Zytiga Tablets(abiraterone acetate 中文药名：阿比特龙片) 为口服给药,治疗去势或无效的转移性前列腺癌，与强的松(类固醇)联合用于治疗晚期(转移)去势抵抗前列腺癌患者。 本申请是在FDA 的优先审评计划下进行评审，此计划对可能在治疗中提供重要进展，或提供不存在适当治疗一种治疗提供加快6个月审评。 Zytiga的批准早于常规目标日期2011年6月20日。 FDA药物审评和研究中心中的肿瘤药品室主任Richard Pazdur, M.D.说“Zytiga延长有晚期前列腺癌已接受既往治疗和很少治疗选择男性的生命”。 批准日期：2011年4月28日；公司：Centocor Ortho Biotech Inc. 美国首次批准：2011 目前的主要变化 剂量和给药方法。 （2.2）05/2014 适应症和用法 ZYTIGA是组合表示与强的松用于治疗转移性去势抗性前列腺癌的治疗CYP17抑制剂。 用法用量 推荐剂量：ZYTIGA 1000毫克（4 250毫克片剂）口服，每日一次联合强的松5毫克口服，每日两次。 ZYTIGA必须采取空着肚子。否应该进食为至少两小时ZYTIGA的剂量被取前和至少一小时取ZYTIGA的剂量后。片剂应整粒吞服水。不要碾碎或咀嚼片剂。 对于患者的基线中度肝受损（Child-Pugh分级B级），每天一次降低ZYTIGA开始剂量为250毫克。 对于谁在治疗过程中培养肝患者，持有ZYTIGA直至痊愈。再处理可在降低的剂量开始。如出现严重的肝毒性ZYTIGA应停药。 剂型和规格 片剂250毫克 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZYTIGA safely and effectively. See full prescribing information for ZYTIGA. ZYTIGA ® (abiraterone acetate) Tablets For Oral Administration Initial U.S. Approval: 2011 RECENT MAJOR CHANGES Dosage and Administration. (2.2) 05/2014 INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. (1) DOSAGE AND ADMINISTRATION Recommended dose: ZYTIGA 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. The tablets should be swallowed whole with water. Do not crush or chew tablets. (2.1) For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the ZYTIGA starting dose to 250 mg once daily. (2.2) For patients who develop hepatotoxicity during treatment, hold ZYTIGA until recovery. Retreatment may be initiated at a reduced dose. ZYTIGA should be discontinued if patients develop severe hepatotoxicity. (2.2) DOSAGE FORMS AND STRENGTHS Tablet 250 mg (3) CONTRAINDICATIONS ZYTIGA is contraindicated in women who are or may become pregnant. (4.1, 8.1) WARNINGS AND PRECAUTIONS Mineralocorticoid excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with LVEF < 50% or NYHA Class III or IV heart failure in Study 1 or LVEF < 50% or NYHA Class II to IV heart failure in Study 2 was not established. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. (5.1) Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. (5.2) Hepatotoxicity: Increases in liver enzymes have led to drug interruption, dose modification and/or discontinuation. Monitor liver function and modify, interrupt, or discontinue ZYTIGA dosing as recommended. (5.3) ADVERSE REACTIONS The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency. (2.3, 7.1) CYP2D6 Substrates: Avoid co-administration of ZYTIGA 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) USE IN SPECIFIC POPULATIONS Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 5/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dose of ZYTIGA is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken [see Clinical Pharmacology (12.3)]. The tablets should be swallowed whole with water. Do not crush or chew tablets. 2.2 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 ZYTIGA to 250 mg once daily. A once daily dose of 250 mg in patients with moderate hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 1,000 mg once daily. However, there are no clinical data at the dose of 250 mg once daily in patients with moderate hepatic impairment and caution is advised. 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× upper limit of normal (ULN) or total bilirubin greater than 3× ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA and do not re-treat patients with ZYTIGA [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). Hepatotoxicity For patients who develop hepatotoxicity during treatment with ZYTIGA (ALT and/or AST greater than 5× ULN or total bilirubin greater than 3× ULN), interrupt treatment with ZYTIGA [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× ULN and total bilirubin less than or equal to 1.5× 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× ULN and total bilirubin less than or equal to 1.5× ULN. If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with ZYTIGA. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20× ULN and/or bilirubin greater than or equal to 10× ULN is unknown. 2.3 Dose Modification Guidelines for Strong CYP3A4 Inducers Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. Although there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA 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)]. 3 DOSAGE FORMS AND STRENGTHS ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval-shaped tablets debossed with AA250 on one side. 4 CONTRAINDICATIONS 4.1 Pregnancy ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions (6)]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. 5.2 Adrenocortical Insufficiency Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions (5.1)]. 5.3 Hepatotoxicity In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5× ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5× ULN and total bilirubin less than or equal to 1.5× ULN [see Dosage and Administration (2.2)]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20× ULN and/or bilirubin greater than or equal to 10× ULN is unknown. 6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, Hypokalemia, and Fluid Retention 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)]. 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 enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered 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 control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5× ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5× ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Prednisone (N=791) Placebo with Prednisone (N=394) System/Organ Class   Adverse reaction All Grades % Grade 3–4 % All Grades % Grade 3–4 % Musculoskeletal and connective tissue disorders   Joint swelling/discomfort 29.5 4.2 23.4 4.1   Muscle discomfort 26.2 3.0 23.1 2.3 General disorders   Edema 26.7 1.9 18.3 0.8 Vascular disorders   Hot flush 19.0 0.3 16.8 0.3   Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders   Diarrhea 17.6 0.6 13.5 1.3   Dyspepsia 6.1 0 3.3 0 Infections and infestations   Urinary tract infection 11.5 2.1 7.1 0.5   Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders   Cough 10.6 0 7.6 0 Renal and urinary disorders   Urinary frequency 7.2 0.3 5.1 0.3   Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications   Fractures 5.9 1.4 2.3 0 Cardiac disorders   Arrhythmia 7.2 1.1 4.6 1.0   Chest pain or chest discomfort 3.8 0.5 2.8 0   Cardiac failure 2.3 1.9 1.0 0.3 Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3–4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1  Abiraterone (N=791) Placebo (N=394) Laboratory Abnormality All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5× ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2  ZYTIGA with Prednisone (N=542) Placebo with Prednisone (N=540) System/Organ Class   Adverse reaction All Grades % Grade 3–4 % All Grades % Grade 3–4 % General disorders   Fatigue 39.1 2.2 34.3 1.7   Edema† 25.1 0.4 20.7 1.1   Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders   Joint swelling/discomfort‡ 30.3 2.0 25.2 2.0   Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders   Constipation 23.1 0.4 19.1 0.6   Diarrhea 21.6 0.9 17.8 0.9   Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders   Hot flush 22.3 0.2 18.1 0.0   Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders   Cough 17.3 0.0 13.5 0.2   Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders   Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications   Contusion 13.3 0.0 9.1 0.0   Falls 5.9 0.0 3.3 0.0 Infections and infestations   Upper respiratory tract infection 12.7 0.0 8.0 0.0   Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders   Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders   Rash 8.1 0.0 3.7 0.0 Adverse events graded according to CTCAE version 3.0 Includes terms Edema peripheral, Pitting edema, and Generalized edema 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 ZYTIGA arm compared to placebo in Study 2. Grade 3–4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2  Abiraterone (N=542) Placebo (N=540) Laboratory Abnormality Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 %   Hematology   Lymphopenia 38.2 8.7 31.7 7.4 Chemistry   Hyperglycemia* 56.6 6.5 50.9 5.2   High ALT 41.9 6.1 29.1 0.7   High AST 37.3 3.1 28.7 1.1   Hypernatremia 32.8 0.4 25.0 0.2   Hypokalemia 17.2 2.8 10.2 1.7 Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3–4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3–4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. 6.2 Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. 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. 7 DRUG INTERACTIONS 7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes Based on in vitro data, ZYTIGA 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 ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) 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 ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax 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, exercise caution and 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 ZYTIGA [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4.1)]. ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6–17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. 8.3 Nursing Mothers ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of ZYTIGA in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% 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 ZYTIGA 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 ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5× ULN or total bilirubin >3× ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) 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 (2.2), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. 11 DESCRIPTION Abiraterone acetate, the active ingredient of ZYTIGA is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is: Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone acetate 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. Inactive ingredients in the tablets are colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Abiraterone acetate (ZYTIGA) 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. ZYTIGA decreased serum testosterone and other androgens in patients in the placebo-controlled Phase 3 clinical trial. It is not necessary to monitor the effect of ZYTIGA 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. 12.3 Pharmacokinetics Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects and in patients with metastatic castration-resistant prostate cancer (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 Cmax 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). Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. In healthy subjects abiraterone Cmax and AUC0–∞ 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 ZYTIGA with meals has the potential to result in increased and highly variable exposures. Therefore, no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. The tablets should be swallowed whole with water [see Dosage and Administration (2.1)]. Distribution and Protein Binding 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. 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. Metabolism Following oral administration of 14C-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 14C-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). 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 [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]. 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 ZYTIGA 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 [see Use in Specific Populations (8.7)]. Drug Interactions In vitro studies with human hepatic microsomes showed that abiraterone has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5. In an in vivo drug-drug interaction trial, the Cmax 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 [see Drug Interactions (7.2)]. In a clinical study to determine the effects of abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed. Abiraterone is a substrate of CYP3A4, in vitro. 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% [see Drug Interactions (7.1)]. In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Drug Interactions (7.1)]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate [see Drug Interactions (7.2)]. 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. 12.6 QT Prolongation In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received ZYTIGA 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. 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 did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. ZYTIGA has the potential to impair reproductive function and fertility in humans based on findings in animals. 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 [see Nonclinical Toxicology (13.2)]. 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 fertility studies in rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in males dosed for 4 weeks at ≥30 mg/kg/day. Mating of untreated females with males that received 30 mg/kg/day 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. Female rats dosed 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. 13.2 Animal Toxicology and/or Pharmacology 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. A dose-dependent increase in cataracts was observed in rats at 26 weeks starting at ≥50 mg/kg/day (similar to the human clinical exposure based on AUC). In the 39-week monkey study, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC). All other toxicities associated with abiraterone acetate reversed or were partially resolved after a 4-week recovery period. 14 CLINICAL STUDIES The efficacy and safety of ZYTIGA in patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized, placebo-controlled, multicenter Phase 3 clinical trials. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials. Study 1 Patients with metastatic CRPC who had received prior docetaxel chemotherapy: A total of 1195 patients were randomized 2:1 to receive either ZYTIGA 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 39–95) and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0–1 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 ZYTIGA compared to patients in the placebo arm (Table 5 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 5). Table 5: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 1 (Intent-to-Treat Analysis)  ZYTIGA (N=797) Placebo (N=398) Primary Survival Analysis Deaths (%) 333 (42%) 219 (55%) Median survival (months) (95% CI) 14.8 (14.1, 15.4) 10.9 (10.2, 12.0) p-value* <0.0001 Hazard ratio (95% CI)† 0.646 (0.543, 0.768) Updated Survival Analysis Deaths (%) 501 (63%) 274 (69%) Median survival (months) (95% CI) 15.8 (14.8, 17.0) 11.2 (10.4, 13.1) Hazard ratio (95% CI)† 0.740 (0.638, 0.859) 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). † Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA Figure 1: Kaplan-Meier Overall Survival Curves in Study 1 (Intent-to-Treat Analysis) Study 2 Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy In Study 2, 1088 patients were randomized 1:1 to receive either ZYTIGA at a dose of 1,000 mg once daily (N=546) or Placebo 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 ZYTIGA was 95.4% 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 0–1 (asymptomatic) in 66% of patients and 2–3 (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 ZYTIGA compared to those treated with placebo (Table 6 and Figure 2). Sixty-five percent of patients on the ZYTIGA arm and 78% of patients on the placebo arm used subsequent therapies that may prolong OS in metastatic CRPC. ZYTIGA was used as a subsequent therapy in 13% of patients on the ZYTIGA arm and 44% of patients on the placebo arm. Table 6: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)  Overall Survival ZYTIGA (N=546) Placebo (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* 0.0033 Hazard ratio† (95% CI) 0.81 (0.70, 0.93) p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1). Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA Figure 2: Kaplan Meier Overall Survival Curves in Study 2 At the pre-specified rPFS analysis, 150 (28%) patients treated with ZYTIGA and 251 (46%) patients treated with placebo had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 7 and Figure 3). Table 7: Radiographic Progression-free Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis) Radiographic Progression-free Survival ZYTIGA (N=546) Placebo (N=542) NR=Not reached   Progression or death 150 (28%) 251 (46%) Median rPFS (months) (95% CI) NR (11.66, NR) 8.28 (8.12, 8.54) p-value* <0.0001 Hazard ratio† (95% CI) 0.425 (0.347, 0.522) NR=Not reached * p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1). † Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA  Figure 3: Kaplan Meier Curves of Radiographic Progression-free Survival in Study 2 (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 receiving ZYTIGA and 16.8 months for patients receiving placebo (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 ZYTIGA 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 ZYTIGA arm. 16 HOW SUPPLIED/STORAGE AND HANDLING ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval tablets debossed with AA250 on one side. ZYTIGA 250 mg tablets are available in high-density polyethylene bottles of 120 tablets. NDC Number 57894-150-12 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]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations (8.1)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician's instructions. Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Patients should be advised that their liver function will be monitored using blood tests. Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4e338e89-3cf2-48eb-b6e2-a06c608c6513 FDA批准增加醋酸阿比特龙（Zytiga）的适应症，即可于去势治疗无效的晚期转移性列腺癌患者在进行化疗治疗前使用。 在该药安全性和有效性的试验结果发布在新英国医学杂志的当天，更新后的批准文书获得了公布。阿比特龙能够减少参与睾酮合成的一种必须蛋白质P450 17A的生成，从而抑制癌细胞的生长。该药物最先于2011年被批准用于既往使用多西紫杉醇治疗不佳的晚期前列腺癌患者。 FDA声明，批准这一新适应症是该机构作为优先审查项目开展的。3期临床试验入组了1088名从未接受过化疗的晚期前列腺癌患者，分别给予强的松和阿比特龙，或强的松和安慰剂。该试验终点是总体生存率（OS）和射线确认病灶无进展生存率。 强的松-阿比特龙联合用药组的射线确认病灶无进展生存率的中位数是16.5个月，强的松-安慰剂组的中位数则为8.3个月（前者较后者的危害比为0.53,95%CI0.45to0.62,P<0.001）。 尽管强的松-阿比特龙联合用药组的随诊中位时间是22.2个月，但总体生存率有所提高，强的松-安慰剂组的平均总体生存率是27.2个月（HR0.75,95%CI0.61to0.93,P=0.01）。 阿比特龙提高了转移性前列腺癌患者的射线确认病灶无进展存活率，并且有提高总体存活率的趋势，还显著延迟了临床疗效下降和化疗启动的时间。 强的松-阿比特龙联合用药组较为常见的是分级为3级或4级的不良事件，包括疲倦，关节肿胀或不适，液体潴留（主要是关节），热感，腹泻，呕吐，咳嗽，高血压，呼吸短促，尿路感染和擦伤等。 常见试验指标异常包括红细胞计数降低；磷酸胆碱酶升高；血液脂肪酸，血糖，肝酶升高；血液淋巴细胞水平降低，以及低磷和低钾等。 本申请是在FDA 的优先审评计划下进行评审，此计划对可能在治疗中提供重要进展，或提供不存在适当治疗一种治疗提供加快6个月审评。 Zytiga的批准早于常规目标日期2011年6月20日。 FDA药物审评和研究中心中的肿瘤药品室主任Richard Pazdur, M.D.说“Zytiga延长有晚期前列腺癌已接受既往治疗和很少治疗选择男性的生命”。 美国初始批准– 2011；本申请为优先审评 适应证和用途 ZYTIGA是一种CYP17抑制剂适用于与泼尼松联用为治疗既往接受含多烯紫杉醇[docetaxel]化疗转移去势难治性前列腺癌患者。 剂量和给药方法 推荐剂量：ZYTIGA 1,000 mg口服给予每天1次与泼尼松联用5 mg口服给予每天2次。必须空腹服用ZYTIGA。在服用ZYTIGA 剂量前至少2小时和服用ZYTIGA剂量后至少1小时不应消耗食物。 （1）对基线中度肝受损(Child-Pugh类别B)患者，减低ZYTIGA开始剂量至250 mg每天1次。 （2）对治疗期间发生肝毒性患者，不用ZYTIGA直至恢复。可在减低剂量再次治疗。如患者发生严重肝毒性应终止ZYTIGA。 剂型和规格 250mg片 禁忌证 妊娠或可能成为妊娠妇女禁忌用ZYTIGA。 警告和注意事项 （1）盐皮质激素过量：有心血管疾病史患者谨慎使用ZYTIGA。尚未确定在有射血分量LVEF < 50%或NYHA类别III或IV心衰患者中ZYTIGA的安全性。治疗前控制高血压和纠正低钾血症。至少每月1次监查血压，血清钾和液体潴留症状。 （2）肾上腺皮质功能不全：监视肾上腺皮质功能不全的症状和征象。应急情况前，期间和后可能适应增加皮质激素剂量。 （3）肝毒性：肝酶增加曾导致药物中断，剂量调整和/或终止。监查肝功能和如建议调整，中断或终止ZYTIGA给药。 （4）食物影响：必须空腹服用ZYTIGA。当与食物同时服用醋酸阿比特龙[abiraterone acetate]阿比特龙的暴露(曲线下面积)增加达10倍。 不良反应 最常见不良反应(≥ 5%)是关节肿胀或不适，低钾血症，水肿，肌肉不适，热潮红，腹泻，泌尿道感染，咳嗽，高血压，心律失常，尿频，夜尿，消化不良，和上呼吸道感染。 为报告怀疑不良反应, 联系Centocor Ortho Biotech Inc电话 800-457-6399和www.centocororthobiotech.com或FDA电话1-800-FDA-1088或www.fda.gov/medwatch. 药物相互作用 ZYTIGA是一种肝药物代谢酶CYP2D6是抑制剂。因为治疗指数窄，避免ZYTIGA与CYP2D6底物共同给药。如果不能使用另外治疗，小心对待和考虑减低同时给予CYP2D6底物剂量。 特殊人群中使用 在基线严重肝受损(Child-Pugh类别 C)患者中不要使用ZYTIGA。