How Much Does Abiraterone Cost in Mexico vs the USA?

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 )

­ 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 )].

Mineralocorticoid excess: Closely monitor patients with cardiovascular disease. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. ( 5.1 ) Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. ( 5.2 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue abiraterone acetate dosing as recommended. ( 5.3 ) Increased fractures and mortality in combination with radium Ra 223 dichloride: Use of abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride is not recommended. (5.4) Embryo-Fetal Toxicity: Abiraterone acetate can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.5 , 8.1 , 8.3 ) Hypoglycemia: Severe hypoglycemia has been reported in patients with pre-existing diabetes who are taking medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes and assess if antidiabetic agent dose modifications are required. (5.6) 5.1 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology ( 12.1 )]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with abiraterone acetate. In the combined data from 4 placebo-controlled trials using prednisone 5 mg twice daily in combination with 1,000 mg abiraterone acetate daily, grades 3 to 4 hypokalemia were detected in 4% of patients on the abiraterone acetate arm and 2% of patients on the placebo arm. Grades 3 to 4 hypertension were observed in 2% of patients each arm and grades 3 to 4 fluid retention in 1% of patients each arm. In LATITUDE (a randomized placebo-controlled, multicenter clinical trial), which used prednisone 5 mg daily in combination with 1,000 mg abiraterone acetate daily, grades 3 to 4 hypokalemia were detected in 10% of patients on the abiraterone acetate arm and 1% of patients on the placebo arm, grades 3 to 4 hypertension were observed in 20% of patients on the abiraterone acetate arm and 10% of patients on the placebo arm. Grades 3 to 4 fluid retention occurred in 1% of patients each arm [see Adverse Reactions ( 6 )]. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. In postmarketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate. The safety of abiraterone acetate in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301 and LATITUDE) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies ( 14 )]. 5.2 Adrenocortical Insufficiency Adrenal insufficiency occurred in 0.3% of 2,230 patients taking abiraterone acetate and in 0.1% of 1,763 patients taking placebo in the combined data of the 5 randomized, placebo-controlled clinical studies. Adrenocortical insufficiency was reported in patients receiving abiraterone acetate in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from 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 abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions ( 5.1 )]. 5.3 Hepatotoxic ity In postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions ( 6.2 )]. In the combined data of 5 randomized clinical trials, grade 3 to 4 ALT or AST increases (at least 5 x ULN) were reported in 6% of 2,230 patients who received abiraterone acetate, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to ALT and AST increases or abnormal hepatic function occurred in 1.1% of 2,230 patients taking abiraterone acetate. In these clinical trials, no deaths clearly related to abiraterone acetate were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with abiraterone acetate, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced abiraterone acetate dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt abiraterone acetate treatment and closely monitor liver function. Re-treatment with abiraterone acetate at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5 x ULN and total bilirubin less than or equal to 1.5 x ULN [see Dosage and Administration ( 2.4 )]. Permanently discontinue abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration ( 2.4 )]. The safety of abiraterone acetate re-treatment of patients who develop AST or ALT greater than or equal to 20 x ULN and/or bilirubin greater than or equal to 10 x ULN is unknown. 5.4 Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride Abiraterone acetate plus prednisone/prednisolone is not recommended for use in combination with radium 223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. 5.5 Embryo-Fetal Toxicity The safety and efficacy of abiraterone acetate have not been established in females. Based on animal reproductive studies and mechanism of action, abiraterone acetate can cause fetal harm and loss of pregnancy when administered to a pregnant female. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with abiraterone acetate and for 3 weeks after the last dose of abiraterone acetate [see Use in Specific Populations ( 8.1 , 8.3 )]. Abiraterone acetate should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling ( 16 )]. 5.6 Hypoglycemia Severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions ( 7.2 )]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with abiraterone acetate. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

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 )].

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)).

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.