YONSA

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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 Stro…

5 WARNINGS AND PRECAUTIONS 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 YONSA dosing as recommended. ( 5.3 ) Increased fractures and mortality in combination with radium Ra 223 dichloride: Use of YONSA plus methylprednisolone in combination with radium Ra 223 dichloride is not recommended. ( 5.4 ) Embryo-Fetal Toxicity: YONSA 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 YONSA 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 YONSA. 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 abiraterone acetate [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 YONSA 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) 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 the two randomized clinical studies in 0.5% of patients taking abiraterone acetate and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving abiraterone acetate in combination with a corticosteroid, 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 corticosteroids, have corticosteroid 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 YONSA. 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 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 two randomized clinical t…

4 CONTRAINDICATIONS None. None

7 DRUG INTERACTIONS 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 )] .

8.1 Pregnancy Risk Summary The safety and efficacy of YONSA have not been established in females. Based on findings from animal studies and the mechanism of action, YONSA can cause fetal harm and potential loss of pregnancy. There are no human data on the use of YONSA in pregnant women. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis, caused adverse developmental effects at maternal exposures of 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 6-17). 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.

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, 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…