Zytiga: Package Insert and Label Information

ZYTIGA- abiraterone acetate tablet
ZYTIGA- abiraterone acetate tablet, film coated
Janssen Biotech, Inc.

1 INDICATIONS AND USAGE

ZYTIGA 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)

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 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.

2.3 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.

2.4 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 [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 5 × ULN or total bilirubin greater than 3 × 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 2.5 × 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 [see Warnings and Precautions (5.3)].

2.5 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Tablets (500 mg): purple, oval-shaped, film-coated tablets debossed with “AA” one side and “500” on the other side.

Tablets (250 mg): white to off-white, oval-shaped tablets debossed with “AA250” on one side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions 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)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA.

In the combined data from 4 placebo-controlled trials using prednisone 5 mg twice daily in combination with 1,000 mg abiraterone acetate daily, grades 3–4 hypokalemia were detected in 4% of patients on the ZYTIGA arm and 2% of patients on the placebo arm. Grades 3–4 hypertension were observed in 2% of patients each arm and grades 3–4 fluid retention in 1% of patients each arm.

In LATITUDE (a randomized placebo-controlled, multicenter clinical trial), which used prednisone 5 mg daily in combination with 1,000 mg abiraterone acetate daily, grades 3–4 hypokalemia were detected in 10% of patients on the ZYTIGA arm and 1% of patients on the placebo arm, grades 3–4 hypertension were observed in 20% of patients on the ZYTIGA arm and 10% of patients on the placebo arm. Grades 3–4 fluid retention occurred in 1% of patients each arm [see Adverse Reactions (6)].

Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. In postmarketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking ZYTIGA.

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 COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)].

5.2 Adrenocortical Insufficiency

Adrenal insufficiency occurred in 0.3% of 2230 patients taking ZYTIGA and in 0.1% of 1763 patients taking placebo in the combined data of the 5 randomized, placebo-controlled clinical studies. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress.

Monitor patients 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 postmarketing experience, there have been ZYTIGA-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2)].

In the combined data of 5 randomized clinical trials, grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 6% of 2230 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 ALT and AST increases or abnormal hepatic function occurred in 1.1% of 2230 patients taking ZYTIGA. In these clinical trials, 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 2.5 × ULN and total bilirubin less than or equal to 1.5 × ULN [see Dosage and Administration (2.4)].

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 [see Dosage and Administration (2.4)].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20 × ULN and/or bilirubin greater than or equal to 10 × ULN is unknown.

5.4 Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride

ZYTIGA plus prednisone/prednisolone is not recommended for use in combination with radium Ra 223 dichloride outside of clinical trials.

The clinical efficacy and safety of concurrent initiation of ZYTIGA plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.

At the primary analysis, increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received ZYTIGA plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with ZYTIGA plus prednisone/prednisolone.

5.5 Embryo-Fetal Toxicity

The safety and efficacy of ZYTIGA have not been established in females. Based on animal reproductive studies and mechanism of action, ZYTIGA can cause fetal harm and loss of pregnancy when administered to a pregnant female. 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. Advise males with female partners of reproductive potential to use effective contraception during treatment with ZYTIGA and for 3 weeks after the last dose of ZYTIGA [see Use in Specific Populations (8.1, 8.3)]. ZYTIGA should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)].

5.6 Hypoglycemia

Severe hypoglycemia has been reported when ZYTIGA was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2)]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with ZYTIGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

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 (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 (0.1, 43) for ZYTIGA-treated patients and 7.2 months (0.1, 43) 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 * Grade 3–4 All Grades Grade 3–4
Adverse reaction % % % %
*
Adverse events graded according to CTCAE version 3.0.
Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.
Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness.
§
Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema.
Includes all fractures with the exception of pathological fracture.
#
Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia.
Þ
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).
ß
Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased.
Musculoskeletal and connective tissue disorders
Joint swelling/discomfort 30 4.2 23 4.1
Muscle discomfort 26 3.0 23 2.3
General disorders
Edema § 27 1.9 18 0.8
Vascular disorders
Hot flush 19 0.3 17 0.3
Hypertension 8.5 1.3 6.9 0.3
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 0.5
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 0.3
Nocturia 6.2 0 4.1 0
Injury, poisoning and procedural complications
Fractures 5.9 1.4 2.3 0
Cardiac disorders
Arrhythmia # 7.2 1.1 4.6 1.0
Chest pain or chest discomfort Þ 3.8 0.5 2.8 0
Cardiac failure ß 2.3 1.9 1.0 0.3

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 1.5
Hypokalemia 28 5.3 20 1.0
Hypophosphatemia 24 7.2 16 5.8
High ALT 11 1.4 10 0.8
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 * Grade 3–4 All Grades Grade 3–4
Adverse reaction % % % %
*
Adverse events graded according to CTCAE version 3.0.
Includes terms Edema peripheral, Pitting edema, and Generalized edema.
Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.
General disorders
Fatigue 39 2.2 34 1.7
Edema 25 0.4 21 1.1
Pyrexia 8.7 0.6 5.9 0.2
Musculoskeletal and connective tissue disorders
Joint swelling/discomfort 30 2.0 25 2.0
Groin pain 6.6 0.4 4.1 0.7
Gastrointestinal disorders
Constipation 23 0.4 19 0.6
Diarrhea 22 0.9 18 0.9
Dyspepsia 11 0.0 5.0 0.2
Vascular disorders
Hot flush 22 0.2 18 0.0
Hypertension 22 3.9 13 3.0
Respiratory, thoracic and mediastinal disorders
Cough 17 0.0 14 0.2
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 0.0
Falls 5.9 0.0 3.3 0.0
Infections and infestations
Upper respiratory tract infection 13 0.0 8.0 0.0
Nasopharyngitis 11 0.0 8.1 0.0
Renal and urinary disorders
Hematuria 10 1.3 5.6 0.6
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%
*
Based on non-fasting blood draws
Hematology
Lymphopenia 38 8.7 32 7.4
Chemistry
Hyperglycemia * 57 6.5 51 5.2
High ALT 42 6.1 29 0.7
High AST 37 3.1 29 1.1
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 *
ZYTIGA with Prednisone(N=597) Placebos(N=602)
System/Organ Class Adverse reaction All Grades % Grade 3–4% All Grades% Grade 3–4%
*
All patients were receiving an GnRH agonist or had undergone orchiectomy.
Adverse events graded according to CTCAE version 4.0
Reported as an adverse event or reaction
§
Including cough, productive cough, upper airway cough syndrome
Vascular disorders
Hypertension 37 20 13 10
Hot flush 15 0.0 13 0.2
Metabolism and nutrition disorders
Hypokalemia 20 10 3.7 1.3
Investigations
Alanine aminotransferase increased 16 5.5 13 1.3
Aspartate aminotransferase increased 15 4.4 11 1.5
Infections and infestations
Urinary tract infection 7.0 1.0 3.7 0.8
Upper respiratory tract infection 6.7 0.2 4.7 0.2
Nervous system disorders
Headache 7.5 0.3 5.0 0.2
Respiratory, Thoracic and Mediastinal Disorders
Cough § 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 1.8
Chemistry
Hypokalemia 30 9.6 6.7 1.3
Elevated ALT 46 6.4 45 1.3
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.

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