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)].

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.

6.2 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.

Musculoskeletaland 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)).