YONSA SIDE EFFECTS
- Generic Name: abiraterone acetate tablets
- Brand Name: Yonsa
- Drug Class: Antineoplastics, Antiandrogen, Antiandrogens
SIDE EFFECTS
The following are discussed in more detail in other sections of the labeling:
- Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess.
- Adrenocortical Insufficiency.
- Hepatotoxicity.
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 abiraterone acetate was administered at a dose equivalent to 500 mg of YONSA daily in combination with a different corticosteroid twice daily in the active treatment arms. Placebo plus corticosteroid 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 abiraterone acetate 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 abiraterone acetate was 8 months.
Table 1: Adverse Reactions due to Abiraterone Acetate in Study 1
| System Organ Class Adverse Reaction |
Abiraterone Acetate with Corticosteroid (N=791) |
Placebo with Corticosteroid (N=394) |
||
| 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 | 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 | ||||
| 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 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 |
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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 abiraterone acetate arm.
Table 2: Laboratory Abnormalities of Interest in Study 1
| Laboratory Abnormality | Abiraterone Acetate with Corticosteroid (N=791) |
Placebo with Corticosteroid (N=394) |
||
| 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 |
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 abiraterone acetate arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with abiraterone acetate was 13.8 months.
Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in Study 2
| System Organ Class Adverse Reaction |
Abiraterone Acetate with Corticosteroid (N=542) |
Placebo with Corticosteroid (N=540) |
||
| 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 |
| 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 |
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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 Study 2.
Table 4: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Arm of Study 2
| Laboratory Abnormality | Abiraterone Acetate with Corticosteroid (N=542) |
Placebo with Corticosteroid (N=540) |
||
| 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 |
| 1 Based 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 abiraterone acetate compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking abiraterone acetate 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 abiraterone acetate arms and no deaths in the placebo arms. There were 7 (0.5 %) deaths due to cardiorespiratory arrest in the abiraterone acetate 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 abiraterone acetate arms.
Post Marketing Experience
The following additional adverse reactions have been identified during post approval use of abiraterone acetate with a different corticosteroid. 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.
SRC: NLM .