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-------------------------­
`
`
`
`
`05/2014
`Dosage and Administration. (2.2)
`
`----------------------------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)
`
`
`
`• Adrenocortical insufficiency: Monitor for symptoms and signs of
`
`
`
`adrenocortical insufficiency. Increased dosage of corticosteroids may be
`
`
`
`indicated before, during and after stressful situations. (5.2)
`
`
`
`• Hepatotoxicity: 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, hyperglycemia, 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
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`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
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trial Experience
`
`
`
`6.2 Post Marketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes
`
`7.2 Effects of Abiraterone on Drug Metabolizing
`
`Enzymes
`
`
`
`Reference ID: 3759951
`
`
`
`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
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 1
`
`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` INDICATIONS AND USAGE
` 1
`
` 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
`
`
`
`
`
`
`
`
`
`
`
` 2
`
`Reference ID: 3759951
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 2
`
`

`
`
`
`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)].
`
`
`
`
`
`
`Reference ID: 3759951
`
`
`
` 3
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 3
`
`

`
`
`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
`
`inhibition [see Clinical
`increased mineralocorticoid
`levels resulting from CYP17
`
`
`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 adrenocortical 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
`
`
`
`
`
`
`
`
`
` 4
`
`Reference ID: 3759951
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 4
`
`

`
`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
`
`
`
`
`
`
`
`
` 5
`
`Reference ID: 3759951
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 5
`
`

`
`
`
`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.
`
`
`
`The most common laboratory abnormalities (>20%) reported in the two randomized clinical
`
`
`
`trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia,
`
`
`
`
`
`
`
`
`elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia,
`hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
`
`
`Study 1: Metastatic CRPC Following Chemotherapy
`
`
`
`
`Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel
`
`
`
`
`chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 XULN 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.
`
`
`
`
`
`Reference ID: 3759951
`
`
`
` 6
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 6
`
`

`
`
` Table 1:
`
`
`
`
`
` Adverse Reactions due to ZYTIGA in Study 1
`
`
`
`
`
`
`
`
`
`
`
` Placebo with Prednisone
`
` (N=394)
`
`
` Grade 3-4
`
` All Grades
`
` %
`
` %
`
`
`
` 23.4
`
` 23.1
`
`
` 18.3
`
`
` 16.8
` 6.9
`
`
`
` 13.5
` 3.3
`
`
`
` 7.1
`
` 2.5
`
`
`
` 7.6
`
`
` 5.1
`
` 4.1
`
`
`
` 2.3
`
`
` 4.6
`
` 2.8
`
` 1.0
`
`
`
` 4.1
`
` 2.3
`
`
` 0.8
`
`
` 0.3
`
` 0.3
`
`
` 1.3
`
` 0
`
`
` 0.5
`
` 0
`
`
`
` 0
`
`
` 0.3
`
` 0
`
`
`
` 0
`
`
` 1.0
`
` 0
` 0.3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ZYTIGA with Prednisone
`
` (N=791)
`
` All Grades1
`
`
` Grade 3-4
`
` %
`
` %
`
`
` 29.5
`
` 26.2
`
`
` 26.7
`
`
` 19.0
` 8.5
`
`
`
` 17.6
` 6.1
`
`
`
` 11.5
` 5.4
`
`
`
` 10.6
`
`
` 7.2
`
` 6.2
`
`
` 4.2
`
` 3.0
`
`
` 1.9
`
`
` 0.3
`
` 1.3
`
`
` 0.6
`
` 0
`
`
` 2.1
`
` 0
`
`
`
` 0
`
`
` 0.3
`
` 0
`
`
`
` 1.4
`
`
` 1.1
`
` 0.5
`
` 1.9
`
`
` 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
`
`
` 5.9
`
`
`
`
` Cardiac disorders
`
`
`
` Arrhythmia6
`
` 7.2
`
` Chest pain or chest discomfort7
`
`
` 3.8
`
`
` Cardiac failure8
`
`
` 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
`
`
`
`
`
`
`
`
`
`
` 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.
`
`Reference ID: 3759951
`
`
`
` 7
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 7
`
`

`
`
` Table 2:
`
`
` Laboratory Abnormality
`
` Hypertriglyceridemia
`
` High AST
` Hypokalemia
`
` Hypophosphatemia
`
` High ALT
` High Total Bilirubin
`
`
`
`
`
`
`
`
`
`
` Laboratory Abnormalities of Interest in Study 1
`
`
`
` Placebo (N=394)
`
` Abiraterone (N=791)
`
` Grade 3-4 (%)
`
` Grade 3-4 (%) All Grades (%)
`
`
`
` All Grades (%)
` 0
`
`
` 0.4
`
`
` 53.0
`
` 62.5
`
` 1.5
`
`
` 2.1
`
` 36.3
`
` 30.6
`
` 1.0
`
`
` 5.3
`
` 19.8
`
` 28.3
`
` 5.8
`
`
` 7.2
`
` 15.7
`
` 23.8
`
` 0.8
`
`
` 1.4
`
` 10.4
`
` 11.1
`
`
` 0.1
` 4.6
`
` 6.6
`
` 0
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`Reference ID: 3759951
`
`
`
` 8
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 8
`
`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3:
`
`
`
`
`
`
`
`
` Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2
`
`
`
`
` Placebo with Prednisone
`
` (N=540)
`
` Grade 3-4
`
` All Grades
`
` %
`
` %
`
`
`
`
` 34.3
`
` 20.7
` 5.9
`
`
`
`
` 25.2
` 4.1
`
`
`
` 19.1
`
` 17.8
` 5.0
`
`
`
` 18.1
`
` 13.1
`
`
`
` 13.5
` 9.6
`
`
` 11.3
`
`
`
`
`
` 9.1
`
` 3.3
`
`
`
` 8.0
`
` 8.1
`
`
` 5.6
`
` 3.7
`
`
`
`
`
`
` 1.7
`
` 1.1
`
` 0.2
`
`
`
` 2.0
`
` 0.7
`
`
` 0.6
`
` 0.9
`
` 0.2
`
`
` 0.0
`
` 3.0
`
`
`
` 0.2
`
` 0.9
`
` 0.0
`
`
`
`
`
` 0.0
`
` 0.0
`
`
`
` 0.0
`
` 0.0
`
`
` 0.6
`
` 0.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ZYTIGA with Prednisone (N=542)
`
` All Grades1
`
` Grade 3-4
`
`
`
`
` %
`
` %
`
`
`
`
` 39.1
`
` 25.1
` 8.7
`
`
`
` 30.3
` 6.6
`
`
`
` 23.1
`
` 21.6
`
` 11.1
`
`
` 22.3
`
` 21.6
`
`
` 17.3
`
` 11.8
`
` 13.5
`
`
`
`
` 13.3
` 5.9
`
`
`
`
` 12.7
`
` 10.7
`
` 10.3
`
`
`
`
`
`
` 2.2
`
` 0.4
`
` 0.6
`
`
`
` 2.0
`
` 0.4
`
`
` 0.4
`
` 0.9
`
` 0.0
`
`
` 0.2
`
` 3.9
`
`
`
` 0.0
`
` 2.4
`
` 0.2
`
`
`
`
`
` 0.0
`
` 0.0
`
`
`
` 0.0
`
` 0.0
`
`
` 1.3
`
` 0.0
`
`
`
`
`
`
` 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
`
`
` 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
`
`
`
`
`
`
`
`
` 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.
`
`Reference ID: 3759951
`
`
`
` 9
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 9
`
`

`
`
` Table 4:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Grade 3-4
`
` %
`
`
`
` 8.7
`
`
` 6.5
`
` 6.1
`
` 3.1
`
` 0.4
`
` 2.8
`
`
`
`
`
` Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2
`
`
`
` Placebo (N=540)
`
`
` Abiraterone (N=542)
` Grade 1-4
`
`
`
`
` Grade 1-4
`
` Grade 3-4
` Laboratory Abnormality
`
` %
`
` %
`
` %
`
`
` Hematology
`
`
`
` Lymphopenia
` 38.2
`
`
` 31.7
`
` 7.4
`
`
` Chemistry
`
`
` Hyperglycemia1
`
` 56.6
`
`
` 50.9
`
` 5.2
`
` 41.9
`
` High ALT
`
`
` 29.1
`
` 0.7
`
` High AST
`
` 37.3
`
`
` 28.7
`
` 1.1
`
` Hypernatremia
`
` 32.8
`
`
` 25.0
`
` 0.2
`
` 17.2
`
`
`
` 10.2
`
` 1.7
` Hypokalemia
`
` 1 Based on non-fasting blood draws
`
`
`
`
`
`
`
`
`
`
` Cardiovascular Adverse Reactions:
`
`
`
` In the combined data for studies 1 and 2, cardiac failure occurred more commonly in
`
`
` patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).
`
` Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5
`
`
`
`
` treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of
`
`
`
` patients taking placebo. There were no treatment discontinuations and one death due to
`
`
` cardiac failure in the placebo group.
`
`
`
`
`
`
`
`
`
` In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death
`
`
` associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no
`
`
` deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the
`
`
`
`
`
`
` ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial
`
`
`
`
` infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.2 Post Marketing Experience
`
`
`The following additional adverse reactions have been identified during post approval use of
`ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain
`size, it is not always possible to reliably estimate their frequency or establish a causal
`
`
` relationship to drug exposure.
`
`
`
` Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.
`
`
`
` Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.
`
`
` 7 DRUG INTERACTIONS
` 7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes
`
`
`
` Based on in vitro data, ZYTIGA is a substrate of CYP3A4.
`
`
`
`
`
`
`Reference ID: 3759951
`
`
`
` 10
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 10
`
`

`
`In a dedicated 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 [see Dosage and Administration (2.3) and Clinical
`
`
`
`Pharmacology (12.3)].
`
`
`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 [see
`Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`7.2 Effects of Abiraterone on Drug Metabolizing Enzymes
`
`
`
`ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8.
`In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6
`
`
`
`
`
`
`substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given
`
`
`
`with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid
`co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow
`
`
`
`
`
`
`therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise
`
`caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see
`
`
`Clinical Pharmacology (12.3)].
`
`
`
`
`In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone
`
`
`(CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a
`
`
`
`single dose of 1,000 mg abiraterone acetate. Therefore, 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)].
`
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`Pregnancy Category X [see Contraindications (4.1)].
`
`
`
`
`
`
`ZYTIGA can cause fetal harm when administered to a pregnant woman based on its
`
`mechanism of action and findings in animals. While there are no adequate and well-
`controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in
`
`
`
`women, it is important to know that maternal use of a CYP17 inhibitor could affect
`
`
`development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats
`
`
`
`at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is
`contraindicated in women who are or may become pregnant while receiving the drug. 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
`
`
`
`
`
`Reference ID: 3759951
`
`
`
` 11
`
`MYLAN PHARMS. INC. EXHIBIT 1065 PAGE 11
`
`

`
`loss. Advise females of reproductive potential to avoid becoming pregnant during treatment
`
`
`with ZYTIGA.
`
`
`
`In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused
`
`developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day
`
`
`
`throughout the period of organogenesis (gestational days 6-17). Findings included embryo-
`
`
`fetal lethality (increased post implantation loss and resorptions and decreased number of live
`
`fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter
`
`
`
`
`dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day,
`
`
`
`
`
`and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal
`
`
`
`
`toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03,
`0.1 and 0.3 times, respectively, the AUC in patients.
`
`
`
`
`
`
`
`8.3 Nursing Mothers
`
`
`ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted
`
`
`
`
`in human milk. Because many drugs are excreted in human milk, and because of the
`potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should
`
`be made to either discontinue nursing, or discontinue the drug taking into account the
`
`
`importance of the drug to the mother.
`
`
`8.4 Pediatric Use
`
`
`Safety and effectiveness of ZYTIGA in pediatric patients have not been established.
`
`
`
`
`
`8.5 Geriatric Use
`
`
`Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were
`
`
`
`
`
`
`
`65 years and over and 30% were 75 years and over. No overall differences in safety or
`
`
`
`
`
`effectiveness were observed between these elderly patients and younger patients. Other
`
`
`reported clinical experience