Birato 250 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 Hypertension, Hypokalemia and Fluid Retention due to Mineralocorticoid Excess under Precautions], Adrenocortical Insufficiency [see Adrenocortical Insufficiency under Precautions], Hepatotoxicity [see Hepatotoxicity under 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 (COU-AA-301 and COU-AA302) 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. Additionally, two other randomized, placebo-controlled trials were conducted in patients with metastatic CRPC. The safety data pooled from patients in the randomized controlled trials constitute the basis for the data presented in the Precautions, Grade 1 to 4 adverse reactions, and Grade 1 to 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 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 to 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 4 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. (See Table 4.)

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Table 5 shows laboratory abnormalities of interest from COU-AA-301. (See Table 5.)

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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 ≥2.5X ULN and patients were excluded if they had liver metastases. Table 6 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. (See Table 6.)

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Table 7 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. (See Table 7.)

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