Abirateroneside effects

The following are discussed in more detail in other sections of the labeling:

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess.

Adrenocortical Insufficiency.

Hepatotoxicity.

Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride. The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-233-2001 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 was 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 trial (LATITUDE) enrolled patients who had metastatic high-risk CSPC in which abiraterone acetate was 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 for abiraterone acetate-treated patients and 7.2 months for placebo-treated patients. The most common adverse reactions (≥10%) that occurred more commonly (>2%) in the abiraterone acetate 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 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 arm and 46% of patients in the placebo arm. Treatment discontinuation was reported in 14% of patients in the abiraterone acetate arm and 13% of patients in the placebo arm. The common adverse events (≥1%) resulting in discontinuation of abiraterone acetate 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 arm and 6.6% of patients in the placebo arm. Of the patients in the abiraterone acetate 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 >5x ULN. Table 1 shows adverse reactions on the abiraterone acetate 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 with prednisone was 8 months.

Table 1: Adverse Reactions due to Abiraterone Acetate in COU-AA-301 Abiraterone Acetate with Prednisone (N=791) Placebo with Prednisone (N=394) System/Organ Class Adverse reaction All Grades 1 % Grade 3-4 % All Grades % Grade 3-4 % Musculoskeletal and connective tissue disorders Joint swelling/discomfort 2 30 4.2 23 4.1 Muscle discomfort 3 26 3.0 23

2.3 General disorders

Edema 4 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 5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia 6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort 7 3.8 0.5 2.8 0 Cardiac failure 8 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 COU-AA-301.

Table 2: Laboratory Abnormalities of Interest in COU-AA-301 Abiraterone Acetate 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 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 with prednisone was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in COU-AA-302 Abiraterone Acetate with Prednisone (N=542) Placebo with Prednisone (N=540) System/Organ Class Adverse reaction All Grades 1 % Grade 3-4 % All Grades % Grade 3-4 % General disorders Fatigue 39 2.2 34 1.7 Edema 2 25 0.4 21 1.1 Pyrexia 8.7 0.6 5.9

0.2 Musculoskeletal and connective tissue disorders

Joint swelling/discomfort 3 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 COU-AA-302.

Table 4: Laboratory Abnormalities in >15% of Patients in the Abiraterone Acetate Arm of COU-AA-302 Abiraterone Acetate 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 1 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 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 and prednisone was 24 months. Table 5 shows adverse reactions on the abiraterone acetate 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 Arm in LATITUDE 1 Abiraterone Acetate with Prednisone (N=597) Placebos (N=602) System/Organ Class Adverse reaction All Grades 2 % 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 3 16 5.5 13 1.3 Aspartate aminotransferase increased 3 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 4 6.5 0.0 3.2 0 1 All patients were receiving an GnRH agonist or had undergone orchiectomy. 2 Adverse events graded according to CTCAE version 4.0 3 Reported as an adverse event or reaction 4 Including cough, productive cough, upper airway cough syndrome Table 6 shows laboratory abnormalities that occurred in >15% of patients, and more frequently (>5%) in the abiraterone acetate arm compared to placebos.

Table 6: Laboratory Abnormalities in >15% of Patients in the Abiraterone Acetate Arm of LATITUDE Abiraterone Acetate with Prednisone (N=597) Placebos (N=602) Laboratory Abnormality 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 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 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 arms and five deaths in the placebo arms. There were 7 (0.3%) deaths due to cardiorespiratory arrest in the abiraterone acetate 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 arms.

6.2 Postmarketing

Experience The following additional adverse reactions have been identified during post approval use of abiraterone acetate 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)).