PUTTING
`PREDNISONE
`IN PERSPECTIVE
`Understanding the role of prednisone
`in combination with ZYTIGA®
`(abiraterone acetate)
`
`ZYTIGA® is indicated in combination with prednisone for the treatment
`of patients with metastatic castration-resistant prostate cancer (mCRPC).
`
`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. ZYTIGA® may cause hypertension, hypokalemia, and
`fluid retention as a consequence of increased mineralocorticoid levels
`resulting from CYP17 inhibition. Safety has not been established in patients
`with 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.
`
`Please see Important Safety Information
`on the last page.
`Please see the full Prescribing Information.
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 1
`
`

`
`Prednisone reduces the incidence and severity
`of mineralocorticoid-related adverse reactions
`associated with ZYTIGA® (abiraterone acetate)
`
`Mechanism of action
`
` ZYTIGA® is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17a-hydroxylase/
`
`C17,20 lyase (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
`
` Secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland drives the production of
`
`mineralocorticoids, androgens, and glucocorticoids, such as cortisol, in the adrenal cortex1
`
`Endogenous cortisol production under normal conditions2
`
`anterior
`pituitary
`
`ACTH
`
`adrenal
`glands
`
`cortisol
`
`Adapted with permission from Macmillan Publishers Ltd: Nature Reviews Endocrinology. Vassiliadi DA, Tsagarakis S. Endocrine incidentalomas—challenges imposed by
`incidentally discovered lesions. Nat Rev Endocrinol. 2011;7(11):668-680. Copyright 2011.
`
`
`
` Secreted levels of ACTH increase in response to decreased levels of cortisol due to CYP17 complex inhibition1,3
`
` Coadministration of prednisone suppresses the ACTH drive and reduces the incidence and severity of
`
`mineralocorticoid excess adverse reactions
`
`Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® 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 AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the 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.
`
`Please see Important Safety Information on the last page.
`Please see the full Prescribing Information.
`
`2
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 2
`
`

`
`Coadministration of a corticosteroid suppresses the
`ACTH* drive, reducing the incidence and severity of
`mineralocorticoid adverse reactions
`
`cortisol production
`is driven by ACTH
`
`cortisol levels become
`decreased during treatment
`with ZYTIGA® due
`to the inhibition
`of the CYP17
`enzyme complex
`
`adding prednisone suppresses
`the ACTH drive, therefore
`lessening the system’s response
`to a net cortisol def icit
`
`
`
` The endogenous production of cortisol may range from 9.5 mg/day to 22 mg/day†4-8
`
` 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 basis4,9,10
`
`Recommended dosing
`
` 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. The tablets should be swallowed whole with water. Do not crush
`
`or chew tablets. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the ZYTIGA®
`starting dose to 250 mg once daily. Do not use ZYTIGA® in patients with baseline severe hepatic impairment
`(Child-Pugh Class C)‡
`
`* Adrenocorticotropic hormone.
`† Endogenous cortisol levels vary per individual.
`‡ Please see full Prescribing Information, Dosage and Administration section, for dose modifications based on hepatic function and concomitant strong CYP3A4 inducers.
`
`References: 1. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am. 2001;30(1):101-119.
`2. Vassiliadi DA, Tsagarakis S. Endocrine incidentalomas—challenges imposed by incidentally discovered lesions. Nat Rev Endocrinol. 2011;7(11):668-680. 3. 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. 4. Krasner AS. Glucocorticoid-induced adrenal
`insufficiency. JAMA. 1999;282(7):671-676. 5. Kraan GPB, Dullaart RPF, Pratt JJ, Wolthers
`BG, Drayer NM, De Bruin R. The daily cortisol production reinvestigated
`in healthy men. The serum and urinary cortisol production rates are not significantly different.
`J Clin Endocrinol Metab. 1998;83(4):1247-1252. 6. Debono M, Ross RJ, Newell-Price J. Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy.
`Eur J Endocrinol. 2009;160:719-729. 7. U.S. Department of Health and Human Services. National Health Statistics Reports. Anthropometric reference data for children and adults:
`United States, 2003-2006. 2008;10:1-48. 8. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317(17):1098. 9. Petri MA, Lahita RG, van Vollenhoven RF, et al.
`Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis & Rheumatism.
`2002;46(7):1820-1829. 10. Prednisolone Tablets 5 mg Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/10816/spc. Accessed January 08, 2015.
`
`Please see Important Safety Information on the last page.
`Please see the full Prescribing Information.
`
`3
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 3
`
`

`
`003307-150130
`
`IMPORTANT SAFETY INFORMATION
`
` Contraindications—ZYTIGA® (abiraterone acetate) is not indicated for use in women. ZYTIGA® can cause fetal harm
`(Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may
`become pregnant.
`
` 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. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of
`increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with 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.
`
` Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® 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 AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the 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.
`
` Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® 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 ZYTIGA®, 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 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.
`
` Increased ZYTIGA® Exposures with Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten 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. Abiraterone
`Cmax and AUC0-∞ (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 (≥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, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
` Drug Interactions—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 (2.3)]. 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.
`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, exercise caution and
`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 the CYP2C8 substrate with a narrow therapeutic
`index if used concomitantly with ZYTIGA®.
` Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).
`
`www.zytigahcp.com
`Please see the full Prescribing Information.
`
`Janssen Biotech, Inc.
`© Janssen Biotech, Inc. 2015 3/15 003722-150218
`
`MYLAN PHARMS. INC. EXHIBIT 1019 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*
`1
`INDICATIONS AND USAGE
`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
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`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
`
`MYLAN PHARMS. INC. EXHIBIT 1019 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.
`2
`DOSAGE AND ADMINISTRATION
`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.
`4
`CONTRAINDICATIONS
`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
`5.1
` Hypertension, Hypokalemia and Fluid Retention 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)]. 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
`
`MYLAN PHARMS. INC. EXHIBIT 1019 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
`Placebo with
` ZYTIGA 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
`M