DOSING & MONITORING

ZYTIGA^® Dosing & Monitoring

HOW TO TAKE ZYTIGA^® (abiraterone acetate)

Zytiga® Dosing & Monitoring - Tablet Empty Stomach

ZYTIGA^® 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 ZYTIGA^®
ZYTIGA^® should not be taken with food. ZYTIGA^® taken with food causes increased exposure and may result in adverse reactions

Zytiga® Dosing & Monitoring - Tablet Glass

Tablets should be swallowed whole with water
Tablets should not be crushed or chewed

Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy

The recommended dose of ZYTIGA^®

For Men With Metastatic High-Risk CSPC
For Men With mCRPC

ZYTIGA® Dosage Information for men with metastatic high-risk CSPC

ZYTIGA® Dosage Information for men with mCRPC

Tablets shown are not actual size.

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 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)].

For more information on Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity and information on Dose Modification Guidelines, see When To Modify Dose.

THE ROLE OF PREDNISONE

Co-administration of Prednisone Supresses Adrenocorticotropic Hormone (ACTH) Drive, Reducing the Incidence and Severity of Mineralocorticoid-Related Adverse Reactions¹

ZYTIGA® and prednisone | The Role of Prednisone

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)].

MONITORING CONSIDERATIONS

Schedule for Required Monitoring of Patients Receiving ZYTIGA^® Plus Prednisone

Assessment	Frequency*
Hypertension, hypokalemia, and fluid retention	Baseline and at least once a month
Liver function tests (ALT, AST, bilirubin)	Baseline and every 2 weeks for the first 3 months of treatment and monthly thereafter^†

Control hypertension and correct hypokalemia before starting and during treatment with ZYTIGA^®
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^®.
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.
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.
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
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.
For more information on Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity and information on Dose Modification Guidelines for Strong CYP3A4 Inducers, see When To Modify Dose

^* Assess more frequently as required.

^† Suggested schedule for patients with no or mild baseline hepatic impairment. For patients with baseline hepatic impairment or who develop hepatotoxicity during treatment, see When to Modify Dose. Do not use ZYTIGA^® in patients with baseline severe hepatic impairment (Child-Pugh Class C). Please see additional safety information below and full Prescribing Information for complete Dosage and Administration and Warnings and Precautions.

WHEN TO MODIFY DOSE

HEPATIC IMPAIRMENT AT BASELINE

No/Mild Hepatic Impairment	Moderate Hepatic Impairment (Child-Pugh Class B) Prior to treatment	Severe Hepatic Impairment (Child Pugh Class C) Prior to treatment
No dosage adjustment is necessary	Reduce ZYTIGA^® dose to 250mg orally QD	Do not use ZYTIGA^® in patients with severe hepatic impairment (Child-Pugh Class C)

OD = once daily; BID= twice daily.

For patients with moderate hepatic impairment (Child-Pugh Class B) monitor serum transaminases (ALT [alanine aminotransferase] and AST [aspartate aminotransferase]) and bilirubin levels

Prior to the start of treatment
For the first month of treatment, monitor every week
For the following 2 months of treatment, monitor every 2 weeks
Monthly thereafter

If elevations in ALT and/or AST >5 x ULN (upper limit of normal) or total bilirubin >3 x ULN occur, discontinue ZYTIGA^® and do not re-treat patients with ZYTIGA^®.

HEPATOTOXICITY

Permanently discontinue ZYTIGA^® (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.

First occurrence of hepatotoxicity

Patient develops hepatotoxicity during treatment with ZYTIGA^®: ALT (alanine aminotransferase) and/or AST (aspartate aminotransferase) >5 x ULN (upper limit ofnormal) or total bilirubin >3 x ULN
- - Withhold ZYTIGA^® treatment and monitor LFTs^*
- - Patient's LFTs return to baseline levels or patient's AST and ALT ≤2.5 x ULN and total bilirubin ≤1.5 x ULN
  Resume ZYTIGA^® at 750 mg once daily
- Monitor AST, ALT, and bilirubin at a minimum of every 2 weeks for 3 months and monthly thereafter

Recurrence of hepatotoxicity (at 750 mg dose)

If hepatotoxicity recurs at 750 mg once daily:
- - Withhold ZYTIGA^® treatment and monitor LFTs^*
- - When patient's LFTs return to baseline levels or patient's AST and ALT ≤2.5 x ULN and total bilirubin ≤1.5 x ULN
  Resume ZYTIGA^® at 500 mg once daily

^*LFT: Liver Function Test.

Recurrence of hepatotoxicity (at 500 mg dose)

If hepatotoxicity recurs at 500 mg once daily:
- – Discontinue treatment with ZYTIGA^®

The safety of ZYTIGA^® re-treatment of patients who develop AST or ALT ≥20 x ULN and/or bilirubin ≥10 x ULN is unknown.

STRONG CYP3A4 INDUCERS

For patients taking strong CYP3A4 inducers

Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA^® treatment
If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA^® dosing frequency to twice a day only during the co-administration period (eg, from 1,000 mg once daily to 1,000 mg twice a day)
Reduce the dose back to previous dose and frequency if the concomitant strong CYP3A4 inducer is discontinued

Effects of Abiraterone on Drug Metabolizing Enzymes

For patients taking CYP2D6 and CYP2C8 substrates

Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine)
If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug
Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrates with a narrow therapeutic index if used concomitantly with ZYTIGA^®

References:1. Attard G, Reid AHM, A’HernR, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27(23):3742-3748. 2. Attard G, Reid AHM, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26(28):4563-4571. 3. Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA. 1999;282(7):671-676.

Learn more about the resources that are available to your and your ZYTIGA^® (abiraterone acetate) patients.

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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