Zytiga (abiraterone acetate 250 mg) Dailymed

• Mineralocorticoid excess: Closely monitor patients with cardiovascular disease. 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: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue ZYTIGA dosing as recommended. (5.3)
• Increased fractures and mortality in combination with radium Ra 223 dichloride: Use of ZYTIGA plus prednisone/prednisolone in combination with radium Ra 223 dichloride is not recommended. (5.4)
• Embryo-Fetal Toxicity: ZYTIGA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. (5.5, 8.1, 8.3)
• Hypoglycemia: Severe hypoglycemia has been reported in patients with pre-existing diabetes who are taking medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes and assess if antidiabetic agent dose modifications are required. (5.6)

5.1Hypokalemia, 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)].

5.2Adrenocortical 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)].

5.3Hepatotoxicity

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.

5.4Increased 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.

5.5Embryo-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:

• Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions 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)].
• Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride [see Warnings and Precautions (5.4)].

The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. (6.1)

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia. (6.1)

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.

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.

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 GradesAdverse 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/discomfortIncludes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.	30	4.2	23	4.1
  Muscle discomfortIncludes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness.	26	3.0	23	2.3
General disorders
  EdemaIncludes terms Edema, Edema peripheral, Pitting edema, and Generalized 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
  FracturesIncludes all fractures with the exception of pathological fracture.	5.9	1.4	2.3	0
Cardiac disorders
  ArrhythmiaIncludes 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	1.0
  Chest pain or chest discomfortIncludes 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 failureIncludes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased.	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 GradesAdverse 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	1.7
  EdemaIncludes terms Edema peripheral, Pitting edema, and Generalized edema.	25	0.4	21	1.1
  Pyrexia	8.7	0.6	5.9	0.2
Musculoskeletal and connective tissue disorders
  Joint swelling/discomfortIncludes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.	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%
Hematology
  Lymphopenia	38	8.7	32	7.4
Chemistry
  HyperglycemiaBased on non-fasting blood draws	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 LATITUDEAll patients were receiving an GnRH agonist or had undergone orchiectomy.

	ZYTIGA with Prednisone(N=597)		Placebos(N=602)
System/Organ Class  Adverse reaction	All GradesAdverse 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	0.2
Metabolism and nutrition disorders
  Hypokalemia	20	10	3.7	1.3
Investigations
  Alanine aminotransferase increasedReported as an adverse event or reaction	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
  CoughIncluding 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	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.

6.2Postmarketing 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)).