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WARNINGS AND PRECAUTIONS

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions Due to Mineralocorticoid Excess - ZYTIGA^® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment.

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 ZYTIGA^®.

The safety of ZYTIGA^® in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301) 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)].

Adrenocortical Insufficiency - Adrenocortical insufficiency was reported in patients receiving ZYTIGA^® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency if prednisone is stopped or withdrawn, if the prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA^®. Perform appropriate tests, if clinically indicated, to confirm adrenocortical insufficiency. Increased dosages of corticosteroids may be used before, during, and after stressful situations [see Warnings and Precautions (5.1)].

Hepatotoxicity - In postmarketing experience, there have been ZYTIGA^®-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure, and deaths. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA^®, every two weeks for the first three months of treatment, and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA^® dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA^® treatment and closely monitor liver function. Re-treatment with ZYTIGA^® at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5 x ULN and total bilirubin less than or equal to 1.5 x ULN [see Dosage and Administration (2.4)].

Permanently discontinue ZYTIGA^® 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.

The safety of ZYTIGA^® 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.

Increased Fractures and Mortality in Combination With Radium Ra 223 Dichloride- ZYTIGA^® plus prednisone/prednisolone is not recommended for use in combination with radium Ra 223 dichloride outside of clinical trials. Increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received ZYTIGA^® plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with ZYTIGA^®plus prednisone/prednisolone [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity - The safety and efficacy of ZYTIGA^®have not been established in females. Based on animal reproductive studies and mechanism of action, ZYTIGA^®can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with ZYTIGA^®and for 3 weeks after the last dose of ZYTIGA^®[see Use in Specific Populations (8.1, 8.3)]. ZYTIGA^®should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)].

Hypoglycemia - Severe hypoglycemia has been reported when ZYTIGA^® 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 ZYTIGA^®. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

ADVERSE REACTIONS

Adverse Reactions - The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory tract infection, cough, and headache.

Laboratory Abnormalities - The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.

DRUG INTERACTIONS

Drugs That Inhibit or Induce CYP3A4 Enzymes - Based on in vitro data, ZYTIGA^® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA^® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA^® dosing frequency only during the co-administration period [see Dosage and Administration (2.5)]. 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)].

Effects of Abiraterone on Drug-Metabolizing Enzymes - ZYTIGA^® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA^®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA^® [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.6)].

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential - ZYTIGA^® can cause fetal harm and potential loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of ZYTIGA^® [see Use in Specific Populations (8.1)]. ZYTIGA^® may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

Hepatic Impairment - In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA^® to 250 mg once daily. Do not use ZYTIGA^® in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5 x ULN or total bilirubin >3 x ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA^® treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

Please read the full Prescribing Information and Patient Information for ZYTIGA^®.

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