6 ADVERSE REACTIONS

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

•: Seizure [see Warnings and Precautions (5.1)]
•: Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.2)]
•: Hypersensitivity [see Warnings and Precautions (5.3)]
•: Ischemic Heart Disease [see Warnings and Precautions (5.4)]
•: Falls and Fractures [see Warnings and Precautions (5.5)]
•: Dysphagia or Choking [see Warnings and Precautions (5.7)]

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 practice.

The data in WARNINGS and PRECAUTIONS reflect eight randomized, controlled trials [AFFIRM, PREVAIL, TERRAIN, PROSPER, ARCHES, EMBARK, Asian PREVAIL (NCT02294461), and STRIVE (NCT01664923)] that were pooled to conduct safety analyses in patients with CRPC (N = 3651), mCSPC (N = 752), or nmCSPC with high‑risk BCR (N = 707) treated with XTANDI. Patients received XTANDI 160 mg (N = 5110) or placebo orally once daily (N = 2829) or bicalutamide 50 mg orally once daily (N = 387). In these eight trials, the median duration of treatment was 22.1 months (range: < 0.1 to 95.0) in patients that received XTANDI.

In five placebo-controlled trials (AFFIRM, PROSPER, PREVAIL, ARCHES, and EMBARK), the median duration of treatment was 19.4 months (range: < 0.1 to 90.4) in the XTANDI group [see Clinical Studies (14)]. In these five trials, the most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture and headache.

AFFIRM: XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy

AFFIRM enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse reactions were reported for 16% of XTANDI-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in AFFIRM that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in AFFIRM
	XTANDI (N = 800)		Placebo (N = 399)
	Grade 1-4* (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
* CTCAE v 4. † Includes asthenia and fatigue. ‡ Includes dizziness and vertigo. § Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. ¶ Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. # Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.
General Disorders
Asthenic Conditions†	51	9	44	9
Peripheral Edema	15	1	13	0.8
Musculoskeletal and Connective Tissue Disorders
Back Pain	26	5	24	4
Arthralgia	21	2.5	17	1.8
Musculoskeletal Pain	15	1.3	12	0.3
Muscular Weakness	10	1.5	7	1.8
Musculoskeletal Stiffness	2.6	0.3	0.3	0
Gastrointestinal Disorders
Diarrhea	22	1.1	18	0.3
Vascular Disorders
Hot Flush	20	0	10	0
Hypertension	6	2.1	2.8	1.3
Nervous System Disorders
Headache	12	0.9	5	0
Dizziness‡	9	0.5	7	0.5
Spinal Cord Compression and Cauda Equina Syndrome	7	7	4.5	3.8
Paresthesia	7	0	4.5	0
Mental Impairment Disorders§	4.3	0.3	1.8	0
Hypoesthesia	4	0.3	1.8	0
Infections and Infestations
Upper Respiratory Tract Infection¶	11	0	6	0.3
Lower Respiratory Tract And Lung Infection#	8	2.4	4.8	1.3
Psychiatric Disorders
Insomnia	9	0	6	0.5
Anxiety	6	0.3	4	0
Renal and Urinary Disorders
Hematuria	7	1.8	4.5	1
Pollakiuria	4.8	0	2.5	0
Injury, Poisoning and Procedural Complications
Fall	4.6	0.3	1.3	0
Non-pathologic Fractures	4	1.4	0.8	0.3
Skin and Subcutaneous Tissue Disorders
Pruritus	3.8	0	1.3	0
Dry Skin	3.5	0	1.3	0
Respiratory Disorders
Epistaxis	3.3	0.1	1.3	0.3

PREVAIL: XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC

PREVAIL enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse reactions were reported for 6% of XTANDI-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in PREVAIL that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 2. Adverse Reactions in PREVAIL
	XTANDI (N = 871)		Placebo (N = 844)
	Grade 1-4* (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
* CTCAE v 4. † Includes asthenia and fatigue. ‡ Includes dizziness and vertigo. § Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. ¶ Includes dyspnea, exertional dyspnea, and dyspnea at rest. # Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. Þ Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.
General Disorders
Asthenic Conditions†	47	3.4	33	2.8
Peripheral Edema	12	0.2	8	0.4
Musculoskeletal and Connective Tissue Disorders
Back Pain	29	2	22	3
Arthralgia	21	1.6	16	1.1
Gastrointestinal Disorders
Constipation	23	0.7	17	0.4
Diarrhea	17	0.3	14	0.4
Vascular Disorders
Hot Flush	18	0.1	8	0
Hypertension	14	7	4.1	2.3
Nervous System Disorders
Dizziness‡	11	0.3	7	0
Headache	11	0.2	7	0.4
Dysgeusia	8	0.1	3.7	0
Mental Impairment Disorders§	6	0	1.3	0.1
Restless Legs Syndrome	2.1	0.1	0.4	0
Respiratory Disorders
Dyspnea¶	11	0.6	8	0.6
Infections and Infestations
Upper Respiratory Tract Infection#	16	0	11	0
Lower Respiratory Tract And Lung InfectionÞ	8	1.5	4.7	1.1
Psychiatric Disorders
Insomnia	8	0.1	6	0
Renal and Urinary Disorders
Hematuria	9	1.3	6	1.3
Injury, Poisoning and Procedural Complications
Fall	13	1.6	5	0.7
Non-Pathological Fracture	9	2.1	3	1.1
Metabolism and Nutrition Disorders
Decreased Appetite	19	0.3	16	0.7
Investigations
Weight Decreased	12	0.8	8	0.2
Reproductive System and Breast Disorders
Gynecomastia	3.4	0	1.4	0

TERRAIN: XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC

TERRAIN enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with XTANDI and 5.8 months with bicalutamide. Discontinuations with an adverse reaction as the primary reason were reported for 8% of XTANDI-treated patients and 6% of bicalutamide-treated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDI-treated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse reactions (≥ 10%) in XTANDI-treated patients.

Table 3. Adverse Reactions in TERRAIN
	XTANDI (N = 183)		Bicalutamide (N = 189)
	Grade 1-4* (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
* CTCAE v 4. † Including asthenia and fatigue. ‡ Including musculoskeletal pain and pain in extremity. § Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.
Overall	94	39	94	38
General Disorders
Asthenic Conditions†	32	1.6	23	1.1
Musculoskeletal and Connective Tissue Disorders
Back Pain	19	2.7	18	1.6
Musculoskeletal Pain‡	16	1.1	14	0.5
Vascular Disorders
Hot Flush	15	0	11	0
Hypertension	14	7	7	4.2
Gastrointestinal Disorders
Nausea	14	0	18	0
Constipation	13	1.1	13	0.5
Diarrhea	12	0	9	1.1
Infections and Infestations
Upper Respiratory Tract Infection§	12	0	6	0.5
Investigational
Weight Loss	11	0.5	8	0.5

PROSPER: XTANDI versus Placebo in Non-metastatic CRPC Patients

PROSPER enrolled 1401 patients with non-metastatic CRPC, of whom 1395 received at least one dose of study drug. Patients were randomized 2:1 and received either XTANDI at a dose of 160 mg once daily (N = 930) or placebo (N = 465). The median duration of treatment at the time of analysis was 18.4 months (range: 0.0 to 42 months) with XTANDI and 11.1 months (range: 0.0 to 43 months) with placebo.

Overall, 32 patients (3.4%) receiving XTANDI died from adverse reactions. The reasons for death with ≥ 2 patients included coronary artery disorders (n = 7), sudden death (n = 2), cardiac arrhythmias (n = 2), general physical health deterioration (n = 2), stroke (n = 2), and secondary malignancy (n = 5; one each of acute myeloid leukemia, brain neoplasm, mesothelioma, small cell lung cancer, and malignant neoplasm of unknown primary site). Three patients (0.6%) receiving placebo died from adverse reactions of cardiac arrest (n = 1), left ventricular failure (n = 1), and pancreatic carcinoma (n = 1). Grade 3 or higher adverse reactions were reported among 31% of XTANDI-treated patients and 23% of placebo‑treated patients. Discontinuations with an adverse reaction as the primary reason were reported for 9% of XTANDI-treated patients and 6% of placebo-treated patients. Of these, the most common adverse reaction leading to treatment discontinuation was fatigue, which occurred in 1.6% of the XTANDI-treated patients compared to none of the placebo-treated patients. Table 4 shows adverse reactions reported in PROSPER that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm.

Table 4. Adverse Reactions in PROSPER
	XTANDI (N = 930)		Placebo (N = 465)
	Grade 1-4* (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
* CTCAE v 4. † Includes dizziness and vertigo. ‡ Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. § Includes asthenia and fatigue. ¶ Includes all osseous fractures from all sites.
Metabolism and Nutrition Disorders
Decreased Appetite	10	0.2	3.9	0.2
Nervous System Disorders
Dizziness†	12	0.5	5	0
Headache	9	0.2	4.5	0
Cognitive and Attention Disorders‡	4.6	0.1	1.5	0
Vascular Disorders
Hot Flush	13	0.1	8	0
Hypertension	12	4.6	5	2.2
Gastrointestinal Disorders
Nausea	11	0.3	9	0
Constipation	9	0.2	7	0.4
General Disorders and Administration Site Conditions
Asthenic Conditions§	40	4	20	0.9
Investigations
Weight Decreased	6	0.2	1.5	0
Injury, Poisoning and Procedural Complications
Fall	11	1.3	4.1	0.6
Fractures¶	10	2	4.9	1.7
Psychiatric Disorders
Anxiety	2.8	0.2	0.4	0

ARCHES: XTANDI versus Placebo in Metastatic CSPC Patients

ARCHES randomized 1150 patients with mCSPC, of whom 1146 received at least one dose of study drug. All patients received either a gonadotropin-releasing hormone (GnRH) analog concurrently or had bilateral orchiectomy. Patients received either XTANDI at a dose of 160 mg once daily (N = 572) or placebo (N = 574). The median duration of treatment was 12.8 months (range: 0.2 to 26.6 months) with XTANDI and 11.6 months (range: 0.2 to 24.6 months) with placebo.

Overall, 10 patients (1.7%) receiving XTANDI died from adverse reactions. The reasons for death in ≥ 2 patients included heart disease (n = 3), sepsis (n = 2) and pulmonary embolism (n = 2). Eight patients (1.4%) receiving placebo died from adverse reactions. The reasons for death in ≥ 2 patients included heart disease (n = 2) and sudden death (n = 2). Grade 3 or higher adverse reactions were reported in 24% of patients treated with XTANDI. Permanent discontinuation due to adverse reactions as the primary reason was reported in 4.9% of XTANDI-treated patients and 3.7% of placebo-treated patients. The most common adverse reactions resulting in permanent discontinuation in XTANDI-treated patients were alanine aminotransferase increased, aspartate aminotransferase elevation, and seizure, each in 0.3%. The most common adverse reactions leading to permanent discontinuation in placebo-treated patients were arthralgia, and fatigue, each in 0.3%.

Dose reductions due to an adverse reaction occurred in 4.4% of patients who received XTANDI. Fatigue/asthenia was the most frequent adverse reaction requiring dose reduction in 2.1% of XTANDI-treated patients and 0.7% of placebo-treated patients.

Table 5 shows adverse reactions reported in ARCHES that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm.

Table 5. Adverse Reactions in ARCHES
	XTANDI (N = 572)		Placebo (N = 574)
	Grade 1-4* (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
* CTCAE v 4.03. † Includes memory impairment, amnesia, cognitive disorder, dementia, disturbance in attention, transient global amnesia, dementia alzheimer’s type, mental impairment, senile dementia and vascular dementia. ‡ Includes asthenia and fatigue. § Includes Fracture related preferred terms under high level terms: fractures NEC; fractures and dislocations NEC; limb fractures and dislocations; pelvic fractures and dislocations; skull and brain therapeutic procedures; skull fractures, facial bone fractures and dislocations; spinal fractures and dislocations; thoracic cage fractures and dislocations.
Metabolism and Nutrition Disorders
Decreased Appetite	4.9	0.2	2.6	0
Nervous System Disorders
Cognitive and Memory Impairment†	4.5	0.7	2.1	0
Restless Legs Syndrome	2.4	0	0.3	0
Vascular Disorders
Hot Flush	27	0.3	22	0
Hypertension	8	3.3	6	1.7
General Disorders and Administration Site Conditions
Asthenic conditions‡	24	1.7	20	1.6
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Pain	6	0.2	4	0.2
Injury, Poisoning and Procedural Complications
Fractures§	6	1.0	4.2	1

EMBARK: XTANDI versus Placebo in Non-metastatic CSPC Patients with High-Risk BCR

EMBARK enrolled 1068 patients with high-risk BCR, of whom 1061 patients received at least one dose of study drug. Patients received XTANDI at a dose of 160 mg once daily concurrently with leuprolide (N = 353), XTANDI at a dose of 160 mg once daily as open‑label monotherapy (N = 354), or placebo concurrently with leuprolide (N = 354). At week 37, treatment was suspended for patients whose PSA values were undetectable (<0.2 ng/mL) at week 36. Treatment was reinitiated when PSA values increased to ≥2.0 ng/mL for patients with prior prostatectomy or ≥5.0 ng/mL for patients without prior prostatectomy. For patients whose PSA values were detectable (≥0.2 ng/mL) at week 36, treatment continued without suspension until permanent treatment discontinuation criteria were met.

Table 6 shows the total duration of treatment for the three treatment arms.

Table 6. Drug Treatment and Suspension in EMBARK
	XTANDI + Leuprolide (N = 353)	Placebo + Leuprolide (N = 354)	XTANDI (N = 354)
* Inclusive of time receiving drug treatment plus any time during which drug treatment was suspended because of undetectable PSA levels.
Total Duration of Treatment*
Median, months	60.6	55.6	60.4
Range, months	0.1 - 90.4	0.7 - 94.1	0.4 – 95.0
Duration Receiving Drug Treatment
Median, months	32.4	35.4	45.9
Range, months	0.1 – 83.4	0.7 – 85.7	0.4 – 88.9
Duration of Suspension from Drug Treatment
Median, months	20.2	16.8	11.1
Range, months	5.7 – 87.9	3.4 – 83.0	2.3 – 84.9
Patients who had Drug Treatment Suspended at Week 37
Number of Patients (%)	321 (90.9)	240 (67.8)	304 (85.9)

Overall, deaths from adverse reactions during the total duration of treatment occurred in 6 patients (1.7%) receiving XTANDI plus leuprolide, 8 patients (2.3%) receiving XTANDI as a single agent, and 3 patients (0.8%) receiving placebo plus leuprolide. The reason for death in ≥ 2 patients receiving XTANDI plus leuprolide was infection (n = 2), and the reason for death in ≥ 2 patients receiving XTANDI as a single agent was arterial thromboembolism (n=2).

Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide. The most common adverse reactions resulting in permanent discontinuation included fatigue (3.4% of patients treated with XTANDI plus leuprolide, 3.7% of patients receiving XTANDI as a single agent, and 1.4% of patients receiving placebo plus leuprolide), hot flush (2% of patients treated with XTANDI plus leuprolide, 0% of patients receiving XTANDI as a single agent, and 1.1% of patients receiving placebo plus leuprolide), nausea (1.1% of patients treated with XTANDI plus leuprolide, 0.6% of patients receiving XTANDI as a single agent, and 0.3% of patients receiving placebo plus leuprolide), and cognitive disorder (1.1% of patients treated with XTANDI plus leuprolide, 1.4% of patients receiving XTANDI as a single agent, and 0.8% of patients receiving placebo plus leuprolide).

Dose reductions due to an adverse reaction occurred in 7% of patients who received XTANDI plus leuprolide, 16% of patients who received XTANDI as a single agent, and 4.5% of patients who received placebo plus leuprolide. Fatigue was the most frequent adverse reaction requiring dose reduction in 3.1% of patients treated with XTANDI plus leuprolide, 10% of patients receiving XTANDI as a single agent, and 1.7% of patients receiving placebo plus leuprolide.

Table 7 shows adverse reactions reported in EMBARK that occurred at a ≥ 5% (Grade 1-4) or ≥ 2% (Grade 3-4) higher frequency in either of the XTANDI arms than in the placebo arm.

Table 7. Adverse Reactions in EMBARK
	XTANDI + Leuprolide (N = 353)		Placebo + Leuprolide (N = 354)		XTANDI (N = 354)
	Grade 1-4* (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3‑4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
* CTCAE v 4.03. † Includes multiple terms.
Nervous System Disorders
Cognitive Disorder†	10	0.3	4.8	0.6	10	0.3
Syncope	4.8	4.2	2.3	1.7	2.5	2
Vascular Disorders
Hot Flush	69	0.6	57	0.8	22	0.3
Hemorrhage†	20	3.4	15	1.7	21	3.7
Gastrointestinal Disorders
Diarrhea†	15	0.6	9	0.8	14	0.3
Nausea	12	0.3	8	0.3	15	0.6
Investigations
Weight Decreased	7	0.3	3.4	0	11	0.3
General Disorders and Administration Site Conditions
Fatigue†	50	4	38	1.7	54	4.8
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Pain†	50	4.8	43	2.3	48	3.1
Osteoarthritis	6	2.8	4.2	0.6	5	0.6
Injury, Poisoning and Procedural Complications
Fall	21	1.1	14	1.1	16	2
Fracture†	18	4	13	2.5	11	2
Reproductive System and Breast Disorders
Gynecomastia†	9	0	10	0	49	0.8
Breast tenderness†	5	0	2.8	0	35	0
Cardiac Disorders
Ischemic Heart Disease†	5	4	6	3.1	9	6

Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 7 include hypertension (XTANDI plus leuprolide, 25%; XTANDI as a single agent, 21%), angioedema (XTANDI plus leuprolide, 2.5%; XTANDI as a single agent, 2%), and seizure (XTANDI plus leuprolide, 1.1%; XTANDI as a single agent, 0.8%).

Laboratory Abnormalities

Table 8 shows laboratory abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies.

Table 8. Laboratory Abnormalities
	XTANDI (N = 3526)		Placebo (N = 2636)
	Grade 1-4 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
Hematology
Hemoglobin decreased	50	1.8	47	1.5
Neutrophil count decreased	20	1	17	0.5
White blood cell decreased	18	0.5	11	0.2
Chemistry
Hyperglycemia	86	3.7	78	4.3
Hypermagnesemia	17	0.1	14	0.3
Hyponatremia	14	1.6	9	1.4
Hypophosphatemia	10	1.4	7	0.8
Hypercalcemia	8	0.1	5	0.1

Hypertension

In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14% of patients receiving XTANDI and 7% of patients receiving placebo. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

6.2 Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of XTANDI. 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.

Gastrointestinal Disorders: vomiting, dysphagia (including choking related to XTANDI product size)

Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx)

Neurological Disorders: posterior reversible encephalopathy syndrome (PRES), dysgeusia

Skin and Subcutaneous Tissue Disorders: rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP))