 0.3 Table 2 shows laboratory abnormalities of interest from COU-AA-301.

Table 2: Laboratory Abnormalities of Interest in COU-AA-301 Abiraterone Acetate Tablets with Prednisone (N = 791) Placebo with Prednisone (N = 394) Laboratory Abnormality All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Hypertriglyceridemia 63 0.4 53 0 High AST 31 2.1 36 1.5 Hypokalemia 28 5.3 20 1.0 Hypophosphatemia 24 7.2 16 5.8 High ALT 11 1.4 10 0.8 High Total Bilirubin 6.6 0.1 4.6 0 COU-AA-302 Metastatic CRPC Prior to Chemotherapy COU-AA-302 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy.

Patients were ineligible if AST and/or ALT ≥ 2.5 x ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the abiraterone acetate tablets arm in COU-AA-302 that occurred in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to placebo.

The median duration of treatment with abiraterone acetate tablets with prednisone was 13.8 months.

Table 3: Adverse Reactions in ≥ 5% of Patients on the Abiraterone Acetate Tablets Arm in COU-AA-302 System/Organ Class Abiraterone Acetate Tablets with Prednisone (N = 542) Placebo with Prednisone (N = 540) All Grades Adverse events graded according to CTCAE version 3.0.

Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39 2.2 34 1.7 Edema Includes terms Edema peripheral, Pitting edema, and Generalized edema.

25 0.4 21 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.

30 2.0 25 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23 0.4 19 0.6 Diarrhea 22 0.9 18 0.9 Dyspepsia 11 0.0 5.0 0.2 Vascular disorders Hot flush 22 0.2 18 0.0 Hypertension 22 3.9 13 3.0 Respiratory, thoracic and mediastinal disorders Cough 17 0.0 14 0.2 Dyspnea 12 2.4 9.6 0.9 Psychiatric disorders Insomnia 14 0.2 11 0.0 Injury, poisoning and procedural complications Contusion 13 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 13 0.0 8.0 0.0 Nasopharyngitis 11 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (> 5%) in the abiraterone acetate tablets arm compared to placebo in COU-AA-302.

Table 4: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Tablets Arm of COU-AA-302 Abiraterone Acetate Tablets with Prednisone (N = 542) Placebo with Prednisone (N = 540) Laboratory Abnormality Grade 1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 % Hematology Lymphopenia 38 8.7 32 7.4 Chemistry Hyperglycemia Based on non-fasting blood draws 57 6.5 51 5.2 High ALT 42 6.1 29 0.7 High AST 37 3.1 29 1.1 Hypernatremia 33 0.4 25 0.2 Hypokalemia 17 2.8 10 1.7 LATITUDE Patients with Metastatic High-Risk CSPC LATITUDE enrolled 1199 patients with newly-diagnosed metastatic, high-risk CSPC who had not received prior cytotoxic chemotherapy.

Patients were ineligible if AST and/or ALT ≥ 2.5 x ULN or if they had liver metastases.

All the patients received GnRH analogs or had prior bilateral orchiectomy during the trial.

The median duration of treatment with abiraterone acetate tablets and prednisone was 24 months.

Table 5 shows adverse reactions on the abiraterone acetate tablets arm that occurred in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to those on the placebos arm.

Table 5: Adverse Reactions in ≥ 5% of Patients on the Abiraterone Acetate Tablets Arm in LATITUDE All patients were receiving an GnRH agonist or had undergone orchiectomy.

System/Organ Class Adverse reaction Abiraterone Acetate Tablets with Prednisone (N = 597) Placebos (N = 602) All Grades Adverse events graded according to CTCAE version 4.0 % Grade 3-4 % All Grades % Grade 3-4 % Vascular disorders Hypertension 37 20 13 10 Hot flush 15 0.0 13 0.2 Metabolism and nutrition disorders Hypokalemia 20 10 3.7 1.3 Investigations Alanine aminotransferase increased Reported as an adverse event or reaction 16 5.5 13 1.3 Aspartate aminotransferase increased 15 4.4 11 1.5 Infections and infestations Urinary tract infection 7.0 1.0 3.7 0.8 Upper respiratory tract infection 6.7 0.2 4.7 0.2 Nervous system disorders Headache 7.5 0.3 5.0 0.2 Respiratory, Thoracic and Mediastinal Disorders Cough Including cough, productive cough, upper airway cough syndrome 6.5 0.0 3.2 0 Table 6 shows laboratory abnormalities that occurred in ≥ 15% of patients, and more frequently (> 5%) in the abiraterone acetate tablets arm compared to placebos.

Table 6: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Tablets Arm of LATITUDE Laboratory Abnormality Abiraterone Acetate Tablets with Prednisone (N = 597) Placebos (N= 602) Grade 1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 % Hematology Lymphopenia 20 4.1 14 1.8 Chemistry Hypokalemia 30 9.6 6.7 1.3 Elevated ALT 46 6.4 45 1.3 Elevated total bilirubin 16 0.2 6.2 0.2 Cardiovascular Adverse Reactions In the combined data of 5 randomized, placebo-controlled clinical studies, cardiac failure occurred more commonly in patients on the abiraterone acetate tablets arm compared to patients on the placebo arm (2.6% versus 0.9%).

Grade 3-4 cardiac failure occurred in 1.3% of patients taking abiraterone acetate tablets and led to 5 treatment discontinuations and 4 deaths.

Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo.

There were no treatment discontinuations and two deaths due to cardiac failure in the placebo group.

In the same combined data, the majority of arrhythmias were grade 1 or 2.

There was one death associated with arrhythmia and three patients with sudden death in the abiraterone acetate tablets arms and five deaths in the placebo arms.

There were 7 (0.3%) deaths due to cardiorespiratory arrest in the abiraterone acetate tablets arms and 2 (0.1%) deaths in the placebo arms.

Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 3 deaths in the abiraterone acetate tablets arms.

6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of abiraterone acetate tablets with prednisone.

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, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death.

Cardiac Disorders: QT prolongation and Torsades de Pointes (observed in patients who developed hypokalemia or had underlying cardiovascular conditions).

Immune System Disorders: Hypersensitivity: anaphylactic reactions (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).