Abiraterone Acetate (Page 2 of 7)
In postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2)].
In the combined data of 5 randomized clinical trials, grade 3 to 4 ALT or AST increases (at least 5 x ULN) were reported in 6% of 2,230 patients who received abiraterone acetate, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to ALT and AST increases or abnormal hepatic function occurred in 1.1% of 2,230 patients taking abiraterone acetate. In these clinical trials, no deaths clearly related to abiraterone acetate were reported due to hepatotoxicity events.
Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with abiraterone acetate, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced abiraterone acetate dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt abiraterone acetate treatment and closely monitor liver function.
Re-treatment with abiraterone acetate at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5 x ULN and total bilirubin less than or equal to 1.5 x ULN [see Dosage and Administration (2.4)].
Permanently discontinue abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.4)].
The safety of abiraterone acetate re-treatment of patients who develop AST or ALT greater than or equal to 20 x ULN and/or bilirubin greater than or equal to 10 x ULN is unknown.
5.4 Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride
Abiraterone acetate plus prednisone/prednisolone is not recommended for use in combination with radium 223 dichloride outside of clinical trials.
The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.
At the primary analysis, increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone.
5.5 Embryo-Fetal Toxicity
The safety and efficacy of abiraterone acetate have not been established in females. Based on animal reproductive studies and mechanism of action, abiraterone acetate can cause fetal harm and loss of pregnancy when administered to a pregnant female. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with abiraterone acetate and for 3 weeks after the last dose of abiraterone acetate [see Use in Specific Populations (8.1, 8.3)]. Abiraterone acetate should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)].
Severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2)]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with abiraterone acetate. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
- Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions 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)].
- Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride [see Warnings and Precautions (5.4)].
6.1 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. Another randomized placebo-controlled, multicenter clinical trial (LATITUDE) enrolled patients who had metastatic high-risk CSPC in which abiraterone acetate was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg once daily. 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 2,230 patients in the 5 randomized controlled trials constitute the basis for the data presented in the Warnings and 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 1,195 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 >5 x 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.
Table 1: Adverse Reactions due to Abiraterone Acetat e in COU-AA-301
|System/Organ Class||Abiraterone Acetate with Prednisone (N=791)||Placebo with Prednisone (N=394)|
|Adverse reaction||All Grades1 %||Grade 3 to 4%||All Grades1 %||Grade 3 to 4%|
|Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 Muscle discomfort3||3026||4.2 3.0||23 23||4.1 2.3|
|General disorders Edema4||27||1.9||18||0.8|
|Vascular disorders Hot flush Hypertension||19 8.5||0.3 1.3||176.9||0.3 0.3|
|Gastrointestinal disorders Diarrhea Dyspepsia||186.1||0.6 0||143.3||1.3 0|
|Infections and infestations Urinary tract infection Upper respiratory tract infection||12 5.4||2.1 0||7.1 2.5||0.5 0|
|Respiratory, thoracic and mediastinal disorders Cough||11||0||7.6||0|
|Renal and urinary disorders Urinary frequency Nocturia||7.2 6.2||0.3 0||5.1 4.1||0.3 0|
|Injury, poisoning and procedural complications Fractures5||5.9||1.4||2.3||0|
|Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8||7.2 3.8 2.3||1.1 0.5 1.9||4.6 2.8 1.0||1.0 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 tablets 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 COU-AA-301.
Table 2: Laboratory Abnormalities of Interest i n COU-AA-301
|Abiraterone Acetate with Prednisone (N=791)||Placebo with Prednisone(N=394)|
|Laboratory Abnormality||All Grades(%)||Grade 3 to 4(%)||All Grades(%)||Grade 3 to 4(%)|
|Hypertriglyceridemia High AST Hypokalemia Hypophosphatemia High ALT High Total Bilirubin||63 3128 24 116.6||0.4 2.1 5.3 7.2 1.4 0.1||53 36 201610 4.6||0 1.5 1.0 5.8 0.8 0|
COU-AA-302 : Metastatic CRPC Prior to Chemotherapy
COU-AA-302 enrolled 1,088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5 x 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.
Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in COU-AA-302
|System/Organ Class||Abiraterone Acetate with Prednisone (N=542)||Placebo with Prednisone (N=540)|
|Adverse reaction||All Grades%||Grade 3 to 4%||All Grades%||Grade 3 to 4%|
|General disorders Fatigue Edema2 PyrexiaMusculoskeletal and connective tissue disorders Joint swelling/discomfort3 Groin pain Gastrointestinal disorders Constipation Diarrhea Dyspepsia Vascular disorders Hot flush Hypertension Respiratory, thoracic and mediastinal disorders Cough Dyspnea Psychiatric disorders InsomniaInjury, poisoning and procedural complications Contusion Falls Infections and infestations Upper respiratory tract infection NasopharyngitisRenal and urinary disorders HematuriaSkin and subcutaneous tissue disorders Rash||39 258.7 30 6.6 23 2211 22 22 17 1214 135.9 13 11 10 8.1||2.2 0.4 0.6 2.0 0.4 0.4 0.9 0.0 0.2 3.9 0.0 2.4 0.2 0.0 0.0 0.0 0.0 1.3 0.0||34 21 5.9 25 4.1 19 18 5.0 18 13 149.6119.1 3.3 8.0 8.1 5.6 3.7||1.7 1.1 0.2 2.0 0.7 0.6 0.9 0.2 0.0 3.0 0.2 0.9 0.0 0.0 0.0 0.0 0.0 0.6 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 abiraterone acetate arm compared to placebo in COU-AA-302.
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 to 4 (%)||Grade 3 to 4 (%)||Grade 1 to 4 (%)||Grade 3 to 4 (%)|
|Hematology Lymphopenia Chemistry Hyperglycemia1 High ALT High AST Hypernatremia Hypokalemia||3857 42 37 33 17||8.7 6.5 6.1 3.1 0.4 2.8||32 51 29 29 25 10||7.45.2 0.7 1.1 0.2 1.7|
1 Based on non-fasting blood draws.
LATITUDE: Patients with Metastatic High-risk CSPC
LATITUDE enrolled 1,199 patients with newly-diagnosed metastatic, high-risk CSPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5 x ULN or if they had liver metastases. All the patients received GnRH analogs or had prior bilateral orchiectomy during the trial. The median duration of treatment with abiraterone acetate and prednisone was 24 months.
Table 5 shows adverse reactions on the abiraterone acetate arm that occurred in ≥5% of patients with a ≥2% absolute increase in frequency compared to those on the placebos arm.
Table 5: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in LATTITUDE1
|System/Organ Class Adverse reaction||Abiraterone Acetate with Prednisone (N=597)||Placebos (N=602)|
|All Grades2 %||Grade 3 to 4 %||All Grades %||Grade 3 to 4 %|
|Metabolism and nutrition disorders|
|Alanine aminotransferase increased3||16||5.5||13||1.3|
|Aspartate aminotransferase increased3||15||4.4||11||1.5|
|Infections and infestations|
|Urinary tract infection||7.0||1.0||3.7||0.8|
|Upper respiratory tract infection||6.7||0.2||4.7||0.2|
|Nervous system disorders|
|Respiratory, Thoracic and Mediastinal Disorders|
1 All patients were receiving an GnRH agonist or had undergone orchiectomy.
2 Adverse events graded according to CTCAE version 4.0
3 Reported as an adverse event or reaction
4 Including cough, productive cough, upper airway cough syndrome
Table 6 shows laboratory abnormalities that occurred in >15% of patients, and more frequently (>5%) in the abiraterone acetate arm compared to placebos.
Table 6: Laboratory Abnormalities in >15 % of Patients in the Abiraterone Acetate Arm of LATTITUDE
|Laboratory Abnormality||Abiraterone Acetate with Prednisone (N=597)||Placebos (N=602)|
|Grades 1 to 4 %||Grade 3 to 4 %||Grades 1 to 4 %||Grade 3 to 4 %|
|Elevated total bilirubin||16||0.2||6.2||0.2|
Cardiovascular Adverse Reactions
In the combined data of 5 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.
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