FDA label 3ac920c6-a831-abcd-e063-6294a90aa82f

5 WARNINGS AND PRECAUTIONS Mineralocorticoid excess: Closely monitor patients with cardiovascular disease. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. ( 5.1 ) Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. ( 5.2 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue YONSA dosing as recommended. ( 5.3 ) Increased fractures and mortality in combination with radium Ra 223 dichloride: Use of YONSA plus methylprednisolone in combination with radium Ra 223 dichloride is not recommended. ( 5.4 ) Embryo-Fetal Toxicity: YONSA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.5 , 8.1 , 8.3 ) Hypoglycemia: Severe hypoglycemia has been reported in patients with pre-existing diabetes who are taking medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes and assess if antidiabetic agent dose modifications are required. ( 5.6 ) 5.1 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess YONSA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology ( 12.1 )] . Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with YONSA. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with abiraterone acetate [see Adverse Reactions ( 6 )] . Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. In postmarketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate. The safety of YONSA in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies ( 14 )] . 5.2 Adrenocortical Insufficiency Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking abiraterone acetate and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving abiraterone acetate in combination with a corticosteroid, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from corticosteroids, have corticosteroid dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with YONSA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions ( 5.1 )]. 5.3 Hepatotoxicity In postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions ( 6.2 )]. In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received abiraterone acetate, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to ALT and AST increases occurred in 1% of patients taking abiraterone acetate. In these clinical trials, no deaths clearly related to abiraterone acetate were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with YONSA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced YONSA dose of 125 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt YONSA treatment and closely monitor liver function. Re-treatment with YONSA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration ( 2.3 )]. Permanently discontinue treatment with YONSA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration ( 2.3 )]. The safety of YONSA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. 5.4 Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride YONSA plus methylprednisolone is not recommended for use in combination with radium Ra 223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus a corticosteroid and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received abiraterone acetate plus a corticosteroid in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus a corticosteroid. 5.5 Embryo-Fetal Toxicity The safety and efficacy of YONSA have not been established in females. Based on animal reproductive studies and mechanism of action, YONSA can cause fetal harm and loss of pregnancy when administered to a pregnant female. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with YONSA and for 3 weeks after the last dose of YONSA [see Use in Specific Populations ( 8.1 , 8.3 ) ]. YONSA should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling ( 16 ) ]. 5.6 Hypoglycemia Severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions ( 7.2 ) ]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with YONSA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

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, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. ( 6.1 ) The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 (Study 1 and Study 2) enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 abiraterone acetate was administered at a dose equivalent to 500 mg of YONSA daily in combination with a different corticosteroid twice daily in the active treatment arms. Placebo plus corticosteroid was given to control patients. The most common adverse drug reactions ( > 10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the abiraterone acetate arm in Study 1 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 with a corticosteroid was 8 months. Table 1: Adverse Reactions due to Abiraterone Acetate in Study 1 Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid (N=394) System Organ Class Adverse Reaction All Grades1 % Grade 3-4 % All Grades % Grade 3-4 % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 30 4.2 23 4.1 Muscle discomfort3 26 3.0 23 2.3 General Disorders Edema4 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 Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 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 arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the abiraterone acetate with a corticosteroid arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid(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 Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the abiraterone acetate arm in Study 2 that occurred in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with abiraterone acetate with a corticosteroid was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in Study 2 Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(N=540) System Organ Class Adverse Reaction All Grades1 % Grade 3-4 % All Grades % Grade 3-4 % General Disorders Fatigue 39 2.2 34 1.7 Edema2 25 0.4 21 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 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 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the abiraterone acetate arm compared to placebo in Study 2. Table 4: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Arm of Study 2 Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(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 Hyperglycemia1 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 1 Based on non-fasting blood draws Cardiovascular Adverse Reactions In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with abiraterone acetate compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking abiraterone acetate and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the abiraterone acetate arms and no deaths in the placebo arms. There were 7 (0.5 %) deaths due to cardiorespiratory arrest in the abiraterone acetate arms and 3 (0.3 %) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the abiraterone acetate arms. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of abiraterone acetate with a different corticosteroid. 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)).

<table width="100%"><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead><tr><th styleCode="Toprule"/><th colspan="2" align="center" styleCode="Toprule">Abiraterone Acetate with Corticosteroid(N=791)</th><th colspan="2" align="center" styleCode="Toprule">Placebo with Corticosteroid (N=394)</th></tr></thead><tbody><tr><td styleCode="Botrule"><paragraph>System Organ Class</paragraph><paragraph>Adverse Reaction</paragraph></td><td align="center" styleCode="Botrule"><paragraph>All Grades1</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>Grade 3-4</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>All Grades</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>Grade 3-4</paragraph><paragraph>%</paragraph></td></tr><tr><td colspan="5"><paragraph>Musculoskeletal and connective tissue disorders</paragraph></td></tr><tr><td><paragraph>Joint swelling/ discomfort2</paragraph></td><td align="center"><paragraph>30</paragraph></td><td align="center"><paragraph>4.2</paragraph></td><td align="center"><paragraph>23</paragraph></td><td align="center"><paragraph>4.1</paragraph></td></tr><tr><td><paragraph>Muscle discomfort3</paragraph></td><td align="center"><paragraph>26</paragraph></td><td align="center"><paragraph>3.0</paragraph></td><td align="center"><paragraph>23</paragraph></td><td align="center"><paragraph>2.3</paragraph></td></tr><tr><td colspan="5"><paragraph>General Disorders</paragraph></td></tr><tr><td><paragraph>Edema4</paragraph></td><td align="center"><paragraph>27</paragraph></td><td align="center"><paragraph>1.9</paragraph></td><td align="center"><paragraph>18</paragraph></td><td align="center"><paragraph>0.8</paragraph></td></tr><tr><td colspan="5"><paragraph>Vascular Disorders</paragraph></td></tr><tr><td><paragraph>Hot Flush</paragraph></td><td align="center"><paragraph>19</paragraph></td><td align="center"><paragraph>0.3</paragraph></td><td align="center"><paragraph>17</paragraph></td><td align="center"><paragraph>0.3</paragraph></td></tr><tr><td><paragraph>Hypertension</paragraph></td><td align="center"><paragraph>8.5</paragraph></td><td align="center"><paragraph>1.3</paragraph></td><td align="center"><paragraph>6.9</paragraph></td><td align="center"><paragraph>0.3</paragraph></td></tr><tr><td colspan="5"><paragraph>Gastrointestinal Disorders</paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td align="center"><paragraph>18</paragraph></td><td align="center"><paragraph>0.6</paragraph></td><td align="center"><paragraph>14</paragraph></td><td align="center"><paragraph>1.3</paragraph></td></tr><tr><td><paragraph>Dyspepsia</paragraph></td><td align="center"><paragraph>6.1</paragraph></td><td align="center"><paragraph>0</paragraph></td><td align="center"><paragraph>3.3</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td colspan="5"><paragraph>Infections and infestations</paragraph></td></tr><tr><td><paragraph>Urinary tract infection</paragraph></td><td align="center"><paragraph>12</paragraph></td><td align="center"><paragraph>2.1</paragraph></td><td align="center"><paragraph>7.1</paragraph></td><td align="center"><paragraph>0.5</paragraph></td></tr><tr><td><paragraph>Upper respiratory tract infection</paragraph></td><td align="center"><paragraph>5.4</paragraph></td><td align="center"><paragraph>0</paragraph></td><td align="center"><paragraph>2.5</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td colspan="5"><paragraph>Respiratory, thoracic and mediastinal disorders</paragraph></td></tr><tr><td><paragraph>Cough</paragraph></td><td align="center"><paragraph>11</paragraph></td><td align="center"><paragraph>0</paragraph></td><td align="center"><paragraph>7.6</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td colspan="5"><paragraph>Renal and urinary disorders</paragraph></td></tr><tr><td><paragraph>Urinary frequency</paragraph></td><td align="center"><paragraph>7.2</paragraph></td><td align="center"><paragraph>0.3</paragraph></td><td align="center"><paragraph>5.1</paragraph></td><td align="center"><paragraph>0.3</paragraph></td></tr><tr><td><paragraph>Nocturia</paragraph></td><td align="center"><paragraph>6.2</paragraph></td><td align="center"><paragraph>0</paragraph></td><td align="center"><paragraph>4.1</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td colspan="5"><paragraph>Injury, poisoning and procedural complications</paragraph></td></tr><tr><td><paragraph>Fractures5</paragraph></td><td align="center"><paragraph>5.9</paragraph></td><td align="center"><paragraph>1.4</paragraph></td><td align="center"><paragraph>2.3</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td colspan="5"><paragraph>Cardiac disorders</paragraph></td></tr><tr><td><paragraph>Arrhythmia6</paragraph></td><td align="center"><paragraph>7.2</paragraph></td><td align="center"><paragraph>1.1</paragraph></td><td align="center"><paragraph>4.6</paragraph></td><td align="center"><paragraph>1.0</paragraph></td></tr><tr><td><paragraph>Chest pain or chest discomfort7</paragraph></td><td align="center"><paragraph>3.8</paragraph></td><td align="center"><paragraph>0.5</paragraph></td><td align="center"><paragraph>2.8</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td styleCode="Botrule"><paragraph>Cardiac failure8</paragraph></td><td align="center" styleCode="Botrule"><paragraph>2.3</paragraph></td><td align="center" styleCode="Botrule"><paragraph>1.9</paragraph></td><td align="center" styleCode="Botrule"><paragraph>1.0</paragraph></td><td align="center" styleCode="Botrule"><paragraph>0.3</paragraph></td></tr><tr><td colspan="5"><paragraph>1 Adverse events graded according to CTCAE version 3.0</paragraph></td></tr><tr><td colspan="5"><paragraph>2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness</paragraph></td></tr><tr><td colspan="5"><paragraph>3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness</paragraph></td></tr><tr><td colspan="5"><paragraph>4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema</paragraph></td></tr><tr><td colspan="5"><paragraph>5 Includes all fractures with the exception of pathological fracture</paragraph></td></tr><tr><td colspan="5"><paragraph>6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia</paragraph></td></tr><tr><td colspan="5"><paragraph>7 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 arm (1.3% vs. 1.1% respectively).</paragraph></td></tr><tr><td colspan="5" styleCode="Botrule"><paragraph>8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased</paragraph></td></tr></tbody></table>

<table width="100%"><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead><tr><th styleCode="Toprule"/><th colspan="2" align="center" styleCode="Toprule Botrule">Abiraterone Acetate with Corticosteroid(N=791)</th><th colspan="2" align="center" styleCode="Toprule Botrule">Placebo with Corticosteroid(N=394)</th></tr></thead><tbody><tr><td styleCode="Botrule"><paragraph>Laboratory Abnormality</paragraph></td><td align="center" styleCode="Botrule"><paragraph>All Grades</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>Grade 3-4</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>All Grades</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>Grade 3-4</paragraph><paragraph>%</paragraph></td></tr><tr><td><paragraph>Hypertriglyceridemia</paragraph></td><td align="center"><paragraph>63</paragraph></td><td align="center"><paragraph>0.4</paragraph></td><td align="center"><paragraph>53</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td><paragraph>High AST</paragraph></td><td align="center"><paragraph>31</paragraph></td><td align="center"><paragraph>2.1</paragraph></td><td align="center"><paragraph>36</paragraph></td><td align="center"><paragraph>1.5</paragraph></td></tr><tr><td><paragraph>Hypokalemia</paragraph></td><td align="center"><paragraph>28</paragraph></td><td align="center"><paragraph>5.3</paragraph></td><td align="center"><paragraph>20</paragraph></td><td align="center"><paragraph>1.0</paragraph></td></tr><tr><td><paragraph>Hypophosphatemia</paragraph></td><td align="center"><paragraph>24</paragraph></td><td align="center"><paragraph>7.2</paragraph></td><td align="center"><paragraph>16</paragraph></td><td align="center"><paragraph>5.8</paragraph></td></tr><tr><td><paragraph>High ALT</paragraph></td><td align="center"><paragraph>11</paragraph></td><td align="center"><paragraph>1.4</paragraph></td><td align="center"><paragraph>10</paragraph></td><td align="center"><paragraph>0.8</paragraph></td></tr><tr><td styleCode="Botrule"><paragraph>High Total Bilirubin</paragraph></td><td align="center" styleCode="Botrule"><paragraph>6.6</paragraph></td><td align="center" styleCode="Botrule"><paragraph>0.1</paragraph></td><td align="center" styleCode="Botrule"><paragraph>4.6</paragraph></td><td align="center" styleCode="Botrule"><paragraph>0</paragraph></td></tr></tbody></table>

<table width="100%"><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead><tr><th styleCode="Toprule"/><th colspan="2" align="center" styleCode="Toprule">Abiraterone Acetate with Corticosteroid(N=542)</th><th colspan="2" align="center" styleCode="Toprule">Placebo with Corticosteroid(N=540)</th></tr></thead><tbody><tr><td styleCode="Botrule"><paragraph>System Organ Class</paragraph><paragraph>Adverse Reaction</paragraph></td><td align="center" styleCode="Botrule"><paragraph>All Grades1</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>Grade 3-4</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>All Grades</paragraph><paragraph>%</paragraph></td><td align="center" styleCode="Botrule"><paragraph>Grade 3-4</paragraph><paragraph>%</paragraph></td></tr><tr><td colspan="5"><paragraph>General Disorders</paragraph></td></tr><tr><td><paragraph>Fatigue</paragraph></td><td align="center"><paragraph>39</paragraph></td><td align="center"><paragraph>2.2</paragraph></td><td align="center"><paragraph>34</paragraph></td><td align="center"><paragraph>1.7</paragraph></td></tr><tr><td><paragraph>Edema2</paragraph></td><td align="center"><paragraph>25</paragraph></td><td align="center"><paragraph>0.4</paragraph></td><td align="center"><paragraph>21</paragraph></td><td align="center"><paragraph>1.1</paragraph></td></tr><tr><td><paragraph>Pyrexia</paragraph></td><td align="center"><paragraph>8.7</paragraph></td><td align="center"><paragraph>0.6</paragraph></td><td align="center"><paragraph>5.9</paragraph></td><td align="center"><paragraph>0.2</paragraph></td></tr><tr><td colspan="5"><paragraph>Musculoskeletal and connective tissue disorders</paragraph></td></tr><tr><td><paragraph>Joint swelling/ discomfort3</paragraph></td><td align="center"><paragraph>30</paragraph></td><td align="center"><paragraph>2.0</paragraph></td><td align="center"><paragraph>25</paragraph></td><td align="center"><paragraph>2.0</paragraph></td></tr><tr><td><paragraph>Groin Pain</paragraph></td><td align="center"><paragraph>6.6</paragraph></td><td align="center"><paragraph>0.4</paragraph></td><td align="center"><paragraph>4.1</paragraph></td><td align="center"><paragraph>0.7</paragraph></td></tr><tr><td colspan="5"><paragraph>Gastrointestinal Disorders</paragraph></td></tr><tr><td><paragraph>Constipation</paragraph></td><td align="center"><paragraph>23</paragraph></td><td align="center"><paragraph>0.4</paragraph></td><td align="center"><paragraph>19</paragraph></td><td align="center"><paragraph>0.6</paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td align="center"><paragraph>22</paragraph></td><td align="center"><paragraph>0.9</paragraph></td><td align="center"><paragraph>18</paragraph></td><td align="center"><paragraph>0.9</paragraph></td></tr><tr><td><paragraph>Dyspepsia</paragraph></td><td align="center"><paragraph>11</paragraph></td><td align="center"><paragraph>0.0</paragraph></td><td align="center"><paragraph>5.0</paragraph></td><td align="center"><paragraph>0.2</paragraph></td></tr><tr><td colspan="5"><paragraph>Vascular Disorders</paragraph></td></tr><tr><td><paragraph>Hot Flush</paragraph></td><td align="center"><paragraph>22</paragraph></td><td align="center"><paragraph>0.2</paragraph></td><td align="center"><paragraph>18</paragraph></td><td align="center"><paragraph>0.0</paragraph></td></tr><tr><td><paragraph>Hypertension</paragraph></td><td align="center"><paragraph>22</paragraph></td><td align="center"><paragraph>3.9</paragraph></td><td align="center"><paragraph>13</paragraph></td><td align="center"><paragraph>3.0</paragraph></td></tr><tr><td colspan="5"><paragraph>Respiratory, thoracic and mediastinal disorders</paragraph></td></tr><tr><td><paragraph>Cough</paragraph></td><td align="center"><paragraph>17</paragraph></td><td align="center"><paragraph>0.0</paragraph></td><td align="center"><paragraph>14</paragraph></td><td align="center"><paragraph>0.2</paragraph></td></tr><tr><td><paragraph>Dyspnea</paragraph></td><td align="center"><paragraph>12</paragraph></td><td align="center"><paragraph>2.4</paragraph></td><td align="center"><paragraph>9.6</paragraph></td><td align="center"><paragraph>0.9</paragraph></td></tr><tr><td colspan="5"><paragraph>Psychiatric Disorders</paragraph></td></tr><tr><td><paragraph>Insomnia</paragraph></td><td align="center"><paragraph>14</paragraph></td><td align="center"><paragraph>0.2</paragraph></td><td align="center"><paragraph>11</paragraph></td><td align="center"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5"><paragraph>Injury, poisoning and procedural complications</paragraph></td></tr><tr><td><paragraph>Contusion</paragraph></td><td align="center"><paragraph>13</paragraph></td><td align="center"><paragraph>0.0</paragraph></td><td align="center"><paragraph>9.1</paragraph></td><td align="center"><paragraph>0.0</paragraph></td></tr><tr><td><paragraph>Falls</paragraph></td><td align="center"><paragraph>5.9</paragraph></td><td align="center"><paragraph>0.0</paragraph></td><td align="center"><paragraph>3.3</paragraph></td><td align="center"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5"><paragraph>Infections and infestations</paragraph></td></tr><tr><td><paragraph>Upper respiratory tract infection</paragraph></td><td align="center"><paragraph>13</paragraph></td><td align="center"><paragraph>0.0</paragraph></td><td align="center"><paragraph>8.0</paragraph></td><td align="center"><paragraph>0.0</paragraph></td></tr><tr><td><paragraph>Nasopharyngitis</paragraph></td><td align="center"><paragraph>11</paragraph></td><td align="center"><paragraph>0.0</paragraph></td><td align="center"><paragraph>8.1</paragraph></td><td align="center"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5"><paragraph>Renal and urinary disorders</paragraph></td></tr><tr><td><paragraph>Hematuria</paragraph></td><td align="center"><paragraph>10</paragraph></td><td align="center"><paragraph>1.3</paragraph></td><td align="center"><paragraph>5.6</paragraph></td><td align="center"><paragraph>0.6</paragraph></td></tr><tr><td colspan="5"><paragraph>Skin and subcutaneous tissue disorders</paragraph></td></tr><tr><td styleCode="Botrule"><paragraph>Rash</paragraph></td><td align="center" styleCode="Botrule"><paragraph>8.1</paragraph></td><td align="center" styleCode="Botrule"><paragraph>0.0</paragraph></td><td align="center" styleCode="Botrule"><paragraph>3.7</paragraph></td><td align="center" styleCode="Botrule"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5"><paragraph>1 Adverse events graded according to CTCAE version 3.0</paragraph></td></tr><tr><td colspan="5"><paragraph>2 Includes terms Edema peripheral, Pitting edema, and Generalized edema</paragraph></td></tr><tr><td colspan="5" styleCode="Botrule"><paragraph>3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness</paragraph></td></tr></tbody></table>