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

  • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see WARNINGS AND PRECAUTIONS].
  • Adrenocortical Insufficiency [see WARNINGS AND PRECAUTIONS].
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS].
  • Increased ZYTIGA Exposures with Food [see WARNINGS AND PRECAUTIONS].

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 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 ZYTIGA was administered 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 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 ≥ 2.5 XULN 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 ZYTIGA 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 ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1

System/Organ Class Adverse reaction ZYTIGA with Prednisone
(N=791)
Placebo with Prednisone
(N=394)
All Grades1 % Grade 3-4 % All Grades % Grade 3-4 %
Musculoskeletal and connective tissue disorders
  Joint swelling/discomfort2 29.5 4.2 23.4 4.1
  Muscle discomfort3 26.2 3.0 23.1 2.3
General disorders
  Edema4 26.7 1.9 18.3 0.8
Vascular disorders
  Hot flush 19.0 0.3 16.8 0.3
  Hypertension 8.5 1.3 6.9 0.3
Gastrointestinal disorders
  Diarrhea 17.6 0.6 13.5 1.3
  Dyspepsia 6.1 0 3.3 0
Infections and infestations
  Urinary tract infection 11.5 2.1 7.1 0.5
  Upper respiratory tract infection 5.4 0 2.5 0
Respiratory, thoracic and mediastinal disorders
  Cough 10.6 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 ZYTIGA 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 ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1

Laboratory Abnormality Abiraterone
(N=791)
Placebo
(N=394)
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Hypertriglyceridemia 62.5 0.4 53.0 0
High AST 30.6 2.1 36.3 1.5
Hypokalemia 28.3 5.3 19.8 1.0
Hypophosphatemia 23.8 7.2 15.7 5.8
High ALT 11.1 1.4 10.4 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 ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥ 5% of Patients on the ZYTIGA Arm in Study 2

System/Organ Class Adverse reaction ZYTIGA with Prednisone
(N=542)
Placebo with Prednisone
(N=540)
All Grades1 % Grade 3-4 % All Grades % Grade 3-4 %
General disorders
  Fatigue 39.1 2.2 34.3 1.7
  Edema2 25.1 0.4 20.7 1.1
  Pyrexia 8.7 0.6 5.9 0.2
Musculoskeletal and connective tissue disorders
  Joint swelling/discomfort3 30.3 2.0 25.2 2.0
  Groin pain 6.6 0.4 4.1 0.7
Gastrointestinal disorders
  Constipation 23.1 0.4 19.1 0.6
  Diarrhea 21.6 0.9 17.8 0.9
  Dyspepsia 11.1 0.0 5.0 0.2
Vascular disorders
  Hot flush 22.3 0.2 18.1 0.0
  Hypertension 21.6 3.9 13.1 3.0
Respiratory, thoracic and mediastinal disorders
  Cough 17.3 0.0 13.5 0.2
  Dyspnea 11.8 2.4 9.6 0.9
Psychiatric disorders
  Insomnia 13.5 0.2 11.3 0.0
Injury, poisoning and procedural complications
  Contusion 13.3 0.0 9.1 0.0
  Falls 5.9 0.0 3.3 0.0
Infections and infestations
  Upper respiratory tract infection 12.7 0.0 8.0 0.0
  Nasopharyngitis 10.7 0.0 8.1 0.0
Renal and urinary disorders
  Hematuria 10.3 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 ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2

Laboratory Abnormality Abiraterone
(N=542)
Placebo
(N=540)
Grade 1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 %
Hematology
  Lymphopenia 38.2 8.7 31.7 7.4
Chemistry
  Hyperglycemia1 56.6 6.5 50.9 5.2
  High ALT 41.9 6.1 29.1 0.7
  High AST 37.3 3.1 28.7 1.1
  Hypernatremia 32.8 0.4 25.0 0.2
  Hypokalemia 17.2 2.8 10.2 1.7
1Based 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 ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA 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 ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA 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 ZYTIGA arms.

Post Marketing Experience

The following additional adverse reactions have been identified during post approval use of ZYTIGA. 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