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| Product NDC Code | 43598-468 | ||||||
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| Drug Name | Abiraterone acetate |
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| Type | Generic | ||||||
| Pharm Class | Cytochrome P450 17A1 Inhibitor [EPC], Cytochrome P450 17A1 Inhibitors [MoA], Cytochrome P450 2C8 Inhibitors [MoA], Cytochrome P450 2D6 Inhibitors [MoA] |
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| Route | ORAL | ||||||
| Dosage Form | TABLET | ||||||
| RxCUI drug identifier | 1100075, 1918042 |
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| Application Number | ANDA208416 | ||||||
| Labeler Name | Dr. Reddys Laboratories Inc | ||||||
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| Check if available Online | Get Medication Prices online with Discount |
Overdosage of Abiraterone Acetate
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Human experience of overdose with abiraterone acetate is limited. There is no specific antidote. In the event of an overdose, stop abiraterone acetate, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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) ]. The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. ( 6.1 ) The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Grades 1 % Grade 3 to 4% All Grades 1 % Grade 3 to 4% Musculoskeletal and connective tissue disorders Joint swelling/discomfort 2 Muscle discomfort 3 30 26 4.2 3.0 23 23 4.1 2.3 General disorders Edema 4 27 1.9 18 0.8 Vascular disorders Hot flush Hypertension 19 8.5 0.3 1.3 17 6.9 0.3 0.3 Gastrointestinal disorders Diarrhea Dyspepsia 18 6.1 0.6 0 14 3.3 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 Fractures 5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia 6 Chest pain or chest discomfort 7 Cardiac failure 8 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 31 28 24 11 6.6 0.4 2.1 5.3 7.2 1.4 0.1 53 36 20 16 10 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 Edema 2 Pyrexia Musculoskeletal and connective tissue disorders Joint swelling/discomfort 3 Groin pain Gastrointestinal disorders Constipation Diarrhea Dyspepsia Vascular disorders Hot flush Hypertension Respiratory, thoracic and mediastinal disorders Cough Dyspnea Psychiatric disorders Insomnia Injury, poisoning and procedural complications Contusion Falls Infections and infestations Upper respiratory tract infection Nasopharyngitis Renal and urinary disorders Hematuria Skin and subcutaneous tissue disorders Rash 39 25 8.7 30 6.6 23 22 11 22 22 17 12 14 13 5.9 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 14 9.6 11 9.1 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 Hyperglycemia 1 High ALT High AST Hypernatremia Hypokalemia 38 57 42 37 33 17 8.7 6.5 6.1 3.1 0.4 2.8 32 51 29 29 25 10 7.4 5.2 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 LATTITUDE 1 System/Organ Class Adverse reaction Abiraterone Acetate with Prednisone (N=597) Placebos (N=602) All Grades 2 % Grade 3 to 4 % All Grades % Grade 3 to 4 % Vascular disorders Hypertension 37 20 13 10 Hot flush 15 0.0 13 0.2 Metabolism and nutrition disorders Hypokalemia 20 10 3.7 1.3 Investigations Alanine aminotransferase increased 3 16 5.5 13 1.3 Aspartate aminotransferase increased 3 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 Headache 7.5 0.3 5.0 0.2 Respiratory, Thoracic and Mediastinal Disorders Cough4 6.5 0.0 3.2 0 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 % Hematology Lymphopenia 20 4.1 14 1.8 Chemistry Hypokalemia 30 9.6 6.7 1.3 Elevated ALT 46 6.4 45 1.3 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. 6.2 Postmarketing Experien ce 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. Cardiac Disorders: QT prolongation and Torsades de Pointes (observed in patients who developed hypokalemia or had underlying cardiovascular conditions). Immune System Disorders – Hypersensitivity: anaphylactic reactions (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).
| Adverse reaction | All Grades1% | Grade 3 to 4% | All Grades1% | Grade 3 to 4% |
| 30 26 | 4.2 3.0 | 23 23 | 4.1 2.3 | |
| 27 | 1.9 | 18 | 0.8 | |
| 19 8.5 | 0.3 1.3 | 17 6.9 | 0.3 0.3 | |
| 18 6.1 | 0.6 0 | 14 3.3 | 1.3 0 | |
| 12 5.4 | 2.1 0 | 7.1 2.5 | 0.5 0 | |
| 11 | 0 | 7.6 | 0 | |
| 7.2 6.2 | 0.3 0 | 5.1 4.1 | 0.3 0 | |
| 5.9 | 1.4 | 2.3 | 0 | |
| 7.2 3.8 2.3 | 1.1 0.5 1.9 | 4.6 2.8 1.0 | 1.0 0 0.3 | |
| 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 31 28 24 11 6.6 | 0.4 2.1 5.3 7.2 1.4 0.1 | 53 36 20 16 10 4.6 | 0 1.5 1.0 5.8 0.8 0 |
| Adverse reaction | All Grades% | Grade 3 to 4% | All Grades% | Grade 3 to 4% |
| 39 25 8.7 30 6.6 23 22 11 22 22 17 12 14 13 5.9 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 14 9.6 11 9.1 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 | |
| Laboratory Abnormality | Grade 1 to 4 (%) | Grade 3 to 4 (%) | Grade 1 to 4 (%) | Grade 3 to 4 (%) |
| 38 57 42 37 33 17 | 8.7 6.5 6.1 3.1 0.4 2.8 | 32 51 29 29 25 10 | 7.4 5.2 0.7 1.1 0.2 1.7 |
| All Grades2 % | Grade 3 to 4 % | All Grades % | Grade 3 to 4 % | |
| Hypertension | 37 | 20 | 13 | 10 |
| Hot flush | 15 | 0.0 | 13 | 0.2 |
| Hypokalemia | 20 | 10 | 3.7 | 1.3 |
| Alanine aminotransferase increased3 | 16 | 5.5 | 13 | 1.3 |
| Aspartate aminotransferase increased3 | 15 | 4.4 | 11 | 1.5 |
| Urinary tract infection | 7.0 | 1.0 | 3.7 | 0.8 |
| Upper respiratory tract infection | 6.7 | 0.2 | 4.7 | 0.2 |
| Headache | 7.5 | 0.3 | 5.0 | 0.2 |
| Cough4 | 6.5 | 0.0 | 3.2 | 0 |
| Laboratory Abnormality | ||||
| Grades 1 to 4 % | Grade 3 to 4 % | Grades 1 to 4 % | Grade 3 to 4 % | |
| Hematology | ||||
| Lymphopenia | 20 | 4.1 | 14 | 1.8 |
| Chemistry | ||||
| Hypokalemia | 30 | 9.6 | 6.7 | 1.3 |
| Elevated ALT | 46 | 6.4 | 45 | 1.3 |
| Elevated total bilirubin | 16 | 0.2 | 6.2 | 0.2 |
Abiraterone Acetate Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG 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. ( 2.5 , 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 ) 7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. In a dedicated drug interaction trial, 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, increase the abiraterone acetate dosing frequency [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology ( 12.3 )]. 7.2 Effects of Abiraterone on Drug Metabolizing Enzymes Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology ( 12.3 )]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. 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 ) and Warnings and Precautions ( 5.6 )].
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions ( 5.1 )]. Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone acetate decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial. It is not necessary to monitor the effect of abiraterone acetate on serum testosterone levels. Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients. 12.2 Pharmacodynamics Cardiac Electrophysiology In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received abiraterone acetate orally at a dose of 1,000 mg once daily at least 1 hour before or 2 hours after a meal in combination with prednisone 5 mg orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in the QTc interval (i.e., >20 ms) from baseline. However, small increases in the QTc interval (i.e., <10 ms) due to abiraterone acetate cannot be excluded due to study design limitations. 12.3 Pharmacokinetics Following administration of abiraterone acetate, the pharmacokinetics of abiraterone have been studied in healthy subjects and in patients with metastatic CRPC. In vivo , abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels (<0.2 ng/mL) in >99% of the analyzed samples. Absorption Following oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate. At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean ± SD) of C max were 226 ± 178 ng/mL and of AUC were 993 ± 639 ng.hr/mL. No major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 mg (8% increase in the mean AUC). Effect of Food Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. In healthy subjects abiraterone C max and AUC 0-∞ were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal compared to overnight fasting. Abiraterone AUC0-∞ was approximately 7-fold or 1.6-fold higher, respectively, when a single dose of abiraterone acetate was administered 2 hours after or 1 hour before a medium fat meal (25% fat, 491 calories) compared to overnight fasting. Systemic exposures of abiraterone in patients with metastatic CRPC, after repeated dosing of abiraterone acetate were similar when abiraterone acetate was taken with low-fat meals for 7 days and increased approximately 2-fold when taken with high-fat meals for 7 days compared to when taken at least 2 hours after a meal and at least 1 hour before a meal for 7 days. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. Distribution Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ± 13,358 L. Elimination In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Metabolism Following oral administration of 14 C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved in the formation of abiraterone sulphate. Excretion In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14 C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively). Specific Populations Patients with Hepatic Impairment The pharmacokinetics of abiraterone was examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. Systemic exposure to abiraterone after a single oral 1,000 mg dose given under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment. Patients with Renal Impairment The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg abiraterone acetate dose was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function. Drug Interaction Studies Clinical Studies Effect of Other Drugs on Abiraterone Acetate Strong CYP3A4 inducers: In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong CYP3A4 inhibitors: Co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effect of Abiraterone Acetate on Other Drugs CYP2D6 substrates: The C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8-and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold. CYP1A2 substrates: When abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) was given with a single dose of 100 mg theophylline (CYP1A2 substrate), no increase in systemic exposure of theophylline was observed. CYP2C8 substrates: The AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given to healthy subjects with a single dose of 1,000 mg abiraterone acetate. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5. Transporter Systems: In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. In vitro , abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1. There are no clinical data available to confirm transporter based interaction.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions ( 5.1 )]. Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone acetate decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial. It is not necessary to monitor the effect of abiraterone acetate on serum testosterone levels. Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Following administration of abiraterone acetate, the pharmacokinetics of abiraterone have been studied in healthy subjects and in patients with metastatic CRPC. In vivo , abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels (<0.2 ng/mL) in >99% of the analyzed samples. Absorption Following oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate. At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean ± SD) of C max were 226 ± 178 ng/mL and of AUC were 993 ± 639 ng.hr/mL. No major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 mg (8% increase in the mean AUC). Effect of Food Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. In healthy subjects abiraterone C max and AUC 0-∞ were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal compared to overnight fasting. Abiraterone AUC0-∞ was approximately 7-fold or 1.6-fold higher, respectively, when a single dose of abiraterone acetate was administered 2 hours after or 1 hour before a medium fat meal (25% fat, 491 calories) compared to overnight fasting. Systemic exposures of abiraterone in patients with metastatic CRPC, after repeated dosing of abiraterone acetate were similar when abiraterone acetate was taken with low-fat meals for 7 days and increased approximately 2-fold when taken with high-fat meals for 7 days compared to when taken at least 2 hours after a meal and at least 1 hour before a meal for 7 days. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures. Distribution Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ± 13,358 L. Elimination In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Metabolism Following oral administration of 14 C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved in the formation of abiraterone sulphate. Excretion In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14 C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively). Specific Populations Patients with Hepatic Impairment The pharmacokinetics of abiraterone was examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. Systemic exposure to abiraterone after a single oral 1,000 mg dose given under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment. Patients with Renal Impairment The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg abiraterone acetate dose was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function. Drug Interaction Studies Clinical Studies Effect of Other Drugs on Abiraterone Acetate Strong CYP3A4 inducers: In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong CYP3A4 inhibitors: Co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effect of Abiraterone Acetate on Other Drugs CYP2D6 substrates: The C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8-and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold. CYP1A2 substrates: When abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) was given with a single dose of 100 mg theophylline (CYP1A2 substrate), no increase in systemic exposure of theophylline was observed. CYP2C8 substrates: The AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given to healthy subjects with a single dose of 1,000 mg abiraterone acetate. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5. Transporter Systems: In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. In vitro , abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1. There are no clinical data available to confirm transporter based interaction.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS None. None ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Abiraterone acetate USP, the active ingredient of abiraterone acetate tablets, USP is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each abiraterone acetate tablet, USP contains 250 mg or 500 mg of abiraterone acetate USP. Abiraterone acetate USP is designated chemically as (3β)17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is: Abiraterone acetate USP is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C 26 H 33 NO 2 and it has a molecular weight of 391.55. Abiraterone acetate USP is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. Abiraterone acetate tablets are available in 250 mg and 500 mg film-coated tablets with the following inactive ingredients: 250 mg film-coated tablets: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate and titanium dioxide. 500 mg film-coated tablets: colloidal silicon dioxide, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, silicified microcrystalline cellulose, sodium lauryl sulfate, talc and titanium dioxide. FDA approved dissolution test specifications differ from USP.
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Metastatic castration-resistant prostate cancer: • Abiraterone acetate tablets 1,000 mg orally once daily with prednisone 5 mg orally twice daily. ( 2.1 ) Metastatic castration-sensitive prostate cancer: • Abiraterone acetate tablets 1,000 mg orally once daily with prednisone 5 mg orally once daily. ( 2.2 ) Patients receiving abiraterone acetate tablets should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Abiraterone acetate tablets must be taken as a single dose once daily on an empty stomach. Do not eat food 2 hours before and 1 hour after taking abiraterone acetate tablets. The tablets must be swallowed whole with water. Do not crush or chew tablets.( 2.3) Dose Modification: • For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the abiraterone acetate tablets starting dose to 250 mg once daily. ( 2.4 ) • For patients who develop hepatotoxicity during treatment, hold abiraterone acetate tablets until recovery. Retreatment may be initiated at a reduced dose. Abiraterone acetate tablets should be discontinued if patients develop severe hepatotoxicity. ( 2.4 ) 2.1 Recommended Dose for Metastatic CRPC The recommended dose of abiraterone acetate tablets is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with prednisone 5 mg orally twice daily. 2.2 Recommended Dose for Metastatic High-risk CSPC The recommended dose of abiraterone acetate tablets is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with prednisone 5 mg administered orally once daily. 2.3 Important Administration Instructions Patients receiving abiraterone acetate tablets should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Abiraterone acetate tablets must be taken as a single dose once daily on an empty stomach. Do not eat food 2 hours before and 1 hour after taking abiraterone acetate tablets. The tablets must be swallowed whole with water. Do not crush or chew tablets. 2.4 Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity Hepatic Impairment In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of abiraterone acetate tablets to 250 mg once daily. In patients with moderate hepatic impairment monitor 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. If elevations in ALT and/or AST greater than 5 x upper limit of normal (ULN) or total bilirubin greater than 3 x ULN occur in patients with baseline moderate hepatic impairment, discontinue abiraterone acetate tablets and do not re-treat patients with abiraterone acetate tablets [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. Do not use abiraterone acetate tablets in patients with baseline severe hepatic impairment (Child-Pugh Class C). Hepatotoxicity For patients who develop hepatotoxicity during treatment with abiraterone acetate tablets (ALT and/or AST greater than 5 x ULN or total bilirubin greater than 3 x ULN), interrupt treatment with abiraterone acetate tablets [see Warnings and Precautions ( 5.3 )]. Treatment may be restarted at a reduced dose of 750 mg once daily following 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. For patients who resume treatment, monitor serum transaminases and bilirubin at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at a reduced dose of 500 mg once daily following 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. If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with abiraterone acetate tablets. Permanently discontinue abiraterone acetate tablets 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 Warnings and Precautions ( 5.3 )]. 2.5 Dose Modification Guidelines for Strong CYP3A4 Inducers Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abiraterone acetate tablets treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate tablets dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer is discontinued [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Abiraterone acetate tablets USP, 250 mg are white to off-white, oval shaped, film coated tablets debossed with "35" on one side and plain on other side. Abiraterone acetate tablets USP, 500 mg are pinkish brown color, oval shaped, biconvex, film coated tablets, debossed with "46" on one side and plain other side and free from physical defects. Film-Coated Tablets: 250 mg and 500 mg (3)
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Abiraterone acetate tablets are indicated in combination with prednisone for the treatment of patients with Metastatic castration-resistant prostate cancer (CRPC) Metastatic high-risk castration-sensitive prostate cancer (CSPC) Abiraterone acetate tablet is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). ( 1) metastatic high-risk castration-sensitive prostate cancer (CSPC). ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.Abiraterone Acetate Abiraterone Acetate ABIRATERONE ACETATE ABIRATERONE SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE Polyethylene Glycol, Unspecified POVIDONE SODIUM LAURYL SULFATE TITANIUM DIOXIDE white to off white 35 Abiraterone Acetate Abiraterone Acetate ABIRATERONE ACETATE ABIRATERONE SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE Polyethylene Glycol, Unspecified POVIDONE SODIUM LAURYL SULFATE TITANIUM DIOXIDE POLYVINYL ALCOHOL, UNSPECIFIED FERROSOFERRIC OXIDE FERRIC OXIDE RED TALC 46 pinkish brown color structure figure1 figure2 figure3 container figure4 container1 Carton2 carton
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and/or Pharmacology A dose-dependent increase in cataracts was observed in rats after daily oral abiraterone acetate administration for 26 weeks starting at ≥50 mg/kg/day (similar to the human clinical exposure based on AUC). In a 39-week monkey study with daily oral abiraterone acetate administration, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC).
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. Abiraterone acetate and abiraterone was not mutagenic in an in vitro microbial mutagenesis (Ames) assay or clastogenic in an in vitro cytogenetic assay using primary human lymphocytes or an in vivo rat micronucleus assay. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans. In a fertility study in male rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in animals dosed for 4 weeks at ≥30 mg/kg/day orally. Mating of untreated females with males that received 30 mg/kg/day oral abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. In a fertility study in female rats, animals dosed orally for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area. In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. Abiraterone acetate and abiraterone was not mutagenic in an in vitro microbial mutagenesis (Ames) assay or clastogenic in an in vitro cytogenetic assay using primary human lymphocytes or an in vivo rat micronucleus assay. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans. In a fertility study in male rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in animals dosed for 4 weeks at ≥30 mg/kg/day orally. Mating of untreated females with males that received 30 mg/kg/day oral abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. In a fertility study in female rats, animals dosed orally for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area. In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. 13.2 Animal Toxicology and/or Pharmacology A dose-dependent increase in cataracts was observed in rats after daily oral abiraterone acetate administration for 26 weeks starting at ≥50 mg/kg/day (similar to the human clinical exposure based on AUC). In a 39-week monkey study with daily oral abiraterone acetate administration, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC).
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PACKAGE LABEL PRINCIPAL DISPLAY PANEL SECTION 250 mg - Container: Unvarnished Area consists of: 2D Barcode, Lot Number, Expiry Date and Serial Number.
250 mg Carton:
500 mg Container:
500 mg Carton:
Abiraterone Acetate: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions Inform patients that abiraterone acetate is associated with hypertension, hypokalemia, and peripheral edema that may lead to QT prolongation and Torsades de Pointes in patients who develop hypokalemia while taking abiraterone acetate tablets. Advise patients that their blood pressure, serum potassium and signs and symptoms of fluid retention will be monitored clinically at least monthly. Advise patients to adhere to corticosteroids and to report symptoms of hypertension, hypokalemia, or edema to their healthcare provider [see Warnings and Precautions (5.1) ]. Adrenocortical Insufficiency Inform patients that abiraterone acetate with prednisone is associated with adrenal insufficiency. Advise patients to report symptoms of adrenocortical insufficiency to their healthcare provider [see Warnings and Precautions ( 5.2 )]. Hepatotoxicity Inform patients that abiraterone acetate is associated with severe hepatotoxicity. Inform patients that their liver function will be monitored using blood tests. Advise patients to immediately report symptoms of hepatotoxicity to their healthcare provider [see Warnings and Precautions ( 5.3 )] Hypoglycemia Inform patients that severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes who were receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide – antidiabetic drugs. Advise patients with diabetes to monitor glucose levels during and after treatment with abiraterone acetate [see Warnings and Precautions ( 5.6 ) and Drug Interactions ( 7.2 )]. Use in Combination with Radium Ra 223 Dichloride Advise patients that radium Ra 223 dichloride showed an increase in mortality and an increased rate of fracture when used in combination with abiraterone acetate plus prednisone/prednisolone. Inform patients to speak with their healthcare provider about any other medications or treatment they are currently taking for prostate cancer [see Warnings and Precautions (5.4) ]. Dosing and Administration Inform patients that abiraterone acetate tablets are taken once daily with prednisone twice daily (according to their healthcare provider’s instructions) and to not interrupt or stop either of these medications without consulting their healthcare provider. Inform patients receiving GnRH therapy that they need to maintain this treatment during the course of treatment with abiraterone acetate tablets. Instruct patients to take abiraterone acetate tablets as a single dose once daily on an empty stomach . Instruct patients to not eat food 2 hours before and 1 hour after taking abiraterone acetate tablets. Abiraterone acetate tablets taken with food causes increased exposure and may result in adverse reactions. Instruct patients to swallow tablets whole with water and not to crush or chew the tablets [see Dosage and Administration ( 2.3 )]. Inform patients that if they miss a dose of abiraterone acetate tablets or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, inform patients to contact their healthcare provider [see Dosage and Administration ( 2.3 )]. Embryo-Fetal Toxicity Inform patients that abiraterone acetate may harm a developing fetus and can cause loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of abiraterone acetate [see Use in Specific Populations (8.1) ]. Advise females who are pregnant or women who may be pregnant not to handle abiraterone acetate 250 mg tablets if broken, crushed, or damaged without protection, e.g., gloves [see Use in Specific Populations (8.1) and How Supplied/Storage and Handling (16) ]. Infertility Advise male patients that abiraterone acetate may impair fertility [see Use in Specific Populations ( 8.3 )]. R X Only Distributor: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 Made in India Revised: 03/2023
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.PATIENT INFORMATION Abiraterone Acetate ( a” bir a’ ter one as’ e tate) Tablets, USP What are abiraterone acetate tablets? Abiraterone acetate tablets are a prescription medicine that is used along with prednisone. Abiraterone acetate tablets are used to treat men with prostate cancer that has spread to other parts of the body. It is not known if abiraterone acetate tablets are safe and effective in females or children. Before taking abiraterone acetate tablets, tell your healthcare provider about all of your medical conditions, including if you: have heart problems have liver problems have diabetes have a history of adrenal problems have a history of pituitary problems are receiving any other treatment for prostate cancer are pregnant or plan to become pregnant. Abiraterone acetate tablets can cause harm to your unborn baby and loss of pregnancy (miscarriage). Females who are or may become pregnant should not handle abiraterone acetate tablets if broken, crushed, or damaged without protection, such as gloves. have a partner who is pregnant or may become pregnant. Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with abiraterone acetate tablets and for 3 weeks after the last dose of abiraterone acetate tablets. are breastfeeding or plan to breastfeed. It is not known if abiraterone acetate passes into your breast milk. Tell your healthcare provider about all the medicines you take or treatments you receive , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Abiraterone acetate tablets can interact with many other medicines. You should not start or stop any medicine before you talk with the healthcare provider that prescribed abiraterone acetate tablets. Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist when you get a new medicine. How should I take abiraterone acetate tablets? Take abiraterone acetate tablets and prednisone exactly as your healthcare provider tells you. Take your prescribed dose of abiraterone acetate tablets 1 time a day. Your healthcare provider may change your dose if needed. Do not change or stop taking your prescribed dose of abiraterone acetate tablets or prednisone without talking with your healthcare provider first. Take abiraterone acetate tablets as a single dose one time a day on an empty stomach. Do not eat 2 hours before and 1 hour after taking abiraterone acetate tablets. Do not take abiraterone acetate tablets with food. Taking abiraterone acetate tablets with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects. Swallow abiraterone acetate tablets whole. Do not crush or chew tablets. Take abiraterone acetate tablets with water. If you miss a dose of abiraterone acetate tablets or prednisone, take your prescribed dose the following day. If you miss more than 1 dose, tell your healthcare provider right away. Your healthcare provider will do blood tests to check for side effects. What are the possible side effects of abiraterone acetate tablets? Abiraterone acetate tablets may cause serious side effects including: • High blood pressure (hypertension), low blood potassium levels (hypokalemia), fluid retention (edema), and irregular heartbeats can happen during treatment with abiraterone acetate tablets . This can be life threatening. To decrease the chance of this happening, you must take prednisone with abiraterone acetate tablets exactly as your healthcare provider tells you. Your healthcare provider will check your blood pressure, do blood tests to check your potassium levels, and check for any signs and symptoms of fluid retention every month during treatment with abiraterone acetate tablets. Tell your healthcare provider if you get any of the following symptoms: dizziness confusion fast or irregular heartbeats muscle weakness feel faint or lightheaded pain in your legs headache swelling in your legs or feet Adrenal problems may happen if you stop taking prednisone, get an infection, or are under stress. Severe liver problems . You may develop changes in liver function blood tests. Your healthcare provider will do blood tests to check your liver before treatment with abiraterone acetate tablets and during treatment with abiraterone acetate tablets. Liver failure may occur, which can lead to death. Tell your healthcare provider right away if you notice any of the following changes: yellowing of the skin or eyes darkening of the urine severe nausea or vomiting Increased risk of bone fracture and death when abiraterone acetate tablets and prednisone or prednisolone, is used in combination with a type of radiation called radium Ra 223 dichloride. Tell your healthcare provider about any other treatments you are taking for prostate cancer. Severe low blood sugar (hypoglycemia). Severe low blood sugar with abiraterone acetate tablets can happen in people who have diabetes and take certain antidiabetic medicines. You and your healthcare provider should check your blood sugar levels regularly during treatment with abiraterone acetate tablets and after you stop treatment. Your healthcare provider may also need to change the dose of your antidiabetic medicines. Signs and symptoms of low blood sugar may include. headache drowsiness weakness dizziness confusion irritability hunger fast heart beat sweating feeling jittery The most common side effects of abiraterone acetate tablets include: feeling very tired joint pain high blood pressure nausea swelling in your legs or feet low blood potassium levels hot flushes diarrhea vomiting infected nose, sinuses, or throat (cold) cough headache low red blood cells (anemia) high blood cholesterol and triglycerides high blood sugar levels certain other abnormal blood tests Abiraterone acetate tablets may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of abiraterone acetate tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store abiraterone acetate tablets? • Store abiraterone acetate tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep abiraterone acetate tablets and all medicines out of the reach of children. General information about the safe and effective use of abiraterone acetate tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use abiraterone acetate tablets for a condition for which it was not prescribed. Do not give your abiraterone acetate tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about abiraterone acetate tablets that is written for health professionals. What are the ingredients of abiraterone acetate tablets? Active ingredient: abiraterone acetate Inactive ingredients : 250 mg fil-coated tablets: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate and titanium dioxide. 500 mg film-coated tablets: colloidal silicon dioxide, croscarmellose sodium, hypromellose, iron oxide black, iron oxide red, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, silicified microcrystalline cellulose, sodium lauryl sulfate, talc and titanium dioxide. Distributor: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 Made in India For more information, call Dr. Reddy’s Laboratories Inc., at 1-888-375-3784. This Patient Information has been approved by the U.S. Food and Drug Administration. To reorder additional Patient Information Sheets contact Dr. Reddy’s Customer Service at 1-866-733-3952. Revised: 03/2023
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES The efficacy and safety of abiraterone acetate with prednisone was established in three randomized placebo-controlled international clinical studies. All patients in these studies received a GnRH analog or had prior bilateral orchiectomy. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials. Concurrent use of spironolactone was not allowed during the study period. COU-AA-301: Patients with metastatic CRPC who had received prior docetaxel chemotherapy In COU-AA-301 (NCT00638690), a total of 1,195 patients were randomized 2:1 to receive either abiraterone acetate orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient’s baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal. The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39 to 95) and the racial distribution was 93% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0 to 1 and 45% had a Brief Pain Inventory-Short Form score of ≥4 (patient’s reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens. The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival (OS) in patients treated with abiraterone acetate with prednisone compared to patients in the placebo with prednisone arm (Table 9 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 7). Table 7: Overall Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in COU-AA-301 (Intent-to-Treat Analysis) Abiraterone Acetate with Prednisone (N=797) Placebo with Prednisone (N=398) Primary Survival Analysis Deaths (%) Median survival (months) (95% CI) p-value 1 Hazard ratio (95% CI) 2 Updated Survival Analysis Deaths (%) Median survival (months) (95% CI) Hazard ratio (95% CI) 2 333 (42%) 14.8 (14.1, 15.4) 501 (63%) 15.8 (14.8, 17.0) <0.0001 0.646 (0.543, 0.768) 0.740 (0.638, 0.859) 219 (55%) 10.9 (10.2, 12.0) 274 (69%) 11.2 (10.4, 13.1) 1 p-value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs. 2), pain score (absent vs. present), number of prior chemotherapy regimens (1 vs. 2), and type of disease progression (PSA only vs. radiographic). 2 Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors abiraterone acetate with prednisone. Figure 1: Kaplan-Meier Overall Survival Curves in COU-AA-301 (Intent-to-Treat Analysis) COU-AA-302: Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy In COU-AA-302 (NCT00887198), 1,088 patients were randomized 1:1 to receive either abiraterone acetate orally at a dose of 1,000 mg once daily (N=546) or Placebo orally once daily (N=542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded. Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with abiraterone acetate was 95% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0 to 1 (asymptomatic) in 66% of patients and 2 to 3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours). Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression. The planned final analysis for OS, conducted after 741 deaths (median follow up of 49 months) demonstrated a statistically significant OS improvement in patients treated with abiraterone acetate with prednisone compared to those treated with placebo with prednisone (Table 8 and Figure 2). Sixty-five percent of patients on the abiraterone acetate arm and 78% of patients on the placebo arm used subsequent therapies that may prolong OS in metastatic CRPC. Abiraterone acetate was used as a subsequent therapy in 13% of patients on the abiraterone acetate arm and 44% of patients on the placebo arm. Table 8: Overall Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in COU-AA-302 (Intent-to-Treat Analysis) Overall Survival Abiraterone Acetate with Prednisone (N=546) Placebo with Prednisone (N=542) Deaths 354 (65%) 387 (71%) Median survival (months) (95% CI) 34.7 (32.7, 36.8) 30.3 (28.7, 33.3) p-value 1 0.0033 Hazard ratio 2 (95% CI) 0.81 (0.70, 0.93) 1 p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1). 2 Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors abiraterone acetate with prednisone . Figure 2: Kaplan Meier Overall Survival Curves in COU-AA-302 At the pre-specified rPFS analysis, 150 (28%) patients treated with abiraterone acetate with prednisone and 251 (46%) patients treated with placebo with prednisone had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 9 and Figure 3). Table 9: Radiographic Progression-free Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in COU-AA-302 (Intent-to-Treat Analysis) Radiographic Progression-free Survival Abiraterone Acetate with Prednisone (N=546) Placebo with Prednisone (N=542) Progression or death 150 (28%) 251 (46%) Median rPFS (months) (95% CI) NR (11.66, NR) 8.28 (8.12, 8.54) p-value 1 <0.0001 Hazard ratio 2 (95% CI) 0.425 (0.347, 0.522) NR=Not reached. 1 p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1). 2 Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors abiraterone acetate with prednisone. Figure 3: Kaplan Meier Curves of Radiographic Progression-free Survival in COU-AA-302 (Intent-to-Treat Analysis) The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients in the abiraterone acetate arm and 16.8 months for patients in the placebo arm (HR=0.580; 95% CI: [0.487, 0.691], p < 0.0001). The median time to opiate use for prostate cancer pain was not reached for patients receiving abiraterone acetate and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: [0.566, 0.833], p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the abiraterone acetate arm. LATITUDE: Patients with metastatic high-risk CSPC In LATITUDE (NCT01715285), 1199 patients with metastatic high-risk CSPC were randomized 1:1 to receive either abiraterone acetate orally at a dose of 1,000 mg once daily with prednisone 5 mg once daily (N=597) or placebos orally once daily (N=602). High-risk disease was defined as having at least two of three risk factors at baseline: a total Gleason score of ≥8, presence of ≥3 lesions on bone scan, and evidence of measurable visceral metastases. Patients with significant cardiac, adrenal, or hepatic dysfunction were excluded. Patients continued treatment until radiographic or clinical disease progression, unacceptable toxicity, withdrawal or death. Clinical progression was defined as the need for cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to ≥3. Patient demographics were balanced between the treatment arms. The median age was 67 years among all randomized subjects. The racial distribution of patients treated with abiraterone acetate was 69% Caucasian, 2.5% Black, 21% Asian, and 8.1% Other. The ECOG performance status was 0 for 55%, 1 for 42%, and 2 for 3.5% of patients. Baseline pain assessment was 0 to 1 (asymptomatic) in 50% of patients, 2 to 3 (mildly symptomatic) in 23% of patients, and ≥4 in 28% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours). A major efficacy outcome was overall survival. The pre-specified interim analysis after 406 deaths showed a statistically significant improvement in OS in patients on abiraterone acetate with prednisone compared to those on placebos. Twenty-one percent of patients on the abiraterone acetate arm and 41% of patients on the placebos arm received subsequent therapies that may prolong OS in metastatic CRPC. An updated survival analysis was conducted when 618 deaths were observed. The median follow-up time was 52 months. Results from this analysis were consistent with those from the pre-specified interim analysis (Table 10 and Figure 4). At the updated analysis, 29% of patients on the abiraterone acetate arm and 45% of patients on the placebos arm received subsequent therapies that may prolong OS in metastatic CRPC. Table 10: Overall Survival of Patients Treated with Either Abiraterone or Placebos in LATITUDE (Intent-to-Treat Analysis) Abiraterone with Prednisone (N=597) Placebos (N=602) Overall Survival 1 Deaths (%) 169 (28%) 237 (39%) Median survival (months) NE (NE, NE) 34.7 (33.1, NE) (95% CI)p-value 2 <0.0001 Hazard ratio (95% CI) 3 0.62 (0.51, 0.76) Updated Overall Survival Deaths (%) 275 (46%) 343 (57%) Median survival (months) 53.3 36.5 (95% CI)Hazard ratio (95% CI) 3 (48.2, NE) 0.66 (0.56, 0.78) (33.5, 40.0) NE=Not estimable 1 This is based on the pre-specified interim analysis 2 p value is from log-rank test stratified by ECOG PS score (0/1 or 2) and visceral (absent or present). 3 Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors abiraterone acetate with prednisone. Figure 4: Kaplan-Meier Plot of Overall Survival; Intent-to-treat Population in LATITUDE Updated Analysis The major efficacy outcome was supported by a statistically significant delay in time to initiation of chemotherapy for patients in the abiraterone acetate arm compared to those in the placebos arm. The median time to initiation of chemotherapy was not reached for patients on abiraterone acetate with prednisone and was 38.9 months for patients on placebos (HR = 0.44; 95% CI: [0.35, 0.56], p < 0.0001).
| 333 (42%) 14.8 (14.1, 15.4) 501 (63%) 15.8 (14.8, 17.0) | <0.0001 0.646 (0.543, 0.768) 0.740 (0.638, 0.859) | 219 (55%) 10.9 (10.2, 12.0) 274 (69%) 11.2 (10.4, 13.1) |
| Deaths | 354 (65%) | 387 (71%) |
| Median survival (months) (95% CI) | 34.7 (32.7, 36.8) | 30.3 (28.7, 33.3) |
| p-value1 | 0.0033 | |
| Hazard ratio2 (95% CI) | 0.81 (0.70, 0.93) | |
| Progression or death | 150 (28%) | 251 (46%) |
| Median rPFS (months) (95% CI) | NR (11.66, NR) | 8.28 (8.12, 8.54) |
| p-value1 | <0.0001 | |
| Hazard ratio2 (95% CI) | 0.425 (0.347, 0.522) | |
| Deaths (%) | 169 (28%) | 237 (39%) | |
| Median survival (months) | NE (NE, NE) | 34.7 (33.1, NE) | |
| (95% CI)p-value2 | <0.0001 | ||
| Hazard ratio (95% CI)3 | 0.62 (0.51, 0.76) | ||
| Deaths (%) | 275 (46%) | 343 (57%) | |
| Median survival (months) | 53.3 | 36.5 | |
| (95% CI)Hazard ratio (95% CI)3 | (48.2, NE) | 0.66 (0.56, 0.78) | (33.5, 40.0) |
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Of the total number of patients receiving abiraterone acetate in randomized clinical trials, 70% of patients were 65 years and over and 27% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.2 Lactation Risk Summary The safety and efficacy of abiraterone acetate have not been established in females. There is no information available on the presence of abiraterone in human milk, or on the effects on the breastfed child or milk production.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness of abiraterone acetate in pediatric patients have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy 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 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 to 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS • Do not use abiraterone acetate tablets in patients with baseline severe hepatic impairment (Child-Pugh Class C). ( 8.6 ) 8.1 Pregnancy 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 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 to 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. 8.2 Lactation Risk Summary The safety and efficacy of abiraterone acetate have not been established in females. There is no information available on the presence of abiraterone in human milk, or on the effects on the breastfed child or milk production. 8.3 Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies and its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of abiraterone acetate [see Use in Specific Populations ( 8.1 )]. Infertility Based on animal studies, abiraterone acetate may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness of abiraterone acetate in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients receiving abiraterone acetate in randomized clinical trials, 70% of patients were 65 years and over and 27% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of abiraterone acetate increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of abiraterone acetate to 250 mg once daily. Do not use abiraterone acetate in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5 x ULN or total bilirubin >3 x ULN occur in patients with baseline moderate hepatic impairment, discontinue abiraterone acetate treatment [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.3 ), and Clinical Pharmacology ( 12.3 )]. 8.7 Patients with Renal Impairment No dosage adjustment is necessary for patients with renal impairment [see Clinical Pharmacology ( 12.3 )].
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING Abiraterone acetate tablets USP, 250 mg are white to off-white, oval shaped, film coated tablets debossed with “35” on one side and plain on other side. Abiraterone acetate tablets USP, 250 mg are available in high-density polyethylene bottles of 120 tablets and also available in unit dose package of 30 (3 x 10) tablets. Bottles of 120 NDC 43598-358-04 Unit dose package of 30 (3 x 10) NDC 43598-358-31 Abiraterone acetate tablets USP, 500 mg are pinkish brown color, oval shaped, biconvex, film coated tablets, debossed with "46" on one side and plain other side and free from physical defects. Abiraterone acetate tablets USP, 500 mg are available in high-density polyethylene bottles of 60 tablets and unit dose package of 60 (6 x 10) tablets. Bottles of 60 NDC 43598-468-60 Unit dose package of 60 (6 x 10) NDC 43598-468-38 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. Based on its mechanism of action, abiraterone acetate may harm a developing fetus. Women who are pregnant or women who may be pregnant should not handle abiraterone acetate 250 mg tablets if broken, crushed, or damaged without protection, e.g., gloves [see Use in Specific Populations ( 8.1 )].
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API