festations
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
Fractures¶ 5.9 1.4 2.3 0
Cardiac disorders
Arrhythmia# 7.2 1.1 4.6 1.0
Chest pain or chest discomfortÞ 3.8 0.5 2.8 0
Cardiac failureß 2.3 1.9 1.0 0.3
Cardiovascular Adverse Reactions:
Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3–4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms.
Hepatotoxicity:
Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions (5.3)]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations.
In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)]. Patients with elevations of ALT or AST > 20X ULN were not re-treated.
Other Adverse Reactions:
Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%).
Laboratory Abnormalities of Interest:
Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical trial. Grade 3–4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.
Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394)
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