Abiraterone

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 tablets are 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)

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) ] .

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 Amneal Pharmaceuticals at 1-877-835-5472 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-AA-­302) 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. A third 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 1195 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 Acetate in COU-AA-301 System/Organ Class Adverse reaction Abiraterone Acetate with Prednisone (N=791) Placebo with Prednisone (N=394) All Grades 1 % Grade 3 to 4 % All Grades % Grade 3 to 4 % Musculoskeletal and connective tissue disorders Joint swelling/discomfort 2 30 4.2 23 4.1 Muscle discomfort 3 26 3.0 23 2.3 General disorders Edema 4 27 1.9 18 0.8 Vascular disorders Hot flush 19 0.3 17 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 18 0.6 14 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 12 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 11 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures 5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia 6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort 7 3.8 0.5 2.8 0 Cardiac failure 8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0. 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness. 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema. 5 Includes all fractures with the exception of pathological fracture. 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia. 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the abiraterone acetate arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased. Table 2 shows laboratory abnormalities of interest from COU-AA-301. Table 2: Laboratory Abnormalities of Interest in COU-AA-301 Laboratory Abnormality Abiraterone Acetate with Prednisone (N=791) Placebo with Prednisone (N=394) All Grades (%) Grade 3 to 4 (%) All Grades (%) Grade 3 to 4 (%) Hypertriglyceridemia 63 0.4 53 0 High AST 31 2.1 36 1.5 Hypokalemia 28 5.3 20 1.0 Hypophosphatemia 24 7.2 16 5.8 High ALT 11 1.4 10 0.8 High Total Bilirubin 6.6 0.1 4.6 0 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 Adverse reaction Abiraterone Acetate with Prednisone (N=542) Placebo with Prednisone (N=540) All Grades 1 % Grade 3 to 4 % All Grades % Grade 3 to 4 % General disorders Fatigue 39 2.2 34 1.7 Edema 2 25 0.4 21 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort 3 30 2.0 25 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23 0.4 19 0.6 Diarrhea 22 0.9 18 0.9 Dyspepsia 11 0.0 5.0 0.2 Vascular disorders Hot flush 22 0.2 18 0.0 Hypertension 22 3.9 13 3.0 Respiratory, thoracic and mediastinal disorders Cough 17 0.0 14 0.2 Dyspnea 12 2.4 9.6 0.9 Psychiatric disorders Insomnia 14 0.2 11 0.0 Injury, poisoning and procedural complications Contusion 13 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 13 0.0 8.0 0.0 Nasopharyngitis 11 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0. 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema. 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the abiraterone acetate arm compared to placebo in COU-AA-302. Table 4: Laboratory Abnormalities in >15% of Patients in the Abiraterone Acetate Arm of COU-AA-302 Laboratory Abnormality Abiraterone Acetate with Prednisone (N=542) Placebo with Prednisone (N=540) Grade 1 to 4 % Grade 3 to 4 % Grade 1 to 4 % Grade 3 to 4 % Hematology Lymphopenia 38 8.7 32 7.4 Chemistry Hyperglycemia 1 57 6.5 51 5.2 High ALT 42 6.1 29 0.7 High AST 37 3.1 29 1.1 Hypernatremia 33 0.4 25 0.2 Hypokalemia 17 2.8 10 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 tablets and prednisone was 24 months. Table 5 shows adverse reactions on the abiraterone acetate tablets 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 LATITUDE 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 Cough 4 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 LATITUDE Laboratory Abnormality Abiraterone Acetate with Prednisone (N=597) Placebos (N=602) Grade 1 to 4 % Grade 3 to 4 % Grade 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 Experience 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)).

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 tablet 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 AUC 0-∞ 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 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.