Zytiga Drug Information

is indicated in combination with prednisone for the treatment of patients with Metastatic castration-resistant prostate cancer (CRPC) Metastatic high-risk castration-sensitive prostate cancer (CSPC) ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). metastatic high-risk castration-sensitive prostate cancer (CSPC).

Recommended Dose for Metastatic

CRPC The recommended dose of ZYTIGA is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with prednisone 5 mg orally twice daily.

Recommended Dose for Metastatic High-risk

CSPC The recommended dose of ZYTIGA is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with prednisone 5 mg administered orally once daily.

Important

Administration Instructions Patients receiving ZYTIGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ZYTIGA tablets must be taken as a single dose once daily on an empty stomach. Do not eat food 2 hours before and 1 hour after taking ZYTIGA. The tablets must be swallowed whole with water.

Do not crush or chew tablets.

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. 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 5 × upper limit of normal (ULN) or total bilirubin greater than 3 × ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA and do not re-treat patients with ZYTIGA . 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 5 × ULN or total bilirubin greater than 3 × ULN), interrupt treatment with ZYTIGA. 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 2.5 × ULN and total bilirubin less than or equal to 1.5 × 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 2.5 × ULN and total bilirubin less than or equal to 1.5 × ULN. If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with ZYTIGA. Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation .

Dose Modification Guidelines for Strong

CYP3A4 Inducers Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency to twice a day only during the co-administration period (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 .

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 (COU-AA-301 and COU-AA-302) enrolled patients who had metastatic CRPC in which ZYTIGA was administered orally 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 patients on the control arm.

A third randomized placebo-controlled, multicenter clinical trial (LATITUDE) enrolled patients who had metastatic high-risk CSPC in which ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg once daily. Placebos were administered to patients in the control arm. Additionally, two other randomized, placebo-controlled trials were conducted in patients with metastatic CRPC. The safety data pooled from 2230 patients in the 5 randomized controlled trials constitute the basis for the data presented in the Warnings and Precautions, Grade 1–4 adverse reactions, and Grade 1–4 laboratory abnormalities.

In all trials, a gonadotropin-releasing hormone (GnRH) analog or prior orchiectomy was required in both arms. In the pooled data, median treatment duration was 11 months for ZYTIGA-treated patients and 7.2 months for placebo-treated patients. The most common adverse reactions (≥10%) that occurred more commonly (>2%) in the ZYTIGA arm were fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache.

The most common laboratory abnormalities (>20%) that occurred more commonly (≥2%) in the ZYTIGA arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia. Grades 3–4 adverse events were reported for 53% of patients in the ZYTIGA arm and 46% of patients in the placebo arm. Treatment discontinuation was reported in 14% of patients in the ZYTIGA arm and 13% of patients in the placebo arm.

The common adverse events (≥1%) resulting in discontinuation of ZYTIGA and prednisone were hepatotoxicity and cardiac disorders. Deaths associated with treatment-emergent adverse events were reported for 7.5% of patients in the ZYTIGA arm and 6.6% of patients in the placebo arm. Of the patients in the ZYTIGA arm, the most common cause of death was disease progression (3.3%). Other reported causes of death in ≥5 patients included pneumonia, cardio-respiratory arrest, death (no additional information), and general physical health deterioration.

COU-AA-301: Metastatic CRPC Following Chemotherapy COU-AA-301 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 × ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5 × ULN. Table 1 shows adverse reactions on the ZYTIGA arm in COU-AA-301 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 with prednisone was 8 months. Table 1: Adverse Reactions due to ZYTIGA in COU-AA-301 ZYTIGA with Prednisone (N=791) Placebo with Prednisone (N=394) System/Organ Class All Grades Adverse events graded according to CTCAE version 3.0. Grade 3–4 All Grades Grade 3–4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 30 4.2 23

Muscle discomfort Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and

Musculoskeletal stiffness. 26 3.0 23

General disorders Edema Includes terms Edema, Edema peripheral, Pitting edema, and Generalized

edema. 27 1.9 18

Gastrointestinal disorders Diarrhea 18 0.6 14 1.3 Dyspepsia 6.1 0 3.3 0

Infections and infestations Urinary tract infection 12 2.1 7.1

Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal

disorders Cough 11 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1

Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures Includes

all fractures with the exception of pathological fracture. 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia. 7.2 1.1 4.6

Chest pain or chest discomfort 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). 3.8 0.5 2.8 0 Cardiac failure Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased. 2.3 1.9 1.0

Table 2 shows laboratory abnormalities of interest from

COU-AA-301. Table 2: Laboratory Abnormalities of Interest in COU-AA-301 ZYTIGA with Prednisone (N=791) Placebo with Prednisone (N=394) Laboratory Abnormality All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Hypertriglyceridemia 63 0.4 53 0 High AST 31 2.1 36

Hypokalemia 28 5.3 20 1.0 Hypophosphatemia 24 7.2 16 5.8 High

ALT 11 1.4 10

High Total Bilirubin 6.6 0.1 4.6 0

COU-AA-302: Metastatic CRPC Prior to Chemotherapy COU-AA-302 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5 × ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in COU-AA-302 that occurred in ≥5% of patients with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA with prednisone was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in COU-AA-302 ZYTIGA with Prednisone (N=542) Placebo with Prednisone (N=540) System/Organ Class All Grades Adverse events graded according to CTCAE version 3.0. Grade 3–4 All Grades Grade 3–4 Adverse reaction % % % % General disorders Fatigue 39 2.2 34

Edema Includes terms Edema peripheral, Pitting edema, and Generalized edema. 25 0.4

21

Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort

Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 30 2.0 25

Diarrhea 22 0.9 18 0.9 Dyspepsia 11 0.0 5.0 0.2 Vascular disorders

Hot flush 22 0.2 18

Hypertension 22 3.9 13 3.0 Respiratory, thoracic and mediastinal disorders Cough 17

0.0 14

Dyspnea 12 2.4 9.6 0.9 Psychiatric disorders Insomnia 14 0.2 11 0.0

Injury, poisoning and procedural complications Contusion 13 0.0 9.1

Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection

13 0.0 8.0

Nasopharyngitis 11 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10 1.3

5.6

Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 Table 4

shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in COU-AA-302. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of COU-AA-302 ZYTIGA with Prednisone (N=542) Placebo with Prednisone (N=540) Laboratory Abnormality Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 % Hematology Lymphopenia 38 8.7 32

Chemistry Hyperglycemia

Based on non-fasting blood draws 57 6.5 51

High

ALT 42 6.1 29

High

AST 37 3.1 29

Hypernatremia 33 0.4 25 0.2 Hypokalemia 17 2.8 10 1.7

LATITUDE: Patients with Metastatic High-risk CSPC LATITUDE enrolled 1199 patients with newly-diagnosed metastatic, high-risk CSPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5 × ULN or if they had liver metastases. All the patients received GnRH analogs or had prior bilateral orchiectomy during the trial.

The median duration of treatment with ZYTIGA and prednisone was 24 months. Table 5 shows adverse reactions on the ZYTIGA arm that occurred in ≥5% of patients with a ≥2% absolute increase in frequency compared to those on the placebos arm. Table 5: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in LATITUDE All patients were receiving an GnRH agonist or had undergone orchiectomy.

ZYTIGA with Prednisone (N=597) Placebos (N=602) System/Organ Class Adverse reaction All Grades Adverse events graded according to CTCAE version 4.0 % Grade 3–4 % All Grades % Grade 3–4 % Vascular disorders Hypertension 37 20 13 10 Hot flush 15 0.0 13

Metabolism and nutrition disorders Hypokalemia 20 10 3.7 1.3 Investigations Alanine aminotransferase

increased Reported as an adverse event or reaction 16 5.5 13

Aspartate aminotransferase increased 15 4.4 11 1.5 Infections and infestations Urinary tract

infection 7.0 1.0 3.7

Upper respiratory tract infection 6.7 0.2 4.7 0.2 Nervous system disorders Headache

7.5 0.3 5.0

Respiratory, Thoracic and Mediastinal Disorders Cough Including cough, productive cough, upper airway

cough syndrome 6.5 0.0 3.2 0 Table 6 shows laboratory abnormalities that occurred in >15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebos. Table 6: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of LATITUDE ZYTIGA with Prednisone (N=597) Placebos (N=602) Laboratory Abnormality Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 % Hematology Lymphopenia 20 4.1 14

Chemistry Hypokalemia 30 9.6 6.7 1.3 Elevated

ALT 46 6.4 45

Elevated total bilirubin 16 0.2 6.2 0.2 Cardiovascular Adverse Reactions

In the combined data of 5 randomized, placebo-controlled clinical studies, cardiac failure occurred more commonly in patients on the ZYTIGA arm compared to patients on the placebo arm (2.6% versus 0.9%). Grade 3–4 cardiac failure occurred in 1.3% of patients taking ZYTIGA and led to 5 treatment discontinuations and 4 deaths. Grade 3–4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and two deaths due to cardiac failure in the placebo group.

In the same combined data, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and three patients with sudden death in the ZYTIGA arms and five deaths in the placebo arms. There were 7 (0.3%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 2 (0.1%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 3 deaths in the ZYTIGA arms.

Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of ZYTIGA with prednisone. 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. Hepatobiliary Disorders : fulminant hepatitis, including acute hepatic failure and death. Cardiac Disorders: QT prolongation and Torsades de Pointes (observed in patients who developed hypokalemia or had underlying cardiovascular conditions). Immune System Disorders – Hypersensitivity: anaphylactic reactions (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).

Drugs that Inhibit or Induce

CYP3A4 Enzymes Based on in vitro data, ZYTIGA is a substrate of CYP3A4. 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 . 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 .

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 C max 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, consider a dose reduction of the concomitant CYP2D6 substrate drug . 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 .

Pregnancy Risk Summary The safety and efficacy of ZYTIGA have not been established in females. Based on findings from animal studies and the mechanism of action, ZYTIGA can cause fetal harm and potential loss of pregnancy. There are no human data on the use of ZYTIGA in pregnant women.

In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose (see Data ). Data Animal Data 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.

Pediatric Use Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Human experience of overdose with ZYTIGA is limited. 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.