Abiraterone Acetate (Page 2 of 7)

6 ADVERSE REACTIONS

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 (5.1)].
•Adrenocortical Insufficiency [see Warnings and Precautions (5.2)].
•Hepatotoxicity [see Warnings and Precautions (5.3)].

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical 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. Another randomized placebo-controlled, multicenter clinical trial enrolled patients who had another indication in which abiraterone acetate was administered in combination with prednisone. 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 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-treated patients and 7.2 months (0.1, 43) for placebo-treated patients. The most common adverse reactions (≥10%) that occured 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 patient 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 ≥2.5X 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 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.

1 Adverse events graded according to CTCAE version 3.02 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema5 Includes all fractures with the exception of pathological fracture6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia7 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 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 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 1.8 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

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)
LaboratoryAbnormality 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× 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.

1 Adverse events graded according to CTCAE version 3.02 Includes terms Edema peripheral, Pitting edema, and Generalized edema3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness
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 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

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.

1 Based on non-fasting blood draws
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
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

Cardiovascular Adverse Reactions:
In the combined data of 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.

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