YONSA

Abiraterone acetate, the active ingredient of YONSA tablet is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each YONSA Tablet contains 125 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 micronized (smaller particle size) white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C 26 H 33 NO 2 and it has a molecular weight of 391.55. Abiraterone acetate 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 lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, sodium stearyl fumarate, butylated hydroxyanisole, butylated hydroxytoluene. image description

YONSA is indicated in combination with methylprednisolone for the treatment of patients with metastatic castration-resistant prostate cancer. YONSA is a CYP17 inhibitor indicated in combination with methylprednisolone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). ( 1 )

To avoid medication errors and overdose, be aware that YONSA tablets may have different dosing and food effects than other abiraterone acetate products. Recommended dose: YONSA 500 mg (four 125 mg tablets) administered orally once daily in combination with methylprednisolone 4 mg administered orally twice daily. ( 2.1 ) Patients receiving YONSA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) YONSA tablets must be taken as a single dose once daily with or without food. The tablets should be swallowed whole with water. Do not crush or chew tablets. ( 2.1 ) Dose Modification: For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the YONSA starting dose to 125 mg once daily. ( 2.3 ) For patients who develop hepatotoxicity during treatment, hold YONSA until recovery. Retreatment may be initiated at a reduced dose. YONSA should be discontinued if patients develop severe hepatotoxicity. ( 2.3 ) 2.1 Recommended Dosage The recommended dose of YONSA is 500 mg (four 125 mg tablets) administered orally once daily in combination with methylprednisolone 4 mg administered orally twice daily. 2.2 Important Administration Instructions To avoid medication errors and overdose, be aware that YONSA (abiraterone acetate) tablets may have different dosing and food effects than other abiraterone acetate products. Patients receiving YONSA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. YONSA tablets must be taken as a single dose once daily with or without food [see Clinical Pharmacology ( 12.3 )] . The tablets should be swallowed whole with water. Do not crush or chew tablets. 2.3 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 YONSA to 125 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 5X upper limit of normal (ULN) or total bilirubin greater than 3X ULN occur in patients with baseline moderate hepatic impairment, discontinue YONSA and do not re-treat patients with abiraterone acetate [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. Do not use YONSA in patients with baseline severe hepatic impairment (Child-Pugh Class C). Hepatotoxicity For patients who develop hepatotoxicity during treatment with YONSA (ALT and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment with YONSA [see Warnings and Precautions ( 5.3 )]. Treatment may be restarted at a reduced dose of 375 mg once daily following return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X 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 375 mg once daily, re-treatment may be restarted at a reduced dose of 250 mg once daily following return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN . If hepatotoxicity recurs at the reduced dose of 250 mg once daily, discontinue treatment with YONSA. Permanently discontinue YONSA 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 )]. 2.4 Dose Modification Guidelines for Strong CYP3A4 Inducers Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during YONSA treatment. If a strong CYP3A4 inducer must be co-administered, increase the YONSA dosing frequency to twice a day only during the co-administration period (e.g., from 500 mg once daily to 500 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 )].

None. None

The following are discussed in more detail in other sections of the labeling: Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess [see Warnings and Precautions ( 5.1 )] . Adrenocortical Insufficiency [see Warnings and Precautions ( 5.2 )] . Hepatotoxicity [see Warnings and Precautions ( 5.3 )] . Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride [see Warnings and Precautions ( 5.4 )] . The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. ( 6.1 ) The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.FDA.gov/medwatch 6.1 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 (Study 1 and Study 2) enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 abiraterone acetate was administered at a dose equivalent to 500 mg of YONSA daily in combination with a different corticosteroid twice daily in the active treatment arms. Placebo plus corticosteroid was given to control patients. The most common adverse drug reactions ( > 10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the abiraterone acetate arm in Study 1 that occurred with a ≥ 2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with abiraterone acetate with a corticosteroid was 8 months. Table 1: Adverse Reactions due to Abiraterone Acetate in Study 1 Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid (N=394) System Organ Class Adverse Reaction All Grades1 % Grade 3-4 % All Grades % Grade 3-4 % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 30 4.2 23 4.1 Muscle discomfort3 26 3.0 23 2.3 General Disorders Edema4 27 1.9 18 0.8 Vascular Disorders Hot Flush 19 0.3 17 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal Disorders Diarrhea 18 0.6 14 1.3 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 Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the abiraterone acetate arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the abiraterone acetate with a corticosteroid arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid(N=394) Laboratory Abnormality All Grades % Grade 3-4 % All Grades % Grade 3-4 % Hypertriglyceridemia 63 0.4 53 0 High AST 31 2.1 36 1.5 Hypokalemia 28 5.3 20 1.0 Hypophosphatemia 24 7.2 16 5.8 High ALT 11 1.4 10 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the abiraterone acetate arm in Study 2 that occurred in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with abiraterone acetate with a corticosteroid was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in Study 2 Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(N=540) System Organ Class Adverse Reaction All Grades1 % Grade 3-4 % All Grades % Grade 3-4 % General Disorders Fatigue 39 2.2 34 1.7 Edema2 25 0.4 21 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 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 Study 2. Table 4: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Arm of Study 2 Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(N=540) Laboratory Abnormality Grade 1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 % Hematology Lymphopenia 38 8.7 32 7.4 Chemistry Hyperglycemia1 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 Cardiovascular Adverse Reactions In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with abiraterone acetate compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking abiraterone acetate 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 abiraterone acetate arms and no deaths in the placebo arms. There were 7 (0.5 %) deaths due to cardiorespiratory arrest in the abiraterone acetate 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 abiraterone acetate arms. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of abiraterone acetate with a different corticosteroid. 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)).

CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during YONSA treatment. If a strong CYP3A4 inducer must be co-administered, increase the YONSA dosing frequency ( 2.4 , 7.1 ) CYP2D6 Substrates: Avoid co-administration of YONSA 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 Effect of Other Drugs on YONSA Strong CYP3A4 Inducers The co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during YONSA treatment. If a strong CYP3A4 inducer must be co-administered with YONSA, increase the YONSA dosing frequency [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]. 7.2 Effect of YONSA on Other Drugs CYP2D6 Substrates Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6. The co-administration of YONSA with CYP2D6 substrates increases the concentration of the CYP2D6 substrate, which may increase the frequency and/or severity of adverse reactions of these substrates. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug in accordance with its Prescribing Information [see Clinical Pharmacology ( 12.3 )] . CYP2C8 Substrates Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. The co-administration of YONSA with CYP2C8 substrates increases the concentration of the CYP2C8 substrate, which may increase the frequency and/or severity of adverse reactions of these substrates. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate [see Clinical Pharmacology ( 12.3 )] .