FDA label cceea585-adf1-4f4e-a97f-5f78c9726537

5 WARNINGS AND PRECAUTIONS • Seizure occurred in 0.5% of patients receiving XTANDI. In patients with predisposing factors, seizures were reported in 2.2% of patients. Permanently discontinue XTANDI in patients who develop a seizure during treatment. ( 5.1 ) • Posterior reversible encephalopathy syndrome (PRES): Discontinue XTANDI. ( 5.2 ) • Hypersensitivity: Discontinue XTANDI. ( 5.3 ) • Ischemic Heart Disease: Optimize management of cardiovascular risk factors. Discontinue XTANDI for Grade 3-4 events. ( 5.4 ) • Falls and Fractures occurred in 11% and 10% of patients receiving XTANDI, respectively. Evaluate patients for fracture and fall risk, and treat patients with bone-targeted agents according to established guidelines. ( 5.5 ) • Embryo-Fetal Toxicity: XTANDI can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Seizure Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In these trials, patients with predisposing factors for seizure were generally excluded. Seizure occurred from 13 to 1776 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy, and all seizure events resolved. In a single-arm trial designed to assess the risk of seizure in patients with pre-disposing factors for seizure, 8 of 366 (2.2%) XTANDI-treated patients experienced a seizure. Three of the 8 patients experienced a second seizure during continued treatment with XTANDI after their first seizure resolved. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following pre-disposing factors: the use of medications that may lower the seizure threshold (~ 54%), history of traumatic brain or head injury (~ 28%), history of cerebrovascular accident or transient ischemic attack (~ 24%), and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, past history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection (all < 5%). Approximately 17% of patients had more than one risk factor. Advise patients of the risk of developing a seizure while receiving XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. 5.2 Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI [see Adverse Reactions ( 6.2 )] . PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES. 5.3 Hypersensitivity Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with enzalutamide in seven randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions. 5.4 Ischemic Heart Disease In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on the XTANDI arm compared to 0.7% on the placebo arm. Ischemic events led to death in 0.4% of patients on the XTANDI arm compared to 0.1% on the placebo arm. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease. 5.5 Falls and Fractures Falls and fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo. Grade 3-4 fractures occurred in 3% of patients treated with XTANDI and in 2% of patients treated with placebo. The median time to onset of fracture was 336 days (range: 2 to 1914 days) for patients treated with XTANDI. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the studies. 5.6 Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. Based on animal reproductive studies and mechanism of action, XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI [see Use in Specific Populations ( 8.1 , 8.3 )].

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 )] The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients are asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 seven randomized, controlled trials [AFFIRM, PREVAIL, TERRAIN, PROSPER, ARCHES, Asian PREVAIL (NCT02294461), and STRIVE (NCT01664923)] that were pooled to conduct safety analyses in patients with CRPC (N=3509) or mCSPC (N= 572) treated with XTANDI. Patients received XTANDI 160 mg (N= 4081) or placebo orally once daily (N= 2472) or bicalutamide 50 mg orally once daily (N= 387). All patients continued androgen deprivation therapy (ADT). In these seven trials, the median duration of treatment was 13.8 months (range: <0.1 to 87.6) in the XTANDI group. In four placebo-controlled trials (AFFIRM, PROSPER, PREVAIL, and ARCHES), the median duration of treatment was 14.3 months (range: <0.1 to 87.6) in the XTANDI group [see Clinical Studies ( 14 )]. In these four trials, the most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. AFFIRM (NCT00974311): 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 events 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 CTCAE v4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) General Disorders Asthenic Conditions Includes asthenia and fatigue. 51 9.0 44 9.3 Peripheral Edema 15 1.0 13 0.8 Musculoskeletal and Connective Tissue Disorders Back Pain 26 5.3 24 4.0 Arthralgia 21 2.5 17 1.8 Musculoskeletal Pain 15 1.3 12 0.3 Muscular Weakness 9.8 1.5 6.8 1.8 Musculoskeletal Stiffness 2.6 0.3 0.3 0.0 Gastrointestinal Disorders Diarrhea 22 1.1 18 0.3 Vascular Disorders Hot Flush 20 0.0 10 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12 0.9 5.5 0.0 Dizziness Includes dizziness and vertigo. 9.5 0.5 7.5 0.5 Spinal Cord Compression and Cauda Equina Syndrome 7.4 6.6 4.5 3.8 Paresthesia 6.6 0.0 4.5 0.0 Mental Impairment Disorders Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 4.3 0.3 1.8 0.0 Hypoesthesia 4.0 0.3 1.8 0.0 Infections and Infestations Upper Respiratory Tract Infection Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 11 0.0 6.5 0.3 Lower Respiratory Tract And Lung Infection Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. 8.5 2.4 4.8 1.3 Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal and Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning and Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic Fractures 4.0 1.4 0.8 0.3 Skin and Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 PREVAIL (NCT01212991): 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 events 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 CTCAE v4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) General Disorders Asthenic Conditions Includes asthenia and fatigue. 47 3.4 33 2.8 Peripheral Edema 12 0.2 8.2 0.4 Musculoskeletal and Connective Tissue Disorders Back Pain 29 2.5 22 3.0 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 7.8 0.0 Hypertension 14 7.2 4.1 2.3 Nervous System Disorders Dizziness Includes dizziness and vertigo. 11 0.3 7.1 0.0 Headache 11 0.2 7.0 0.4 Dysgeusia 7.6 0.1 3.7 0.0 Mental Impairment Disorders Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 5.7 0.0 1.3 0.1 Restless Legs Syndrome 2.1 0.1 0.4 0.0 Respiratory Disorders Dyspnea Includes dyspnea, exertional dyspnea, and dyspnea at rest. 11 0.6 8.5 0.6 Infections and Infestations Upper Respiratory Tract Infection Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 16 0.0 11 0.0 Lower Respiratory Tract And Lung Infection Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. 7.9 1.5 4.7 1.1 Psychiatric Disorders Insomnia 8.2 0.1 5.7 0.0 Renal and Urinary Disorders Hematuria 8.8 1.3 5.8 1.3 Injury, Poisoning and Procedural Complications Fall 13 1.6 5.3 0.7 Non-Pathological Fracture 8.8 2.1 3.0 1.1 Metabolism and Nutrition Disorders Decreased Appetite 19 0.3 16 0.7 Investigations Weight Decreased 12 0.8 8.5 0.2 Reproductive System and Breast Disorders Gynecomastia 3.4 0.0 1.4 0.0 TERRAIN (NCT01288911): 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 event as the primary reason were reported for 7.6% of XTANDI-treated patients and 6.3% 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 CTCAE v 4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Overall 94 39 94 38 General Disorders Asthenic Conditions Including asthenia and fatigue. 32 1.6 23 1.1 Musculoskeletal and Connective Tissue Disorders Back Pain 19 2.7 18 1.6 Musculoskeletal Pain Including musculoskeletal pain and pain in extremity. 16 1.1 14 0.5 Vascular Disorders Hot Flush 15 0 11 0 Hypertension 14 7.1 7.4 4.2 Gastrointestinal Disorders Nausea 14 0 18 0 Constipation 13 1.1 13 0.5 Diarrhea 12 0 9.0 1.1 Infections and Infestations Upper Respiratory Tract Infection Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 12 0 6.3 0.5 Investigational Weight Loss 11 0.5 7.9 0.5 PROSPER (NCT02003924): 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 events. 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 events 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 event as the primary reason were reported for 9.4% of XTANDI-treated patients and 6.0% of placebo-treated patients. Of these, the most common adverse event 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 CTCAE v 4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Metabolism and Nutrition Disorders Decreased Appetite 9.6 0.2 3.9 0.2 Nervous System Disorders Dizziness Includes dizziness and vertigo. 12 0.5 5.2 0 Headache 9.1 0.2 4.5 0 Cognitive and Attention Disorders Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 4.6 0.1 1.5 0 Vascular Disorders Hot Flush 13 0.1 7.7 0 Hypertension 12 4.6 5.2 2.2 Gastrointestinal Disorders Nausea 11 0.3 8.6 0 Constipation 9.1 0.2 6.9 0.4 General Disorders and Administration Site Conditions Asthenic Conditions Includes asthenia and fatigue. 40 4.0 20 0.9 Investigations Weight Decreased 5.9 0.2 1.5 0 Injury, Poisoning and Procedural Complications Fall 11 1.3 4.1 0.6 Fractures Includes all osseous fractures from all sites. 9.8 2.0 4.9 1.7 Psychiatric Disorders Anxiety 2.8 0.2 0.4 0 ARCHES (NCT02677896): 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) analogue 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 events. 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 events. The reasons for death in ≥ 2 patients included heart disease (n=2) and sudden death (n=2). Grade 3 or higher adverse events were reported in 24% of patients treated with XTANDI. Permanent discontinuation due to adverse events as the primary reason was reported in 4.9% of XTANDI-treated patients and 3.7% of placebo-treated patients. The most common adverse events 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 events 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 CTCAE v 4.03. (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Metabolism and Nutrition Disorders Decreased Appetite 4.9 0.2 2.6 0 Nervous System Disorders Cognitive and Memory Impairment Includes memory impairment, amnesia, cognitive disorder, dementia, disturbance in attention, transient global amnesia, dementia alzheimer’s type, mental impairment, senile dementia and vascular dementia. 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 8.0 3.3 5.6 1.7 General Disorders and Administration Site Conditions Asthenic conditions Includes asthenia and fatigue. 24 1.7 20 1.6 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain 6.3 0.2 4.0 0.2 Injury, Poisoning and Procedural Complications Fractures 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. 6.5 1.0 4.2 1.0 Laboratory Abnormalities Table 6 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 6. Laboratory Abnormalities XTANDI (N = 3173) Placebo (N = 2282) Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Hematology Neutrophil count decreased 20 0.9 17 0.4 White blood cell decreased 17 0.4 9.8 0.2 Chemistry Hyperglycemia 83 3.2 75 3.1 Hypermagnesemia 16 0.1 13 0 Hyponatremia 13 1.4 8.6 1.5 Hypercalcemia 6.8 0.1 4.5 0 Hypertension In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of patients receiving XTANDI and 5% 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 the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: vomiting Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx) Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) 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))

<table ID="_Ref517944159" width="100%"><caption>Table 1. Adverse Reactions in AFFIRM</caption><col width="51%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">XTANDI</content> <content styleCode="bold">(N = 800)</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 399)</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 1-4</content><footnote ID="_Ref500853139">CTCAE v4</footnote> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade 1-4</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th></tr></thead><tbody><tr><td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenic Conditions<footnote ID="_Ref500853211">Includes asthenia and fatigue.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>51</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>44</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral Edema</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.8</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back Pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Musculoskeletal Pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Muscular Weakness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Musculoskeletal Stiffness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hot Flush</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dizziness<footnote ID="_Ref500853223">Includes dizziness and vertigo.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Spinal Cord Compression and Cauda Equina Syndrome</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Paresthesia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mental Impairment Disorders<footnote ID="_Ref500853231">Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypoesthesia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infections and Infestations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Upper Respiratory Tract Infection<footnote ID="_Ref500853243">Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lower Respiratory Tract And Lung Infection<footnote ID="_Ref500853250">Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anxiety</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Renal and Urinary Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hematuria</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pollakiuria</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Injury, Poisoning and Procedural Complications</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fall</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Non-pathologic Fractures </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dry Skin</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Epistaxis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr></tbody></table>

<table ID="_Ref502938821" cellpadding="0pt" width="100%"><caption> Table 2. Adverse Reactions in PREVAIL</caption><col width="51%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"/><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">XTANDI</content> <content styleCode="bold">(N = 871)</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 844)</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 1-4</content><footnote ID="_Ref500853515">CTCAE v4</footnote> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 1-4</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th></tr></thead><tbody><tr><td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenic Conditions<footnote ID="_Ref500853682">Includes asthenia and fatigue.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hot Flush</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dizziness<footnote ID="_Ref500853719">Includes dizziness and vertigo.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dysgeusia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mental Impairment Disorders<footnote ID="_Ref500853744">Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Restless Legs Syndrome</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea<footnote ID="_Ref500853761">Includes dyspnea, exertional dyspnea, and dyspnea at rest.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.6</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infections and Infestations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Upper Respiratory Tract Infection<footnote ID="_Ref500853771">Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lower Respiratory Tract And Lung Infection<footnote ID="_Ref500853778">Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Renal and Urinary Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hematuria</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Injury, Poisoning and Procedural Complications</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fall</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Non-Pathological Fracture</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Decreased Appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.7</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Investigations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Weight Decreased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.2</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Reproductive System and Breast Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Gynecomastia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.0</paragraph></td></tr></tbody></table>

<table ID="_Ref502938858" width="100%"><caption>Table 3. Adverse Reactions in TERRAIN</caption><col width="51%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">XTANDI</content> <content styleCode="bold">(N = 183)</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Bicalutamide</content> <content styleCode="bold">(N = 189)</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 1-4</content><footnote ID="_Ref500854112">CTCAE v 4</footnote> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 1-4</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Overall</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>94</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>39</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>94</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>38</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Asthenic Conditions<footnote ID="_Ref500854187">Including asthenia and fatigue.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Musculoskeletal Pain<footnote ID="_Ref500854199">Including musculoskeletal pain and pain in extremity.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hot Flush</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4.2</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infections and Infestations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Upper Respiratory Tract Infection<footnote ID="_Ref500854206">Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Investigational</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Weight Loss</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7.9</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.5</paragraph></td></tr></tbody></table>