PUTTING
`
`PREDNISO
`IN PERSPEC
`
`e ofprednisone
`
`nisone for the treatment
`
`rostate cancer (mCRPC).
`
`
`
`T|GA®
`
`Retention Due to
`
`ion in patients with a
`l conditions that might
`sure, hypokalemia, or
`"on, h\/pokalemia, and
`ineralocorticoid levels
`
`established in patients
`(NYHA) Class Ill or IV
`rt failure (in Study 2)
`- randomized clinical
`
`ia before and during
`, and symptoms of
`
`ARGENTUM EX1019
`‘ RGENTUM EX1019
`Page 1
`
`Page 1
`
`

`
`
`
`of mineralocorticoid-related adverse reactions
`
`associated with ZYTlGA® (abiraterone acetate)
`
`Mechanism of action
`
`VZYTIGAO is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17oL—hydroxylase/
`C17,2O Iyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostate tumor tissues and is required
`for androgen biosynthesis
`
`'This inhibition of the CYP17 enzyme complex can result in increased mineralocorticoid production and may
`cause hypertension, hypokalemia, and fluid retention
`
`Vsecretion of adrenocorticotropic hormone (ACTH) by the pituitary gland drives the production of
`mineralocorticoids, androgens, and glucocorticoids, such as cortisol, in the adrenal cortex‘
`
`Endogenous cortisol production under normal conditions’
`
`anterior
`
`pituitary
`
`Adapted with permission from Macmillan Publishers Ltd: Nature Reviews Endocrinology. Vassiliadi DA, Tsagarakis S. Endocrine incidenta|omas—challenges imposed by
`incidentally discovered lesions. Nat Rev Endocrinol. 201l;7(ll):668-680. Copyright 2011.
`
`V Secreted levels of ACTH increase in response to decreased levels of cortisol due to CYP17 complex inhibition”
`
`V Coadministration of prednisone suppresses the ACTH drive and reduces the incidence and severity of
`mineralocorticoid excess adverse reactions
`
`Adrenocortical Insufficiency (AI)—Al was reported in patients receiving ZYT|GA° in combination with prednisone,
`after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms
`and signs ofAI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or ifthe patient experiences
`unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess
`seen in patients treated with ZYTIGA°. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of
`corticosteroids may be used before, during, and after stressful situations.
`
`Page 2
`
`
`
`Please see Important Safety Information on the last page.
`Please see the full Prescribing Information.
`
`Page 2
`
`

`
`
`
`ACTH rive, redun ic setyof
`mineralocorticoid adverse reactions
`
`cortisol production
`is driven by ACTH
`
`cortisol levels become
`
`adding prednisone suppresses
`the ACTH drive, therefore
`lessening the system's response
`to a net cortisol deficit
`
`ecreased during treatment
`with ZY11GA° due
`
`
`
`to the inhibition
`
`ofthe CYP17
`
`enzyme complex
`
`‘The endogenous production of cortisol may range from 9.5 mg/day to 22 mg/day'‘'‘’
`
`V 7.5 mg/day to 10 mg/day of prednisone is approximately the physiologic equivalent of the amount of endogenous
`cortisol normally produced on a daily basis‘-"-‘°
`
`Recommended dosing
`
`VZYTIGAG’ 1,000 mg (four 250-mg tablets) administered orally once daily in combination with prednisone 5 mg
`administered orally twice daily
`
`VZYTIGAG’ must be taken on an empty stomach. The tablets should be swallowed whole with water. Do not crush
`or chew tablets. In patients with baseline moderate hepatic impairment (Chi|d—Pugh Class B), reduce the ZYTIGAP
`starting dose to 250 mg once daily. Do not use ZYTIGAO in patients with baseline severe hepatic impairment
`(Chi|d—Pugh Class C)’
`
`'Adrenocorticotropic hormone.
`‘Endogenous cortisol levelsvary per individual.
`‘Please seefull Prescribing Information, Dosage and Administration section, for dose modifications based on hepatic function and concomitant strong CYP3A4 inducers.
`
`I. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endoainol Metab Gin North Am. 200l;30(l):l0l—'l19.
`References:
`2. Vassiliadi DA, Tsagarakis S. Endocrine incidentalomas—cha||enges imposed by incidentally discovered lesions. NM Rev Endoaind. 20ll;7(1l).668-680. 3. Attard (J, Reid AHM,
`YapTA, et al. Phase I clinical
`trial of a selective inhibitor of CYPI7, abiraterone acetae, confirms that castration-resistant prostate cancer commonly remains homione driven.
`J Clin Oncol. 2008;2b(28):4563-471. 4. Krasner AS. Glucocorticoidinduced adrenal
`insulliciency.
`JQMA.
`l999,282(7):67l—676. 5. Kraan GPB, Ddlaart RPF, Pratt
`JJ, Woldiers
`BG Drayer NM, De Bruin R. The daily cortisol production reinvestigated in healthy men. The senirn and urinary cortisol production rats are not
`significantly dilferent.
`J Clin Endoainol Metab. l998;83(4).l21V-1752. 6. Debono M, Ross RJ, Nevvell-Price J. lnadequacies of glucocorticoid replacement and improvements by physiological circarfian therapy.
`Eur J Endoainol. 2009,l60:7l9~729. 7. U.S. Department of Health and Human Services National Health Statistirs Reports. Anthropometric reference data for children and adults:
`United States, 2003-2006. 2008;10:l~48. 8. Mosteller RD. Simplified calculation of body-surface area. N End J Med. l987;3l7(‘|7):l098. 9. Petri MA, Lahita RC, van Vollenhoven RF, et al.
`Effects of prasterone on corficosteroid requirements of women with systemic lupus erythematosus a double-blind, randomized, placebocontrolled trial. Artlrifis & Rheumatism.
`2002;46(7):l820—l829. I). Prednisolone Tablets 5 mg Summary of Product Characteristics. Available at: http://www.medicines.org.uk/ernc/medicine/10816/spc. Accessed January 08, 2015.
`
`Please see Important Safety Information on the last page.
`Please see the full Prescribing Information.
`
`once-daily
`
`Zytiga®
`
`250 mg tablets
`Page 3
`
`Page 3
`
`

`
`IMPORTANT SAFETY INFORMATION
`
`C‘ Contraindications—ZYTIGA° (abiraterone acetate) is not indicated for use in women. ZYTIGAO can cause fetal harm
`(Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may
`become pregnant.
`
`
`
`C‘ Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with
`a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure,
`hypokalemia, or fluid retention. ZYTIGAO may cause hypertension, hypokalemia, and fluid retention as a consequence of
`increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patientswith LVEF<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)
`because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia
`before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.
`
`C‘Adrenocortica| Insufficiency (AI)—A| was reported in patients receiving ZYTIGAG’ in combination with prednisone, after
`an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and
`signs of Al if prednisone is stopped or withdrawn, if prednisone dose is reduced, or ifthe patient experiences unusual stress.
`Symptoms and signs of Al may be masked by adverse reactions associated with mineralocorticoid excess seen in patients
`treated with ZYTIGAO. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be
`used before, during, and after stressful situations.
`
`C‘ Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYT|GA° dosing as recommended (see
`Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate
`aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYT|GA°, every two weeks for the first three
`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 orALT rise above five times the upper limit of normal (U LN) or the bilirubin rises
`above three times the ULN, interrupt ZYTIGAG’ treatment and closely monitor liver function.
`
`C‘ Increased ZYTIGAP Exposures with Food—ZYT|GA° must be taken on an empty stomach. No food should be eaten for at
`least two hours before the dose ofZYTIGAO is taken and for at least one hour after the dose ofZYT|GA° is taken. Abiraterone
`
`Cm and AUCM, (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone
`acetate was administered with a meal compared to a fasted state.
`
`(‘Adverse Reactions—The most common adverse reactions (210%) are fatigue, joint swelling or discomfort, edema, hot
`flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.
`
`The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia,
`lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
`
`In a drug interaction trial,
`C‘ Drug Interactions—Based on in vitro data, ZYTIGAG is a substrate of CYP3A4.
`co—administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%.Avoid concomitant
`strong CYP3A4 inducers during ZYTIGAO treatment. If a strong CYP3A4 inducer must be co—administered, increase
`the ZYTIGAG’ dosing frequency only during the co—administration period [see Dosage and Administration (2.3)]. 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.
`
`ZYTIGAG’ is an inhibitor of the hepatic drug- metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with
`CYPZD6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and
`consider a dose reduction of the CYPZD6 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 ZYT|GA°.
`Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate with a narrow therapeutic
`index if used concomitantly with ZYTIGAG’.
`
`C‘ Use in Specific Popu|ations— Do not use ZYTIGAP in patients with baseline severe hepatic impairment (Chi|d—Pugh Class C).
`
`003317-‘I$13
`
`www.zytigahcp.com
`
`Please see the full Prescribing Information.
`
`Janssen Biotech, Inc.
`oJmssenaiauaan,Inc-. 2015 ans 003722-150213
`
`once-daily
`
`L
`
`(abiraterone acetate)
`250 mg tablets
`
`Ja ll e II
`W“-*°=""w =°'"~~-1*
`“I
`I
`Page 4
`
`Page 4
`
`

`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ZYTIGA safely
`and effectively. See full prescribing information for ZYTIGA.
` ZYTIGA® (abiraterone acetate) Tablets
`For Oral Administration
`Initial U.S. Approval: 2011
`
`---------------------------------- RECENT MAJOR CHANGES ------------------------------
`Dosage and Administration. (2.2)
`05/2014
`-----------------------------------INDICATIONS AND USAGE ------------------------------
` ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the
`treatment of patients with metastatic castration-resistant prostate cancer. (1)
`
`-------------------------------DOSAGE AND ADMINISTRATION --------------------------
`Recommended dose: ZYTIGA 1,000 mg (four 250 mg tablets) administered orally
`once daily in combination with prednisone 5 mg administered orally twice daily.
` ZYTIGA must be taken on an empty stomach. No food should be consumed for at
`least two hours before the dose of ZYTIGA is taken and for at least one hour
`after the dose of ZYTIGA is taken. The tablets should be swallowed whole with
`water. Do not crush or chew tablets. (2.1)
`• For patients with baseline moderate hepatic impairment (Child-Pugh Class B),
`reduce the ZYTIGA starting dose to 250 mg once daily. (2.2)
`• For patients who develop hepatotoxicity during treatment, hold ZYTIGA until
`recovery. Retreatment may be initiated at a reduced dose. ZYTIGA should be
`discontinued if patients develop severe hepatotoxicity. (2.2)
`
`------------------------------DOSAGE FORMS AND STRENGTHS -------------------------
`Tablet 250 mg (3)
`
`------------------------------------- CONTRAINDICATIONS ---------------------------------
`• ZYTIGA is contraindicated in women who are or may become pregnant.
`(4.1, 8.1)
`-------------------------------WARNINGS AND PRECAUTIONS ---------------------------
`• Mineralocorticoid excess: Use ZYTIGA with caution in patients with a history
`of cardiovascular disease. The safety of ZYTIGA in patients with LVEF < 50%
`or NYHA Class III or IV heart failure in Study 1 or LVEF < 50% or NYHA Class II
`to IV heart failure in Study 2 was not established. Control hypertension and
`correct hypokalemia before treatment. Monitor blood pressure, serum
`potassium and symptoms of fluid retention at least monthly. (5.1)
`
`ZYTIGA® (abiraterone acetate) Tablets
`
`• Adrenocortical
`for symptoms and signs of
`insufficiency: Monitor
`adrenocortical insufficiency. Increased dosage of corticosteroids may be
`indicated before, during and after stressful situations. (5.2)
`• Hepatotoxicity: Increases in liver enzymes have led to drug interruption, dose
`modification and/or discontinuation. Monitor
`liver function and modify,
`interrupt, or discontinue ZYTIGA dosing as recommended. (5.3)
`-------------------------------------ADVERSE REACTIONS ---------------------------------
`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.
`The most common laboratory abnormalities (>20%) are anemia, elevated alkaline
`phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyper-
`glycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech,
`Inc. at 1-800-526-7736
`(1-800-JANSSEN) or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`------------------------------------ DRUG INTERACTIONS ----------------------------------
` •
` CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during ZYTIGA
`treatment. If a strong CYP3A4 inducer must be co-administered, increase the
`ZYTIGA dosing frequency. (2.3, 7.1)
` CYP2D6 Substrates: Avoid co-administration of ZYTIGA 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)
`
`•
`
`------------------------------ USE IN SPECIFIC POPULATIONS ----------------------------
`• Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-
`Pugh Class C). (8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
`labeling.
`
`Revised: 5/2015
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2
` Dose Modification Guidelines in Hepatic Impairment and
`Hepatotoxicity
`2.3 Dose Modification Guidelines for Strong CYP3A4 Inducers
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`4.1 Pregnancy
`
`5 WARNINGS AND PRECAUTIONS
` 5.1
` Hypertension, Hypokalemia and Fluid Retention Due to
`Mineralocorticoid Excess
`5.2 Adrenocortical Insufficiency
`5.3 Hepatotoxicity
`ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`6.2 Post Marketing Experience
`DRUG INTERACTIONS
`7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes
`7.2 Effects of Abiraterone on Drug Metabolizing Enzymes
`
`
`6
`
`7
`
`8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Hepatic Impairment
`8.7 Patients with Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`12.6 QT Prolongation
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information are not
`listed.
`
`1
`
`Page 5
`
`

`
`ZYTIGA® (abiraterone acetate) Tablets
`
`ZYTIGA® (abiraterone acetate) Tablets
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
` ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the
`treatment of patients with metastatic castration-resistant prostate cancer.
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosage
`The recommended dose of ZYTIGA is 1,000 mg (four 250 mg tablets) administered
`orally once daily in combination with prednisone 5 mg administered orally twice
`daily. ZYTIGA must be taken on an empty stomach. No food should be consumed
`for at least two hours before the dose of ZYTIGA is taken and for at least one
`hour after the dose of ZYTIGA is taken [see Clinical Pharmacology (12.3)]. The
`tablets should be swallowed whole with water. Do not crush or chew tablets.
`2.2 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 ZYTIGA to 250 mg once daily. A once daily
`dose of 250 mg in patients with moderate hepatic impairment is predicted to
`result in an area under the concentration curve (AUC) similar to the AUC seen in
`patients with normal hepatic function receiving 1,000 mg once daily. However,
`there are no clinical data at the dose of 250 mg once daily in patients with
`moderate hepatic impairment and caution is advised. 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 ZYTIGA and do
`not re-treat patients with ZYTIGA [see Use in Specific Populations (8.6) and
`Clinical Pharmacology (12.3)].
` Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-
`Pugh Class C).
`Hepatotoxicity
`For patients who develop hepatotoxicity during treatment with ZYTIGA (ALT
`and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt
`treatment with ZYTIGA [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
`2.5X 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 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
`2.5X ULN and total bilirubin less than or equal to 1.5X ULN.
`If hepatotoxicity recurs at the reduced dose of 500  mg once daily, discontinue
`treatment with ZYTIGA. The safety of ZYTIGA re-treatment of patients who
`develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater
`than or equal to 10X ULN is unknown.
`2.3 Dose Modification Guidelines for Strong CYP3A4 Inducers
` Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine,
`rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. Although
`there are no clinical data with this dose adjustment in patients receiving strong
`CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4
`inducer must be co-administered, increase the ZYTIGA 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)].
`3
`DOSAGE FORMS AND STRENGTHS
` ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval-shaped
`tablets debossed with AA250 on one side.
`CONTRAINDICATIONS
`4
`4.1 Pregnancy
` ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA
`is not indicated for use in women. ZYTIGA is contraindicated in women who are
`or may become pregnant. If this drug is used during pregnancy, or if the patient
`becomes pregnant while taking this drug, apprise the patient of the potential
`hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific
`Populations (8.1)].
`5 WARNINGS AND PRECAUTIONS
` Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid
`5.1
`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)]. 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 ZYTIGA
`[see Adverse Reactions (6)].
`
` Co-administration of a corticosteroid suppresses adrenocorticotropic hormone
`(ACTH) drive, resulting in a reduction in the incidence and severity of these
`adverse reactions. Use caution when treating patients whose underlying medical
`conditions might be compromised by increases in blood pressure, hypokalemia
`or fluid retention, e.g., those with heart failure, recent myocardial infarction or
`ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of
`cardiovascular disease. 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 Study 1) or NYHA Class II to IV heart failure (in Study 2) was not
`established because these patients were excluded from these randomized
`clinical trials [see Clinical Studies (14)]. Monitor patients for hypertension,
`hypokalemia, and fluid retention at least once a month. Control hypertension and
`correct hypokalemia before and during treatment with ZYTIGA.
`5.2 Adrenocortical Insufficiency
` Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of
`patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical
`insufficiency was reported in patients receiving ZYTIGA in combination with
`prednisone, following interruption of daily steroids and/or with concurrent
`infection or stress. Use caution and monitor for symptoms and signs of adreno-
`cortical insufficiency, particularly if patients are withdrawn from prednisone, have
`prednisone 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 ZYTIGA. 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 the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at
`least  5X ULN) were reported in 4% of patients who received ZYTIGA, typically
`during the first 3 months after starting treatment. Patients whose baseline ALT or
`AST were elevated were more likely to experience liver test elevation than those
`beginning with normal values. Treatment discontinuation due to liver enzyme
`increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to
` ZYTIGA were reported due to hepatotoxicity events.
`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 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 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see
`Dosage and Administration (2.2)].
`The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater
`than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN
`is unknown.
`6
`ADVERSE REACTIONS
`The following are discussed in more detail in other sections of the labeling:
`• Hypertension, Hypokalemia, and Fluid Retention 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)].
`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 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 ZYTIGA was administered 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
`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.
`in the two
`The most common
`laboratory abnormalities (>20%) reported
`randomized clinical trials that occurred more commonly (≥2%) in the abiraterone
`acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia,
`lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypo-
`phosphatemia, elevated ALT and hypokalemia.
`
`2
`
`Page 6
`
`

`
`ZYTIGA® (abiraterone acetate) Tablets
`
`ZYTIGA® (abiraterone acetate) Tablets
`
`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 ZYTIGA 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 ZYTIGA was 8 months.
`
`Table 1: Adverse Reactions due to ZYTIGA in Study 1
` ZYTIGA with
`Placebo with
`Prednisone (N=394)
`Prednisone (N=791)
`All Grades1 Grade 3-4 All Grades Grade 3-4
`%
`%
`%
`%
`
`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 ZYTIGA arm in Study 2 that occurred
`with a ≥2% absolute increase in frequency compared to placebo. The median
`duration of treatment with ZYTIGA was 13.8 months.
`
`Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2
`ZYTIGA with
`Placebo with
`Prednisone (N=542)
`Prednisone (N=540)
`All Grades1 Grade 3-4 All Grades Grade 3-4
`%
`%
`%
`%
`
`29.5
`26.2
`
`26.7
`
`19.0
`8.5
`
`17.6
`6.1
`
`11.5
`
`5.4
`
`10.6
`
`4.2
`3.0
`
`1.9
`
`0.3
`1.3
`
`0.6
`0
`
`2.1
`
`0
`
`0
`
`23.4
`23.1
`
`18.3
`
`16.8
`6.9
`
`13.5
`3.3
`
`7.1
`
`2.5
`
`7.6
`
`4.1
`2.3
`
`0.8
`
`0.3
`0.3
`
`1.3
`0
`
`0.5
`
`0
`
`0
`
`39.1
`25.1
`8.7
`
`30.3
`6.6
`
`23.1
`21.6
`11.1
`
`22.3
`21.6
`
`17.3
`11.8
`
`2.2
`0.4
`0.6
`
`2.0
`0.4
`
`0.4
`0.9
`0.0
`
`0.2
`3.9
`
`0.0
`2.4
`
`34.3
`20.7
`5.9
`
`25.2
`4.1
`
`19.1
`17.8
`5.0
`
`18.1
`13.1
`
`13.5
`9.6
`
`1.7
`1.1
`0.2
`
`2.0
`0.7
`
`0.6
`0.9
`0.2
`
`0.0
`3.0
`
`0.2
`0.9
`
`System/Organ Class
`Adverse reaction
`Musculoskeletal and connective
`tissue disorders
`Joint swelling/discomfort2
`Muscle discomfort3
`General disorders
`Edema4
`Vascular disorders
`Hot flush
`Hypertension
`Gastrointestinal disorders
`Diarrhea
`Dyspepsia
`Infections and infestations
`Urinary tract infection
`Upper respiratory tract
`infection
`Respiratory, thoracic and
`mediastinal disorders
`Cough
`Renal and urinary disorders
`Urinary frequency
`Nocturia
`Injury, poisoning and
`procedural complications
`Fractures5
`Cardiac disorders
`Arrhythmia6
`Chest pain or chest
`discomfort7
`0.5
`3.8
`Cardiac failure8
`1.9
`2.3
`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
` ZYTIGA 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
`
`5.1
`4.1
`
`2.3
`
`4.6
`
`2.8
`1.0
`
`0.3
`0
`
`0
`
`1.0
`
`0
`0.3
`
`7.2
`6.2
`
`5.9
`
`7.2
`
`0.3
`0
`
`1.4
`
`1.1
`
`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 ZYTIGA arm.
`
`Table 2: Laboratory Abnormalities of Interest in Study 1
`Abiraterone (N=791)
`All Grades
`Grade 3-4
`(%)
`(%)
`62.5
`0.4
`30.6
`2.1
`28.3
`5.3
`23.8
`7.2
`11.1
`1.4
`6.6
`0.1
`
`Laboratory Abnormality
`
`Hypertriglyceridemia
`High AST
`Hypokalemia
`Hypophosphatemia
`High ALT
`High Total Bilirubin
`
`Placebo (N=394)
`All Grades
`Grade 3-4
`(%)
`(%)
`53.0
`0
`36.3
`1.5
`19.8
`1.0
`15.7
`5.8
`10.4
`0.8
`4.6
`0
`
`System/Organ Class
`Adverse reaction
`General disorders
`Fatigue
`Edema2
`Pyrexia
`Musculoskeletal and connective
`tissue disorders
`Joint swelling/discomfort3
`Groin pain
`Gastrointestinal disorders
`Constipation
`Diarrhea
`Dyspepsia
`Vascular disorders
`Hot flush
`Hypertension
`Respiratory, thoracic and
`mediastinal disorders
`Cough
`Dyspnea
`Psychiatric disorders
`Insomnia
`Injury, poisoning and procedural
`complications
`Contusion
`Falls
`Infections and infestations
`Upper respiratory tract
`infection
`Nasopharyngitis
`Renal and urinary disorders
`Hematuria
`Skin and subcutaneous tissue
`disorders
`0.0
`8.1
`Rash
`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
`
`13.5
`
`13.3
`5.9
`
`12.7
`10.7
`
`10.3
`
`0.2
`
`0.0
`0.0
`
`0.0
`0.0
`
`1.3
`
`11.3
`
`9.1
`3.3
`
`8.0
`8.1
`
`5.6
`
`3.7
`
`0.0
`
`0.0
`0.0
`
`0.0
`0.0
`
`0.6
`
`0.0
`
`Table  4 shows laboratory abnormalities that occurred in greater than 15% of
`patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in
`Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine
`aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.
`
`Table 4: Laborato