Abiraterone Acetate is indicated in combination with methylprednisolone for the treatment of patients with metastatic castration-resistant prostate cancer. Abiraterone Acetate is a CYP17 inhibitor indicated in combination with methylprednisolone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). ( 1 )
Contraindications
None. None
Warnings and precautions
Mineralocorticoid excess: Closely monitor patients with cardiovascular disease. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. ( 5.1 ) Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations.
( 5.2 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue Abiraterone Acetate as recommended. ( 5.3 ) Increased fractures and mortality in combination with radium Ra 223 dichloride: Use of Abiraterone Acetate plus methylprednisolone in combination with radium Ra 223 dichloride is not recommended. ( 5.4 ) Embryo-Fetal Toxicity: Abiraterone Acetate can cause fetal harm.
Advise males with female partners of reproductive potential to use effective contraception. ( 5.5 , 8.1 , 8.3 ) Hypoglycemia: Severe hypoglycemia has been reported in patients with pre-existing diabetes who are taking medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes and assess if antidiabetic agent dose modifications are required. ( 5.6 )
5.1Hypokalemia, Fluid Retention, and Cardiovascular Adverse
Reactions due to Mineralocorticoid Excess Abiraterone Acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology ( 12.1 )] . Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with Abiraterone Acetate.
In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with abiraterone acetate [see Adverse Reactions ( 6 )] . Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia.
In postmarketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate. The safety of Abiraterone Acetate in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies ( 14 )] .
5.2Adrenocortical Insufficiency
Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking abiraterone acetate and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving abiraterone acetate in combination with a corticosteroid, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from corticosteroids, have corticosteroid dose reductions, or experience unusual stress.
Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with Abiraterone Acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions ( 5.1 )].
5.3Hepatotoxicity
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 two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of 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 occurred in 1% of 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 125 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 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration ( 2.3 )].
Permanently discontinue treatment with 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 ( 2.3 )]. The safety of Abiraterone Acetate re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
5.4Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride Abiraterone
Acetate plus methylprednisolone is not recommended for use in combination with radium Ra 223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus a corticosteroid and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study 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 a corticosteroid in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus a corticosteroid.
5.5Embryo-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 Abirate
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Interactions
CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during Abiraterone Acetate treatment. If a strong CYP3A4 inducer must be co-administered, increase the Abiraterone Acetate dosing frequency ( 2.4 , 7.1 ) CYP2D6 Substrates: Avoid co-administration of Abiraterone Acetate with CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate ( 7.2 )
7.1Effect of Other Drugs on Abiraterone Acetate Strong CYP3A4 Inducers
The co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during Abiraterone Acetate treatment. If a strong CYP3A4 inducer must be co-administered with Abiraterone Acetate, increase the Abiraterone Acetate dosing frequency [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )].
7.2Effect of Abiraterone Acetate on Other Drugs CYP2D6 Substrates
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6. The co-administration of Abiraterone Acetate with CYP2D6 substrates increases the concentration of the CYP2D6 substrate, which may increase the frequency and/or severity of adverse reactions of these substrates. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug in accordance with its Prescribing Information [see Clinical Pharmacology ( 12.3 )] .
CYP2C8 Substrates Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. The co-administration of Abiraterone Acetate with CYP2C8 substrates increases the concentration of the CYP2C8 substrate, which may increase the frequency and/or severity of adverse reactions of these substrates. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate [see Clinical Pharmacology ( 12.3 )] .
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
The safety and efficacy of Abiraterone Acetate have not been established in females. Based on findings from animal studies and the mechanism of action, Abiraterone Acetate can cause fetal harm and potential loss of pregnancy. There are no human data on the use of Abiraterone Acetate in pregnant women. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis, caused adverse developmental effects at maternal exposures of approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose (see Data ).
Data Animal Data In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses > 10 mg/kg/day, decreased fetal ano-genital distance at > 30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day.
Doses > 10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.
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 )] .
The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. ( 6.1 ) The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.FDA.gov/medwatch
6.1Clinical 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 (Study 1 and Study 2) 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 Abiraterone Acetate 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 ≥ 2.5X 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 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 with a corticosteroid was 8 months.
Table 1: Adverse Reactions due to Abiraterone Acetate in Study 1 Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid (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 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
1.3Dyspepsia 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
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 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 with a corticosteroid arm.
Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid(N=394) Laboratory Abnormality 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 in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to placebo.
The median duration of treatment with abiraterone acetate with a corticosteroid was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in Study 2 Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(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
0.2Musculoskeletal
and connective tissue disorders Joint swelling/ discomfort3 30 2.0 25
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
0.0Infections
and infestations Upper respiratory tract infection 13 0.0 8.0
0.0 Nasopharyngitis 11 0.0 8.1
0.0Renal
and urinary disorders Hematuria 10 1.3 5.6
0.6Skin
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 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 Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(N=540) Laboratory Abnormality Grade 1-4 % Grade 3-4 % G
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
ABIRATERONE ACETATE 125MG
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA210308.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
