---------------------------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 is 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 lead to drug interruption,
`
`dose modification and/or discontinuation. Monitor liver function and
`
`
`modify, interrupt, or discontinue ZYTIGA dosing as recommended. (5.3)
`
`• Food Effect: ZYTIGA must be taken on an empty stomach. Exposure (area
`under the curve) of abiraterone increases up to 10 fold when abiraterone
`
`acetate is taken with meals. (5.4)
`------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (≥ 5%) are joint swelling or discomfort,
`hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract
`infection, cough, hypertension, arrhythmia, urinary frequency, nocturia,
`
`dyspepsia, and upper respiratory tract infection. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Centocor
`Ortho Biotech Inc. at 800-457-6399 and www.centocororthobiotech.com or
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`---------------------------------DRUG INTERACTIONS----------------------------
`
`ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme
`CYP2D6. 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)
`-----------------------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.
`
`Issued: [April 2011]
`
`
`
`
`
` 
` 
`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
` 
` 
`12.4 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
`
`
`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
`----------------------------INDICATIONS AND USAGE----------------------------
`ZYTIGA is a CYP17 inhibitor indicated for use in combination with
`
`prednisone for the treatment of patients with metastatic castration-resistant
`prostate cancer who have received prior chemotherapy containing docetaxel.
`(1)
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`Recommended dose: ZYTIGA 1,000 mg 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. (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)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 
` 
`INDICATIONS AND USAGE
`1
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`2.1 Recommended Dosage
` 
` 
`2.2 Dose Modification Guidelines
` 
` 
`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
` 
` 
`5.4
`Food effect
` 
` 
`6 ADVERSE REACTIONS
` 
` 
`6.1 Clinical Trial Experience
` 
` 
`7 DRUG INTERACTIONS
` 
`7.1 Effects of Abiraterone on Drug Metabolizing
`
` 
`Enzymes
`
` 
` 
`7.2 Drugs that Inhibit or Induce CYP3A4 Enzymes
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed
`
`
`
`Reference ID: 2939553
`
`1
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 1
`
`

`
`
`FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`ZYTIGA in combination with prednisone is indicated for the treatment of patients with
`metastatic castration-resistant prostate cancer
`(CRPC) who have
`received prior
`chemotherapy containing docetaxel.
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`The recommended dose of ZYTIGA is 1,000 mg 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.
`
`2.2 Dose Modification Guidelines
`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)].
`
`
`
`
`
`Avoid ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C), as
`
`ZYTIGA has not been studied in this population, and no dose adjustment can be predicted.
`
`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: 2939553
`
`MYLAN PHARMS. INC. EXHIBIT 1018 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.
`
`
`
` 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
`
`
` 4.1Pregnancy
`ZYTIGA may cause fetal harm when administered to a pregnant woman. 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, the patient should be
`apprised of the potential hazard to the fetus.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid
`Excess
`Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA
`may cause hypertension, hypokalemia, and fluid retention as a consequence of increased
`mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions (6) and
`
`Clinical Pharmacology
` (12.1)]. 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. The safety of ZYTIGA in patients with left ventricular ejection fraction <50%
`or NYHA Class III or IV heart failure has not been established because these patients were
`
`excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia,
`
`Reference ID: 2939553
`
`3
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 3
`
`

`
`
`
`and fluid retention at least once a month. Control hypertension and correct hypokalemia
`
`before and during treatment with ZYTIGA.
`
`5.2Adrenocortical Insufficiency
`
`
`Adrenocortical insufficiency has been reported in clinical trials 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)].
`
`
`
`5.3Hepatotoxicity
`
`
`Marked increases in liver enzymes leading to drug discontinuation or dosage modification
`have occurred [see Adverse Reactions (6)]. 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.
`
`5.4Food effect
`
`
`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
`
`4
`
`Reference ID: 2939553
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 4
`
`

`
`
`
`
`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. The safety of these increased exposures when
`multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage
`and Administration (2.1) and Clinical Pharmacology (12.3)].
`
`
`
` 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)].
`• Food effect [see Warnings and Precautions (5.4)].
`
` 6.1Clinical 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.
`
`
`
`In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic
`
` castration-resistant prostate cancer who were using a gonadotropin-releasing hormone
`(GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at
`a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active
`treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control
`patients (N = 394). The median duration of treatment with ZYTIGA was 8 months.
`
`The most common adverse drug reactions (≥5%) reported in clinical studies were joint
`swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary
`tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and
`upper respiratory tract infection.
`
`The most common adverse drug reactions that resulted in drug discontinuation were
`aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and
`cardiac failure (each in <1% of patients taking ZYTIGA).
`
`Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were
`reported more commonly in patients treated with ZYTIGA than in patients treated with
`placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention
`
`(edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA,
`
`5
`
`Reference ID: 2939553
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 5
`
`

`
`
`
`grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was
`
` reported in 1% of patients [see Warnings and Precautions (5.1)].
`
` Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute
`
`
`increase
`in frequency compared
`to placebo, or were events of special
`interest
`(mineralocorticoid excess, cardiac adverse reactions, and liver toxicities).
`
`
`
`
`
`
`
` Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial
`
`Placebo with Prednisone
`
`(N=394)
`All Grades
`%
`
`
`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
`
`Cardiac disorders
`
`Arrhythmia5
`
`
`Chest pain or chest discomfort6
`
`
`Cardiac failure7
`
`
`
`
`ZYTIGA with Prednisone (N=791)
`All Grades1
`
`Grade 3-4
`%
`%
`
`
`
`
`
`
`
`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
`
`7.2
`3.8
`2.3
`
`
`4.2
`3.0
`
`1.9
`
`0.3
`1.3
`
`0.6
`0
`
`2.1
`0
`
`
`0
`
`0.3
`0
`
`1.1
`0.5
`1.9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`23.4
`23.1
`
`18.3
`
`16.8
`6.9
`
`13.5
`3.3
`
`7.1
`2.5
`
`
`7.6
`
`5.1
`4.1
`
`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
`
`1.0
`0
`0.3
`
`
`
`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 Generalised edema
`5 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular
`tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia.
`
`
`
`6 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).
`7 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly,
`
`Cardiomyopathy, and Ejection fraction decreased
`
`
`Cardiovascular Adverse Reactions:
`
`Reference ID: 2939553
`
`6
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 6
`
`

`
`
`
`Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of
`arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two
`arms. There was one death associated with arrhythmia and one patient with sudden death in
`the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the
`
` placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the
`placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in
`1 patient on both arms.
`
`Hepatotoxicity:
`Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been
`reported in patients treated with ZYTIGA. Across all clinical trials, liver function test
`
`elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who
`
`received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3
`trial, patients whose baseline ALT or AST were elevated were more likely to experience
`
`liver function test elevations than those beginning with normal values. When elevations of
`either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed,
`
`
`ZYTIGA was withheld or discontinued. In two instances marked increases in liver function
`tests occurred [see Warnings and Precautions (5.2)]. These two patients with normal
`baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin
`elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization
`of their liver function tests and one patient was re-treated with ZYTIGA without recurrence
`of the elevations.
`
`In clinical trials, the following patients were excluded: patients with active hepatitis, patients
`with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients
`
`with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver
`
`function tests developing in patients participating in clinical trials were managed by
`interruption, dose modification and/or discontinuation [see Dosage and
`treatment
`Administration (2.2) and Warnings and Precautions (5.3)]. Patients with elevations of ALT
`or AST > 20X ULN were not re-treated.
`
`Other Adverse Reactions:
`Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical
`
`trial (< 1%).
`
`
`Laboratory Abnormalities of Interest:
`
`Reference ID: 2939553
`
`7
`
`MYLAN PHARMS. INC. EXHIBIT 1018 PAGE 7
`
`

`
`
`
`
`
`Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical
`
` trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more
`frequently in the ZYTIGA arm.
`
`Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial
`
`
`
`
`Laboratory Abnormality
`
`High Triglyceride
`
`High AST
`
`Low Potassium
`Low Phosphorus
`
`High ALT
`High total Bilirubin
`
`Abiraterone (N=791)
`
`Grade 3-4
`All Grades
`(%)
`(%)
`
`Placebo (N=394)
`
`Grade 3-4
`All Grades
`(%)
`(%)
`
`
`62.5
`30.6
`28.3
`23.8
`11.1
`6.6
`
`
`0.4
`2.1
`5.3
`7.2
`1.4
`0.1
`
`
`53.0
`36.3
`19.8
`15.7
`10.4
`4.6
`
`
`0
`1.5
`1.0
`5.8
`0.8
`0
`
` 7 DRUG INTERACTIONS
`
`7.1 Effects of Abiraterone on Drug Metabolizing Enzymes
`ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. 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)].
`
`
`
`7.2Drugs that Inhibit or Induce CYP3A4 Enzymes
`Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4
`inhibitors (e.g., ketoconazole,
`itraconazole, clarithromycin, atazanavir, nefazodone,
`saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g.,
`phenytoin, carbamazepine,
`rifampin,
`rifabutin,
`rifapentine, phenobarbital) on
`the
`pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution,
`strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical
`
`Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category X [see Contraindications (4.1)].
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` 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, the patient should be apprised of the potential hazard to the fetus and the potential
`risk for pregnancy loss. Women of childbearing potential should be advised to avoid
`becoming pregnant during treatment with ZYTIGA.
`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
`ZYTIGA is not indicated in children.
`
`8.5 Geriatric Use
` Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years
`
`and over and 28% were 75 years and over. No overall differences in safety or effectiveness
`were observed between these elderly patients and younger patients.
`
`
`
`8.6Patients with Hepatic Impairment
`The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8)
`or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in
`8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of
`abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1­
`fold and 3.6 fold in subjects with mild and moderate baseline hepatic impairment,
`respectively compared to subjects with normal hepatic function.
`
`No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In
`patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the
`recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X
`ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic
`impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and
`Clinical Pharmacology (12.3)].
`
`The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been
`studied. These patients should not receive ZYTIGA.
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` For patients who develop hepatotoxicity during treatment, interruption of treatment and
`
`dosage adjustment may be required [see Dosage and Administration (2.2), Warnings and
`Precautions (5.2), and Clinical Pharmacology (12.3)].
`
`8.7Patients with Renal Impairment
`In a dedicated renal impairment trial, the mean PK parameters were comparable between
`
`healthy subjects with normal renal function (N=8) and those with end stage renal disease
`(ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage
`adjustment is necessary for patients with renal impairment [see Dosage and Administration
`(2.3) and Clinical Pharmacology (12.3)].
`
`10 OVERDOSAGE
`
`There have been no reports of overdose of ZYTIGA during clinical studies.
`
`There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general
`supportive measures, including monitoring for arrhythmias and cardiac failure and assess
`liver function.
`
`11 DESCRIPTION
`
`Abiraterone acetate, the active ingredient of ZYTIGA is the acetyl ester of abiraterone.
`
`Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet
`contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)­
`17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate and its structure is:
`
`
`
`Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its
`molecular formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone
`acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P)
`and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19.
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`Inactive ingredients in the tablets are lactose monohydrate, microcrystalline cellulose,
`croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, and colloidal
`silicon dioxide.
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` 12 CLINICAL PHARMACOLOGY
` 12.1 Mechanism of Action
`
`Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis
`
` inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed
`in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.
`
`CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and
`progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the
`subsequent
`formation of dehydroepiandrosterone
`(DHEA) and androstenedione,
`respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are
`precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased
`mineralocorticoid production by the adrenals (see Warnings and Precautions [5.1]).
`
`Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen
`
` levels. Androgen deprivation therapies, such as treatment with GnRH agonists or
`orchiectomy, decrease androgen production in the testes but do not affect androgen
`production by the adrenals or in the tumor.
`
`ZYTIGA decreased serum testosterone and other androgens in patients in the placebo-
`controlled phase 3 clinical trial. It is not necessary to monitor the effect of ZYTIGA on
`serum testosterone levels.
`
`Changes in serum prostate specific antigen (PSA) levels may be observed but have not been
`shown to correlate with clinical benefit in individual patients.
`
`
`12.3 Pharmacokinetics
`Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and
`abiraterone acetate have been studied in healthy subjects and in patients with metastatic
`castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is converted to
`abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below
`detectable levels (< 0.2 ng/mL) in > 99% of the analyzed samples.
`
`Absorption
`Following oral administration of abiraterone acetate to patients with metastatic CRPC, the
`median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone
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`accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC)
`compared to a single 1,000 mg dose of abiraterone acetate.
`
`At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean ±
`SD) of Cmax were 226 ± 178 ng/mL and of AUC were 1173 ± 690 ng.hr/mL. No major
`deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg.
`
`
`
`
`
` Systemic exposure of abiraterone is increased when abiraterone acetate is administered with
`
`food. Abiraterone Cmax and AUC0-∞ were approximately 7- and 5-fold higher, respectively,
`when abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and
`approximately 17- and 10-fold higher, respectively, when abiraterone acetate was
`administered with a high-fat (57% fat, 825 calories) meal. Given the normal variation in the
`
` content and composition of meals, taking ZYTIGA with meals has the potential to result in
`increased and highly variable exposures. Therefore, 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 [see Dosage and
`Administration (2.1)].
`
`Distribution and Protein Binding
`Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1
`acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ±
`13,358 L. In vitro studies show that at clinically relevant concentrations, abiraterone acetate
`and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an
`
`inhibitor of P-gp. No studies have been conducted with other transporter proteins.
`
`Metabolism
`Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is
`hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase
`
`activity (the esterases have not been identified) and is not CYP mediated. The two main
`circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive)
`
`and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each.
`CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone
`sulphate and SULT2A1 is involved in the formation of abiraterone sulphate.
`
`Excretion
`In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma
`
`(mean ± SD) is 12 ± 5 hours. Following oral administration of 14C-abiraterone acetate,
`
`
`approximately 88% of the radioactive dose is recovered in feces and approximately 5% in
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`urine. The major compounds present in feces are unchanged abiraterone acetate and
`abiraterone (approximately 55% and 22% of the administered