{"adverse_reactions":["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))"],"adverse_reactions_table":["
Table 1. Adverse Reactions in AFFIRM
XTANDI (N = 800)Placebo (N = 399)
Grade 1-4CTCAE v4 (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)
General Disorders
Asthenic ConditionsIncludes asthenia and fatigue.519.0449.3
Peripheral Edema151.0130.8
Musculoskeletal and Connective Tissue Disorders
Back Pain265.3244.0
Arthralgia212.5171.8
Musculoskeletal Pain151.3120.3
Muscular Weakness9.81.56.81.8
Musculoskeletal Stiffness2.60.30.30.0
Gastrointestinal Disorders
Diarrhea221.1180.3
Vascular Disorders
Hot Flush200.0100.0
Hypertension6.42.12.81.3
Nervous System Disorders
Headache120.95.50.0
DizzinessIncludes dizziness and vertigo.9.50.57.50.5
Spinal Cord Compression and Cauda Equina Syndrome7.46.64.53.8
Paresthesia6.60.04.50.0
Mental Impairment DisordersIncludes amnesia, memory impairment, cognitive disorder, and disturbance in attention.4.30.31.80.0
Hypoesthesia4.00.31.80.0
Infections and Infestations
Upper Respiratory Tract InfectionIncludes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.110.06.50.3
Lower Respiratory Tract And Lung InfectionIncludes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.8.52.44.81.3
Psychiatric Disorders
Insomnia8.80.06.00.5
Anxiety6.50.34.00.0
Renal and Urinary Disorders
Hematuria6.91.84.51.0
Pollakiuria4.80.02.50.0
Injury, Poisoning and Procedural Complications
Fall4.60.31.30.0
Non-pathologic Fractures 4.01.40.80.3
Skin and Subcutaneous Tissue Disorders
Pruritus3.80.01.30.0
Dry Skin3.50.01.30.0
Respiratory Disorders
Epistaxis3.30.11.30.3
","
Table 2. Adverse Reactions in PREVAIL
XTANDI (N = 871)Placebo (N = 844)
Grade 1-4CTCAE v4 (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)
General Disorders
Asthenic ConditionsIncludes asthenia and fatigue.473.4332.8
Peripheral Edema120.28.20.4
Musculoskeletal and Connective Tissue Disorders
Back Pain292.5223.0
Arthralgia211.6161.1
Gastrointestinal Disorders
Constipation230.7170.4
Diarrhea170.3140.4
Vascular Disorders
Hot Flush180.17.80.0
Hypertension147.24.12.3
Nervous System Disorders
DizzinessIncludes dizziness and vertigo.110.37.10.0
Headache110.27.00.4
Dysgeusia7.60.13.70.0
Mental Impairment DisordersIncludes amnesia, memory impairment, cognitive disorder, and disturbance in attention.5.70.01.30.1
Restless Legs Syndrome2.10.10.40.0
Respiratory Disorders
DyspneaIncludes dyspnea, exertional dyspnea, and dyspnea at rest.110.68.50.6
Infections and Infestations
Upper Respiratory Tract InfectionIncludes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.160.0110.0
Lower Respiratory Tract And Lung InfectionIncludes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.7.91.54.71.1
Psychiatric Disorders
Insomnia8.20.15.70.0
Renal and Urinary Disorders
Hematuria8.81.35.81.3
Injury, Poisoning and Procedural Complications
Fall131.65.30.7
Non-Pathological Fracture8.82.13.01.1
Metabolism and Nutrition Disorders
Decreased Appetite190.3160.7
Investigations
Weight Decreased120.88.50.2
Reproductive System and Breast Disorders
Gynecomastia3.40.01.40.0
","
Table 3. Adverse Reactions in TERRAIN
XTANDI (N = 183)Bicalutamide (N = 189)
Grade 1-4CTCAE v 4 (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)
Overall94399438
General Disorders
Asthenic ConditionsIncluding asthenia and fatigue.321.6231.1
Musculoskeletal and Connective Tissue Disorders
Back Pain192.7181.6
Musculoskeletal PainIncluding musculoskeletal pain and pain in extremity.161.1140.5
Vascular Disorders
Hot Flush150110
Hypertension147.17.44.2
Gastrointestinal Disorders
Nausea140180
Constipation131.1130.5
Diarrhea1209.01.1
Infections and Infestations
Upper Respiratory Tract InfectionIncluding nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.1206.30.5
Investigational
Weight Loss110.57.90.5
","
Table 4. Adverse Reactions in PROSPER
XTANDI (N = 930)Placebo (N = 465)
Grade 1-4CTCAE v 4 (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)
Metabolism and Nutrition Disorders
Decreased Appetite9.60.23.90.2
Nervous System Disorders
DizzinessIncludes dizziness and vertigo.120.55.20
Headache9.10.24.50
Cognitive and Attention DisordersIncludes amnesia, memory impairment, cognitive disorder, and disturbance in attention.4.60.11.50
Vascular Disorders
Hot Flush130.17.70
Hypertension124.65.22.2
Gastrointestinal Disorders
Nausea110.38.60
Constipation9.10.26.90.4
General Disorders and Administration Site Conditions
Asthenic ConditionsIncludes asthenia and fatigue.404.0200.9
Investigations
Weight Decreased5.90.21.50
Injury, Poisoning and Procedural Complications
Fall111.34.10.6
FracturesIncludes all osseous fractures from all sites.9.82.04.91.7
Psychiatric Disorders
Anxiety2.80.20.40
","Decreased AppetiteCognitive and Memory ImpairmentIncludes memory impairment, amnesia, cognitive disorder, dementia, disturbance in attention, transient global amnesia, dementia alzheimer’s type, mental impairment, senile dementia and vascular dementia.Restless Legs SyndromeHot FlushHypertensionAsthenic conditionsIncludes asthenia and fatigue.Musculoskeletal PainFracturesIncludes 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.
Table 5. Adverse Reactions in ARCHES
XTANDI (N = 572)Placebo (N = 574)
Grade 1-4CTCAE v 4.03. (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)
Metabolism and Nutrition Disorders
4.90.22.60
Nervous System Disorders
4.50.72.10
2.400.30
Vascular Disorders
270.3220
8.03.35.61.7
General Disorders and Administration Site Conditions
241.7201.6
Musculoskeletal and Connective Tissue Disorders
6.30.24.00.2
Injury, Poisoning and Procedural Complications
6.51.04.21.0
","Neutrophil count decreasedWhite blood cell decreasedHyperglycemiaHypermagnesemiaHyponatremiaHypercalcemia
Table 6. Laboratory Abnormalities
XTANDI (N = 3173)Placebo (N = 2282)
Grade 1-4 (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)
Hematology
200.9170.4
170.49.80.2
Chemistry
833.2753.1
160.1130
131.48.61.5
6.80.14.50
"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral enzalutamide doses of 10, 30, and 100 mg/kg/day. Enzalutamide increased the incidence of benign Leydig cell tumors in the testes at all dose levels tested (≥ 0.3 times the human exposure based on AUC) and combined incidence of urothelial papilloma and carcinoma in the urinary bladder in male rats at 100 mg/kg/day (1.4 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of enzalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Administration of enzalutamide to male and female rasH2 transgenic mice by oral gavage daily for 26 weeks did not result in increased incidence of neoplasms at doses up to 20 mg/kg/day. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC)."],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N‑desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro , and decreased tumor volume in a mouse prostate cancer xenograft model. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of enzalutamide 160 mg/day at steady-state on the QTc interval was evaluated in 796 patients with metastatic CRPC. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with XTANDI and that in patients treated with placebo, based on the Fridericia correction method. However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design. 12.3 Pharmacokinetics The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption. Absorption Following oral administration of XTANDI capsules (160 mg daily) in patients with metastatic CRPC, the median time to reach maximum plasma enzalutamide concentrations (C max ) is 1 hour (range 0.5 to 3 hours). At steady-state, the plasma mean C max values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively. Following a single dose administration of 160 mg enzalutamide in healthy male volunteers, enzalutamide extent of absorption (AUC) was comparable between XTANDI tablet and XTANDI capsule, but the mean C max was 10%-28% lower than that of XTANDI capsules. The steady-state pharmacokinetic profiles (AUC and C max ) of enzalutamide and N-desmethyl enzalutamide are similar for XTANDI tablet and XTANDI capsule. With the daily dosing regimen, enzalutamide steady-state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady-state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg. A single 160 mg oral dose of XTANDI was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1 . Distribution and Protein Binding The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV). Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro , there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations. Metabolism Following single oral administration of 14 C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14 C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14 C-AUC 0-inf . In vitro , human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). In vitro data suggest that carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite. In vitro , N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5. Elimination Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of 14 C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide). The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h). The mean terminal half-life (t 1/2 ) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t 1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days. Pharmacokinetics in Special Populations Renal Impairment : A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic CRPC enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end-stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment : The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 22) and with pre-existing mild (N = 8, Child-Pugh Class A) moderate (N = 8, Child-Pugh Class B), or severe (N = 8, Child-Pugh Class C) hepatic impairment. XTANDI was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1 [see Use in Specific Populations ( 8.7 )] . Body Weight and Age: Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (range: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to enzalutamide. Gender : The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated. Race : The majority of XTANDI-treated patients in the randomized clinical trials were Caucasian (81%). Based on pharmacokinetic data from studies in Japanese and Chinese patients with prostate cancer, there were no clinically relevant differences in exposure among the populations. There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races. Drug Interactions Effect of Other Drugs on XTANDI: In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the AUC 0‑inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C max . The results are summarized in Figure 1 [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.1 )] . In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer). Rifampin decreased the AUC 0‑inf of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on C max . The results are summarized in Figure 1 [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.2 )] . In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the AUC 0‑inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on C max . The results are summarized in Figure 1 . Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI # PK parameters (C max and AUC 0-inf ) are for enzalutamide plus N-desmethyl enzalutamide, except in the food-effect trial, where they are for enzalutamide alone. * See Dosage and Administration ( 2.2 ). Effect of XTANDI on Other Drugs: In an in vivo phenotypic cocktail drug-drug interaction trial in patients with metastatic CRPC, a single oral dose of the CYP probe substrate cocktail (for CYP2C8, CYP2C9, CYP2C19, and CYP3A4) was administered before and concomitantly with XTANDI (following at least 55 days of dosing at 160 mg daily). The results are summarized in Figure 2 . Results showed that in vivo , at steady-state, XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer [see Drug Interactions ( 7.3 )] . XTANDI did not cause clinically meaningful changes in exposure to the CYP2C8 substrate. In an in vivo phenotypic cocktail drug-drug interaction trial in patients with CRPC, a single oral dose of the CYP probe substrate cocktail for CYP1A2 and CYP2D6 was administered before and concomitantly with XTANDI (following at least 49 days of dosing at 160 mg daily). The results are summarized in Figure 2 . Results showed that in vivo , at steady-state, XTANDI did not cause clinically meaningful changes in exposure to the CYP1A2 or CYP2D6 substrates. Figure 2. Effect of XTANDI on Other Drugs *See Drug Interactions ( 7.3 ). In vitro , enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical data showed that XTANDI is an inducer of CYP2C9, CYP2C19, and CYP3A4 and had no clinically meaningful effect on CYP2C8 (see Figure 2 ). In vitro , enzalutamide caused time-dependent inhibition of CYP1A2. In vitro studies showed that enzalutamide induces CYP2B6 and CYP3A4 and does not induce CYP1A2 at therapeutically relevant concentrations. In vitro , enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for human P-glycoprotein. In vitro , enzalutamide and N-desmethyl enzalutamide are inhibitors of human P-glycoprotein, while the major inactive carboxylic acid metabolite is not. In vitro , enzalutamide and N-desmethyl enzalutamide do not appear to be substrates of human breast cancer resistance protein (BCRP); however, enzalutamide and N-desmethyl enzalutamide are inhibitors of human BCRP at clinically relevant concentrations. Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI Figure 2. Effect of XTANDI on Other Drugs"],"clinical_studies":["14 CLINICAL STUDIES The efficacy of XTANDI in patients with CRPC (N = 4692) or mCSPC (N = 1150) was demonstrated in five randomized, multicenter clinical trials. All patients received concomitant GnRH therapy or had prior bilateral orchiectomy. Patients were allowed, but not required, to continue or initiate glucocorticoids. AFFIRM (NCT00974311): XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy In AFFIRM, a total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 800) or placebo orally once daily (N = 399). Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible [see Warnings and Precautions ( 5.1 )] . The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the XTANDI arm compared to patients on the placebo arm ( Table 7 and Figure 3 ). Table 7. Overall Survival of Patients Treated with Either XTANDI or Placebo in AFFIRM NR = Not reached. XTANDI (N = 800) Placebo (N = 399) Number of Deaths (%) 308 (38.5) 212 (53.1) Median Survival, months (95% CI) 18.4 (17.3, NR) 13.6 (11.3, 15.8) P-value P-value is derived from a log-rank test stratified by baseline ECOG performance status score (0-1 vs. 2) and mean baseline pain score (BPI-SF score < 4 vs. ≥ 4). p < 0.0001 Hazard Ratio (95% CI) Hazard Ratio is derived from a stratified proportional hazards model. Hazard Ratio < 1 favors XTANDI. 0.63 (0.53, 0.75) Figure 3. Kaplan-Meier Curves of Overall Survival in AFFIRM PREVAIL (NCT01212991): XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC In PREVAIL, 1717 chemotherapy-naïve patients were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 872) or placebo orally once daily (N = 845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression. Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the XTANDI arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons. A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths in patients treated with XTANDI compared to those treated with placebo ( Table 8 ). Forty percent of XTANDI-treated and 70% of placebo-treated patients received subsequent therapies for metastatic CRPC that may prolong overall survival. An updated survival analysis was conducted when 784 deaths were observed. The median follow-up time was 31 months. Results from this analysis were consistent with those from the pre-specified interim analysis ( Table 8 , Figure 4 ). At the updated analysis, 52% of XTANDI-treated and 81% of placebo-treated patients had received subsequent therapies that may prolong overall survival in metastatic CRPC. XTANDI was used as a subsequent therapy in 2% of XTANDI-treated patients and 29% of placebo-treated patients. Table 8. Overall Survival of Patients Treated with Either XTANDI or Placebo in PREVAIL NR = Not reached. XTANDI (N = 872) Placebo (N = 845) Pre-specified Interim Analysis The data cutoff date is 16 Sep 2013. Number of Deaths (%) 241 (28) 299 (35) Median Survival, months (95% CI) 32.4 (30.1, NR) 30.2 (28.0, NR) P-value P-value is derived from an unstratified log-rank test. p < 0.0001 Hazard Ratio (95% CI) Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI. 0.71 (0.60, 0.84) Updated Survival Analysis The data cutoff date is 1 Jun 2014. The planned number of deaths for the final overall survival analysis was ≥ 765. Number of Deaths (%) 368 (42) 416 (49) Median Survival, months (95% CI) 35.3 (32.2, NR) 31.3 (28.8, 34.2) Hazard Ratio (95% CI) 0.77 (0.67, 0.88) Figure 4. Kaplan-Meier Curves of Overall Survival in PREVAIL A statistically significant improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with placebo ( Table 9 , Figure 5 ). Table 9. Radiographic Progression-free Survival of Patients Treated with Either XTANDI or Placebo in PREVAIL NR = Not reached. Note: As of the cutoff date for the rPFS analysis, 1633 patients had been randomized. XTANDI (N = 832) Placebo (N = 801) Number of Progression or Deaths (%) 118 (14) 320 (40) Median rPFS (months) (95% CI) NR (13.8, NR) 3.7 (3.6, 4.6) P-value P-value is derived from an unstratified log-rank test. p < 0.0001 Hazard Ratio (95% CI) Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI. 0.17 (0.14, 0.21) Figure 5. Kaplan-Meier Curves of Radiographic Progression-free Survival in PREVAIL Time to initiation of cytotoxic chemotherapy was prolonged after XTANDI treatment, with a median of 28.0 months for patients on the XTANDI arm versus a median of 10.8 months for patients on the placebo arm [HR = 0.35 (95% CI: 0.30, 0.40), p < 0.0001]. The median time to first skeletal‑related event was 31.1 months for patients on the XTANDI arm versus 31.3 months for patients on the placebo arm [HR = 0.72 (95% CI: 0.61, 0.84), p < 0.0001]. A skeletal‑related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. TERRAIN (NCT01288911): XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC TERRAIN was conducted in 375 chemotherapy-naïve patients who were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 184) or bicalutamide orally at a dose of 50 mg once daily (N = 191). Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate to severe pain from prostate cancer were excluded. Patients could have received prior bicalutamide, but those whose disease had progressed on prior antiandrogen therapy (e.g., bicalutamide) were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event), the initiation of subsequent antineoplastic agent, unacceptable toxicity, or withdrawal. Radiographic disease progression was assessed by Independent Central Review (ICR) using the Prostate Cancer Clinical Trials Working Group 2 criteria and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. Radiographic progression-free survival (rPFS) was defined as the time from randomization to the first objective evidence of radiographic progression as assessed by ICR or death, whichever occurred first. Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 48-96) and the racial distribution was 93% Caucasian, 5% Black, 1% Asian and 1% Other. The ECOG performance status score was 0 for 74% of patients and 1 for 26% of patients. Baseline pain assessment was 0‑1 (asymptomatic) in 58% of patients, and 2‑3 (mildly symptomatic) in 36% of patients as defined by the Brief Pain Inventory Short Form Question 3 (worst pain over past 24 hours at study entry). Ninety-eight percent of patients had objective evidence of disease progression at study entry. Forty-six percent of patients had received prior treatment with bicalutamide while no patients received prior treatment with XTANDI. An improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with bicalutamide ( Table 10 , Figure 6 ). Table 10. Radiographic Progression-free Survival of Patients in TERRAIN XTANDI (N = 184) Bicalutamide (N = 191) NR = Not reached. Number of Progression or Deaths (%) 72 (39) 74 (39) Median rPFS (months) (95% CI) 19.5 (11.8, NR) 13.4 (8.2, 16.4) Hazard Ratio (95% CI) Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI 0.60 (0.43, 0.83) Figure 6. Kaplan-Meier Curves of Radiographic Progression-free Survival in TERRAIN PROSPER (NCT02003924): XTANDI versus Placebo in Non-metastatic CRPC PROSPER enrolled 1401 patients with non-metastatic CRPC who were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 933) or placebo orally once daily (N = 468). All patients in the PROSPER trial received a gonadotropin-releasing hormone (GnRH) analog or had a prior bilateral orchiectomy. Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time (PSADT) and the use of bone-targeting agents. Patients were required to have a PSA doubling time ≤ 10 months, PSA ≥ 2 ng/mL, and confirmation of non-metastatic disease by blinded independent central review (BICR). PSA results were blinded and were not used for treatment discontinuation. Patients randomized to either arm discontinued treatment for radiographic disease progression confirmed by BICR, initiation of new treatment, unacceptable toxicity, or withdrawal. The following patient demographics and baseline characteristics were balanced between the two treatment arms. The median age at randomization was 74 years (range 50-95) and 23% were 80 years of age or older. The racial distribution was 71% Caucasian, 16% Asian, and 2% Black. A majority of patients had a Gleason score of 7 or higher (77%). The median PSADT was 3.7 months. Fifty-four percent (54%) of patients received prior treatment for prostate cancer with either surgery or radiation. Sixty-three percent (63%) of patients received prior treatment with an anti-androgen; 56% of patients received bicalutamide and 11% of patients received flutamide. All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. The major efficacy outcome of the study was metastasis-free survival (MFS), defined as the time from randomization to whichever of the following occurred first 1) loco-regional and/or distant radiographic progression per BICR or 2) death up to 112 days after treatment discontinuation without evidence of radiographic progression. A statistically significant improvement in MFS and OS was demonstrated in patients randomized to receive XTANDI compared with patients randomized to receive placebo. Consistent MFS results were observed when considering only distant radiographic progression events or deaths regardless of the cut-off date. Consistent MFS results were also observed in pre-specified and stratified patient sub-groups of PSADT (< 6 months or ≥ 6 months) and use of a prior bone-targeting agent (yes or no). The efficacy results from PROSPER are summarized in Table 11 , Figure 7 and Figure 8 . Table 11. Summary of Efficacy Results in PROSPER (Intent-to-treat Population) NR = Not reached. XTANDI (N = 933) Placebo (N = 468) Metastasis-free survival Number of Events (%) 219 (23.5) 228 (48.7) Median, months (95% CI) Based on Kaplan-Meier estimates. 36.6 (33.1, NR) 14.7 (14.2, 15.0) Hazard Ratio (95% CI) Hazard ratio from a Cox regression model (with treatment as the only covariate) and p-value from a log-rank test are stratified by PSA doubling time and prior or concurrent use of a bone targeting agent. 0.29 (0.24, 0.35) P-value p < 0.0001 Overall survival The pre-specified final analysis of OS occurred 27 months after the MFS analysis. Number of Events (%) 288 (30.9) 178 (38.0) Median, months (95% CI) 67.0 (64.0, NR) 56.3 (54.4, 63.0) Hazard Ratio (95% CI) 0.73 (0.61, 0.88) P-value p = 0.0011 Figure 7. Kaplan-Meier Curves of Metastasis-free Survival in PROSPER Figure 8. Kaplan-Meier Curves of Overall Survival in PROSPER The primary efficacy outcome was also supported by a statistically significant delay in time to first use of new antineoplastic therapy (TTA) for patients in the XTANDI arm compared to those in the placebo arm. The median TTA was 39.6 months for patients on XTANDI and was 17.7 months for patients on placebo (HR = 0.21; 95% CI: [0.17, 0.26], p < 0.0001). ARCHES (NCT02677896): XTANDI versus Placebo in Metastatic CSPC ARCHES enrolled 1150 patients with mCSPC who were randomized 1:1 to receive XTANDI orally at a dose of 160 mg once daily (N=574) or placebo orally once daily (N=576). All patients in the trial received a GnRH analog or had a prior bilateral orchiectomy. Patients were stratified by volume of disease (low vs high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1-5 cycles, or 6 prior cycles). High volume of disease is defined as metastases involving the viscera or, in the absence of visceral lesions, there must be 4 or more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral column and pelvic bone. Treatment with concurrent docetaxel was not allowed. Patients continued treatment until radiographic disease progression, initiation of new treatment, unacceptable toxicity, or withdrawal. The following patient demographics and baseline characteristics were balanced between the two treatment arms. The median age at randomization was 70 years (range: 42-92) and 30% were 75 years of age or older. The racial distribution was 81% Caucasian, 14% Asian, and 1% Black. Sixty-six percent (66%) of patients had a Gleason score of ≥ 8. Thirty-seven percent (37%) of patients had a low volume of disease and 63% of patients had a high volume of disease. Eighty-two percent (82%) of patients had no prior docetaxel treatment; 2% of patients had 1 to 5 cycles of docetaxel and 16% of patients had 6 prior cycles of docetaxel treatment. Twelve percent (12%) of patients received concomitant bone-targeted agents (bisphosphonates or RANKL inhibitors) which included both prostate and non-prostate cancer indications. The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score was 0 for 78% of patients and 1 for 22% of patients at study entry. The major efficacy outcome measure was radiographic progression-free survival (rPFS) based on blinded independent central review (BICR). Radiographic progression-free survival was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after study drug discontinuation. Radiographic disease progression was defined by identification of 2 or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. Time to new antineoplastic therapy was an additional efficacy endpoint. XTANDI demonstrated a statistically significant improvement in rPFS compared to placebo. Consistent rPFS results were observed in patients with high or low volume of disease and patients with and without prior docetaxel therapy. Overall survival (OS) data were not mature at the time of rPFS analysis (7.3% deaths in the ITT population had been reported). Efficacy results for rPFS from ARCHES are summarized in Table 12 and Figure 9 . Table 12. Efficacy Results in ARCHES based on BICR (Intent-to-Treat Analysis) NR = Not reached XTANDI (N = 574) Placebo (N = 576) Radiographic Progression-free Survival Number of events (%) 89 (15.5) 198 (34.4) Radiographic disease progression 77 (13.4) 185 (32.1) Death within 24 weeks after treatment discontinuation 12 (2.1) 13 (2.3) Median, months (95% CI) Based on Kaplan-Meier estimates. NR 19.4 (16.6, NR) Hazard ratio (95% CI) Hazard Ratio is based on a Cox regression model stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no). 0.39 (0.30, 0.50) P-value P-value is based on a stratified log-rank test by volume of disease (low vs high) and prior docetaxel use (yes or no). p < 0.0001 Figure 9. Kaplan-Meier Curves of rPFS in ARCHES (Intent-to-Treat Analysis) A statistically significant improvement was also reported on the XTANDI arm compared to placebo in time to initiation of a new antineoplastic therapy (HR = 0.28 [95% CI: 0.20, 0.40]; p < 0.0001). Figure 3. Kaplan-Meier Curves of Overall Survival in AFFIRM Figure 4. Kaplan-Meier Curves of Overall Survival in PREVAIL Figure 5. Kaplan-Meier Curves of Radiographic Progression-free Survival in PREVAIL Figure 6. Kaplan-Meier Curves of Radiographic Progression-free Survival in TERRAIN Figure 7. Kaplan-Meier Curves of Metastasis-free Survival in PROSPER Figure 8. Kaplan-Meier Curves of Overall Survival in PROSPER Figure 9. Kaplan-Meier Curves of rPFS in ARCHES (Intent-to-Treat Analysis)"],"clinical_studies_table":["
Table 7. Overall Survival of Patients Treated with Either XTANDI or Placebo in AFFIRM
NR = Not reached.
XTANDI(N = 800)Placebo (N = 399)
Number of Deaths (%) 308 (38.5)212 (53.1)
Median Survival, months (95% CI)18.4 (17.3, NR) 13.6 (11.3, 15.8)
P-valueP-value is derived from a log-rank test stratified by baseline ECOG performance status score (0-1 vs. 2) and mean baseline pain score (BPI-SF score < 4 vs. ≥ 4).p < 0.0001
Hazard Ratio (95% CI)Hazard Ratio is derived from a stratified proportional hazards model. Hazard Ratio < 1 favors XTANDI.0.63 (0.53, 0.75)
","
Table 8. Overall Survival of Patients Treated with Either XTANDI or Placebo in PREVAIL
NR = Not reached.
XTANDI (N = 872)Placebo (N = 845)
Pre-specified Interim AnalysisThe data cutoff date is 16 Sep 2013.
Number of Deaths (%) 241 (28)299 (35)
Median Survival, months (95% CI)32.4 (30.1, NR) 30.2 (28.0, NR)
P-valueP-value is derived from an unstratified log-rank test.p < 0.0001
Hazard Ratio (95% CI)Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI.0.71 (0.60, 0.84)
Updated Survival AnalysisThe data cutoff date is 1 Jun 2014. The planned number of deaths for the final overall survival analysis was ≥ 765.
Number of Deaths (%)368 (42)416 (49)
Median Survival, months (95% CI)35.3 (32.2, NR)31.3 (28.8, 34.2)
Hazard Ratio (95% CI)0.77 (0.67, 0.88)
","
Table 9. Radiographic Progression-free Survival of Patients Treated with Either XTANDI or Placebo in PREVAIL
NR = Not reached. Note: As of the cutoff date for the rPFS analysis, 1633 patients had been randomized.
XTANDI(N = 832)Placebo (N = 801)
Number of Progression or Deaths (%) 118 (14)320 (40)
Median rPFS (months) (95% CI)NR (13.8, NR) 3.7 (3.6, 4.6)
P-valueP-value is derived from an unstratified log-rank test.p < 0.0001
Hazard Ratio (95% CI)Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI.0.17 (0.14, 0.21)
","
Table 10. Radiographic Progression-free Survival of Patients in TERRAIN
XTANDI (N = 184)Bicalutamide (N = 191)
NR = Not reached.
Number of Progression or Deaths (%) 72 (39)74 (39)
Median rPFS (months) (95% CI)19.5 (11.8, NR)13.4 (8.2, 16.4)
Hazard Ratio (95% CI)Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI 0.60 (0.43, 0.83)
","
Table 11. Summary of Efficacy Results in PROSPER (Intent-to-treat Population)
NR = Not reached.
XTANDI (N = 933)Placebo (N = 468)
Metastasis-free survival
Number of Events (%)219 (23.5)228 (48.7)
Median, months (95% CI)Based on Kaplan-Meier estimates.36.6 (33.1, NR)14.7 (14.2, 15.0)
Hazard Ratio (95% CI)Hazard ratio from a Cox regression model (with treatment as the only covariate) and p-value from a log-rank test are stratified by PSA doubling time and prior or concurrent use of a bone targeting agent.0.29 (0.24, 0.35)
P-valuep < 0.0001
Overall survivalThe pre-specified final analysis of OS occurred 27 months after the MFS analysis.
Number of Events (%)288 (30.9)178 (38.0)
Median, months (95% CI)67.0 (64.0, NR)56.3 (54.4, 63.0)
Hazard Ratio (95% CI)0.73 (0.61, 0.88)
P-valuep = 0.0011
","Radiographic disease progressionDeath within 24 weeks after treatment discontinuation
Table 12. Efficacy Results in ARCHES based on BICR (Intent-to-Treat Analysis)
NR = Not reached
XTANDI (N = 574)Placebo (N = 576)
Radiographic Progression-free Survival
Number of events (%)89 (15.5)198 (34.4)
77 (13.4)185 (32.1)
12 (2.1)13 (2.3)
Median, months (95% CI)Based on Kaplan-Meier estimates.NR19.4 (16.6, NR)
Hazard ratio (95% CI)Hazard Ratio is based on a Cox regression model stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no). 0.39 (0.30, 0.50)
P-valueP-value is based on a stratified log-rank test by volume of disease (low vs high) and prior docetaxel use (yes or no).p < 0.0001
"],"contraindications":["4 CONTRAINDICATIONS None. None. ( 4 )"],"description":["11 DESCRIPTION Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro- N -methylbenzamide. The molecular weight is 464.44 and molecular formula is C 21 H 16 F 4 N 4 O 2 S. The structural formula is: Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. XTANDI is available as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide. XTANDI is also available as film-coated tablets for oral administration. Each tablet contains 40 mg or 80 mg of enzalutamide. The inactive ingredients are hypromellose acetate succinate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. The tablet film-coat contains hypromellose, talc, polyethylene glycol, titanium dioxide, and ferric oxide. Structural formula of Enzalutamide"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION XTANDI 160 mg (two 80 mg tablets or four 40 mg tablets or four 40 mg capsules) administered orally once daily. Swallow capsules or tablets whole. ( 2.1 ) Patients receiving XTANDI should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.3 ) 2.1 Dosing Information The recommended dose of XTANDI is 160 mg (two 80 mg tablets or four 40 mg tablets or four 40 mg capsules) administered orally once daily. XTANDI can be taken with or without food [see Clinical Pharmacology ( 12.3 )]. Swallow capsules or tablets whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets [see How Supplied/Storage and Handling ( 16 )] . 2.2 Dose Modifications If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted [see Warnings and Precautions ( 5.1 ), ( 5.2 )] . Concomitant Strong CYP2C8 Inhibitors The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the XTANDI dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]. Concomitant Strong CYP3A4 Inducers The concomitant use of strong CYP3A4 inducers should be avoided if possible. If patients must be co-administered a strong CYP3A4 inducer, increase the XTANDI dose from 160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]. 2.3 Important Administration Instructions Patients receiving XTANDI should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy."],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS XTANDI 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. XTANDI 40 mg tablets are yellow, round, film-coated and debossed with E 40. XTANDI 80 mg tablets are yellow, oval, film-coated and debossed with E 80. Capsule 40 mg ( 3 ) Tablet: 40 mg, 80 mg ( 3 )"],"drug_interactions":["7 DRUG INTERACTIONS • Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. ( 2.2 , 7.1 ) • Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI. ( 2.2 , 7.2 ) • Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. ( 7.3 ) 7.1 Drugs that Inhibit CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold. Co‑administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. 7.2 Drugs that Induce CYP3A4 Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) with XTANDI should be avoided if possible. St John’s wort may decrease enzalutamide exposure and should be avoided. If co-administration of a strong CYP3A4 inducer with XTANDI cannot be avoided, increase the dose of XTANDI [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. 7.3 Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady-state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin, clopidogrel) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology ( 12.3 )] ."],"effective_time":"20210525","geriatric_use":["8.5 Geriatric Use Of 4081 patients who received XTANDI in seven randomized, controlled clinical trials, 78% were 65 and over, while 35% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out."],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING XTANDI (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ and are available in the following package size: • Bottles of 120 capsules with child resistant closures (NDC 0469-0125-99) XTANDI (enzalutamide) 40 mg tablets are supplied as yellow, round, film-coated tablets debossed with E 40, and are available in the following package size: • Bottles of 120 tablets with child resistant closures (NDC 0469-0625-99) XTANDI (enzalutamide) 80 mg tablets are supplied as yellow, oval, film-coated tablets debossed with E 80, and are available in the following package size: • Bottles of 60 tablets with child resistant closures (NDC 0469-0725-60) Recommended storage: Store XTANDI capsules and tablets at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F). Swallow capsules or tablets whole. Do not chew, dissolve or open the capsules. Do not cut, crush, or chew the tablets."],"id":"cceea585-adf1-4f4e-a97f-5f78c9726537","indications_and_usage":["1 INDICATIONS AND USAGE XTANDI ® is indicated for the treatment of patients with: • castration-resistant prostate cancer (CRPC) • metastatic castration-sensitive prostate cancer (mCSPC). XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with: • castration-resistant prostate cancer. ( 1 ) • metastatic castration-sensitive prostate cancer. ( 1 )"],"information_for_patients":["17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) . Seizure • Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they have loss of consciousness or seizure [see Warnings and Precautions ( 5.1 )] . Posterior Reversible Encephalopathy Syndrome (PRES) • Inform patients to contact their healthcare provider right away if they experience rapidly worsening symptoms possibly indicative of PRES such as seizure, headache, decreased alertness, confusion, reduced eyesight, or blurred vision [see Warnings and Precautions ( 5.2 )] . Hypersensitivity • Inform patients that XTANDI may be associated with hypersensitivity reactions that include swelling of the face, lip, tongue, or throat [see Warnings and Precautions ( 5.3 )] . Advise patients who experience these types of symptoms of hypersensitivity to discontinue XTANDI and promptly contact their healthcare provider. Ischemic Heart Disease • Inform patients that XTANDI has been associated with an increased risk of ischemic heart disease. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular event occur [see Warnings and Precautions ( 5.4 )] . Falls and Fractures • Inform patients that XTANDI is associated with an increased incidence of dizziness/vertigo, falls, and fractures. Advise patients to report these adverse reactions to their healthcare provider [see Warnings and Precautions ( 5.5 )] . Hypertension • Inform patients that XTANDI is associated with an increased incidence of hypertension [see Adverse Reactions ( 6.1 )] . Dosing and Administration • Inform patients who have not undergone bilateral orchiectomy and are receiving GnRH therapy that they need to maintain this treatment during the course of treatment with XTANDI. • Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Each capsule or tablet should be swallowed whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets. • Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their healthcare provider. • Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day [see Dosage and Administration ( 2.1 )] . Embryo-Fetal Toxicity • Inform patients that XTANDI can be harmful to a developing fetus and can cause loss of pregnancy. • Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of XTANDI. Advise male patients to use a condom if having sex with a pregnant woman [see Warnings and Precautions ( 5.6 )] . Infertility • Inform male patients that XTANDI may impair fertility [see Use in Specific Populations ( 8.3 )] . Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10017 280168-XTA-USA Rx Only © 2020 Astellas Pharma US, Inc. XTANDI ® is a registered trademark of Astellas Pharma Inc."],"mechanism_of_action":["12.1 Mechanism of Action Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N‑desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro , and decreased tumor volume in a mouse prostate cancer xenograft model."],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral enzalutamide doses of 10, 30, and 100 mg/kg/day. Enzalutamide increased the incidence of benign Leydig cell tumors in the testes at all dose levels tested (≥ 0.3 times the human exposure based on AUC) and combined incidence of urothelial papilloma and carcinoma in the urinary bladder in male rats at 100 mg/kg/day (1.4 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of enzalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Administration of enzalutamide to male and female rasH2 transgenic mice by oral gavage daily for 26 weeks did not result in increased incidence of neoplasms at doses up to 20 mg/kg/day. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC)."],"openfda":{},"overdosage":["10 OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose."],"package_label_principal_display_panel":["PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0469-0625-99 Rx Only Xtandi ® (enzalutamide) tablets 40 mg Swallow tablets whole. Do not cut, crush, or chew the tablets. 120 Tablets Manufactured by Pfizer Pharmaceuticals LLC, for Astellas Pharma US, Inc., Northbrook, IL 60062 PAA135442 234833-XTA-USA Xtandi (enzalutamide) tablets 40 mg label","PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0469-0725-60 Rx Only Xtandi ® (enzalutamide) tablets 80 mg Swallow tablets whole. Do not cut, crush, or chew the tablets. 60 Tablets Manufactured by Pfizer Pharmaceuticals LLC, for Astellas Pharma US, Inc., Northbrook, IL 60062 PAA135444 234833-XTA-USA Xtandi (enzalutamide) tablets 80 mg label"],"pediatric_use":["8.4 Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established."],"pharmacodynamics":["12.2 Pharmacodynamics Cardiac Electrophysiology The effect of enzalutamide 160 mg/day at steady-state on the QTc interval was evaluated in 796 patients with metastatic CRPC. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with XTANDI and that in patients treated with placebo, based on the Fridericia correction method. However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design."],"pharmacokinetics":["12.3 Pharmacokinetics The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption. Absorption Following oral administration of XTANDI capsules (160 mg daily) in patients with metastatic CRPC, the median time to reach maximum plasma enzalutamide concentrations (C max ) is 1 hour (range 0.5 to 3 hours). At steady-state, the plasma mean C max values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively. Following a single dose administration of 160 mg enzalutamide in healthy male volunteers, enzalutamide extent of absorption (AUC) was comparable between XTANDI tablet and XTANDI capsule, but the mean C max was 10%-28% lower than that of XTANDI capsules. The steady-state pharmacokinetic profiles (AUC and C max ) of enzalutamide and N-desmethyl enzalutamide are similar for XTANDI tablet and XTANDI capsule. With the daily dosing regimen, enzalutamide steady-state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady-state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg. A single 160 mg oral dose of XTANDI was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1 . Distribution and Protein Binding The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV). Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro , there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations. Metabolism Following single oral administration of 14 C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14 C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14 C-AUC 0-inf . In vitro , human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). In vitro data suggest that carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite. In vitro , N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5. Elimination Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of 14 C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide). The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h). The mean terminal half-life (t 1/2 ) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t 1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days. Pharmacokinetics in Special Populations Renal Impairment : A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic CRPC enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end-stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment : The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 22) and with pre-existing mild (N = 8, Child-Pugh Class A) moderate (N = 8, Child-Pugh Class B), or severe (N = 8, Child-Pugh Class C) hepatic impairment. XTANDI was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1 [see Use in Specific Populations ( 8.7 )] . Body Weight and Age: Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (range: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to enzalutamide. Gender : The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated. Race : The majority of XTANDI-treated patients in the randomized clinical trials were Caucasian (81%). Based on pharmacokinetic data from studies in Japanese and Chinese patients with prostate cancer, there were no clinically relevant differences in exposure among the populations. There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races. Drug Interactions Effect of Other Drugs on XTANDI: In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the AUC 0‑inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C max . The results are summarized in Figure 1 [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.1 )] . In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer). Rifampin decreased the AUC 0‑inf of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on C max . The results are summarized in Figure 1 [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.2 )] . In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the AUC 0‑inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on C max . The results are summarized in Figure 1 . Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI # PK parameters (C max and AUC 0-inf ) are for enzalutamide plus N-desmethyl enzalutamide, except in the food-effect trial, where they are for enzalutamide alone. * See Dosage and Administration ( 2.2 ). Effect of XTANDI on Other Drugs: In an in vivo phenotypic cocktail drug-drug interaction trial in patients with metastatic CRPC, a single oral dose of the CYP probe substrate cocktail (for CYP2C8, CYP2C9, CYP2C19, and CYP3A4) was administered before and concomitantly with XTANDI (following at least 55 days of dosing at 160 mg daily). The results are summarized in Figure 2 . Results showed that in vivo , at steady-state, XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer [see Drug Interactions ( 7.3 )] . XTANDI did not cause clinically meaningful changes in exposure to the CYP2C8 substrate. In an in vivo phenotypic cocktail drug-drug interaction trial in patients with CRPC, a single oral dose of the CYP probe substrate cocktail for CYP1A2 and CYP2D6 was administered before and concomitantly with XTANDI (following at least 49 days of dosing at 160 mg daily). The results are summarized in Figure 2 . Results showed that in vivo , at steady-state, XTANDI did not cause clinically meaningful changes in exposure to the CYP1A2 or CYP2D6 substrates. Figure 2. Effect of XTANDI on Other Drugs *See Drug Interactions ( 7.3 ). In vitro , enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical data showed that XTANDI is an inducer of CYP2C9, CYP2C19, and CYP3A4 and had no clinically meaningful effect on CYP2C8 (see Figure 2 ). In vitro , enzalutamide caused time-dependent inhibition of CYP1A2. In vitro studies showed that enzalutamide induces CYP2B6 and CYP3A4 and does not induce CYP1A2 at therapeutically relevant concentrations. In vitro , enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for human P-glycoprotein. In vitro , enzalutamide and N-desmethyl enzalutamide are inhibitors of human P-glycoprotein, while the major inactive carboxylic acid metabolite is not. In vitro , enzalutamide and N-desmethyl enzalutamide do not appear to be substrates of human breast cancer resistance protein (BCRP); however, enzalutamide and N-desmethyl enzalutamide are inhibitors of human BCRP at clinically relevant concentrations. Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI Figure 2. Effect of XTANDI on Other Drugs"],"pregnancy":["8.1 Pregnancy Risk Summary 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. There are no human data on the use of XTANDI in pregnant females. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose (see Data). Data Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a C max that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration."],"recent_major_changes":["Dosage and Administration – Dosing Information ( 2.1 ) 10/2020"],"set_id":"381cd215-78c9-4208-8595-7ae7a279b236","spl_patient_package_insert":["PATIENT INFORMATION XTANDI ® (ex TAN dee) (enzalutamide) capsules and tablets What is XTANDI ® ? XTANDI is a prescription medicine used to treat men with prostate cancer that: • no longer responds to a hormone therapy or surgical treatment to lower testosterone OR • has spread to other parts of the body and responds to a hormone therapy or surgical treatment to lower testosterone. It is not known if XTANDI is safe and effective in females. It is not known if XTANDI is safe and effective in children. Before taking XTANDI, tell your healthcare provider about all your medical conditions, including if you: • have a history of seizures, brain injury, stroke, or brain tumors. • have a history of heart disease. • have high blood pressure. • have abnormal amounts of fat or cholesterol in your blood (dyslipidemia). • are pregnant or plan to become pregnant. XTANDI can cause harm to your unborn baby and loss of pregnancy (miscarriage). • have a partner who is pregnant or may become pregnant. o Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with XTANDI and for 3 months after the last dose of XTANDI. o Males must use a condom during sex with a pregnant female. • are breastfeeding or plan to breastfeed. It is not known if XTANDI passes into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XTANDI may affect the way other medicines work, and other medicines may affect how XTANDI works. You should not start or stop any medicine before you talk with the healthcare provider that prescribed XTANDI. Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine. How should I take XTANDI? • Take XTANDI exactly as your healthcare provider tells you. • Take your prescribed dose of XTANDI 1 time a day, at the same time each day. • Your healthcare provider may change your dose if needed. • Do not change or stop taking your prescribed dose of XTANDI without talking with your healthcare provider first. • XTANDI can be taken with or without food. • Swallow XTANDI capsules or tablets whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets. • If you are receiving gonadotropin-releasing hormone (GnRH) therapy, you should continue with this treatment during your treatment with XTANDI unless you have had a surgery to lower the amount of testosterone in your body (surgical castration). • If you miss a dose of XTANDI, take your prescribed dose as soon as you remember that day. If you miss your daily dose, take your prescribed dose at your regular time the next day. Do not take more than your prescribed dose of XTANDI each day. If you take too much XTANDI, call your healthcare provider or go to the nearest emergency room right away. You may have an increased risk of seizure if you take too much XTANDI. What are the possible side effects of XTANDI? XTANDI may cause serious side effects including: • Seizure. If you take XTANDI you may be at risk of having a seizure. You should avoid activities where a sudden loss of consciousness could cause serious harm to yourself or others. Tell your healthcare provider right away if you have loss of consciousness or seizure. • Posterior Reversible Encephalopathy Syndrome (PRES). If you take XTANDI you may be at risk of developing a condition involving the brain called PRES. Tell your healthcare provider right away if you have a seizure or quickly worsening symptoms such as headache, decreased alertness, confusion, reduced eyesight, blurred vision or other visual problems. Your healthcare provider will do a test to check for PRES. • Allergic Reactions. Allergic reactions have happened in people who take XTANDI. Stop taking XTANDI and get medical help right away if you develop swelling of the face, tongue, lip or throat. • Heart disease. Blockage of the arteries in the heart (ischemic heart disease) that can lead to death has happened in some people during treatment with XTANDI. Your healthcare provider will monitor you for signs and symptoms of heart problems during your treatment with XTANDI. Call your healthcare provider or go to the nearest emergency room right away if you get chest pain or discomfort at rest or with activity or shortness of breath during your treatment with XTANDI. • Falls and fractures. XTANDI treatment may increase your risk for falls and fractures. Falls were not caused by loss of consciousness (fainting) or seizures. Your healthcare provider will monitor your risks for falls and fractures during treatment with XTANDI. Your healthcare provider will stop treatment with XTANDI if you have serious side effects. The most common side effects of XTANDI include: • weakness or feeling more tired than usual • back pain • hot flashes • constipation • joint pain • decreased appetite • diarrhea • high blood pressure XTANDI may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of XTANDI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store XTANDI? • XTANDI capsules and tablets come in a child-resistant bottle. • Store XTANDI capsules and tablets between 68°F to 77°F (20°C to 25°C). • Keep XTANDI capsules and tablets dry and in a tightly closed container. Keep XTANDI and all medicines out of the reach of children. General information about the safe and effective use of XTANDI. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XTANDI for a condition for which it was not prescribed. Do not give XTANDI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about XTANDI that is written for health professionals. What are the ingredients in XTANDI? XTANDI capsules Active ingredient: enzalutamide Inactive ingredients: caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, black iron oxide XTANDI tablets Active ingredient: enzalutamide Inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. The tablet film-coat contains hypromellose, talc, polyethylene glycol, titanium dioxide, and ferric oxide. Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10017 280168-XTA-USA © 2020 Astellas Pharma US, Inc. XTANDI ® is a registered trademark of Astellas Pharma Inc. For more information go to www.Xtandi.com or call 1-800-727-7003. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: October 2020"],"spl_patient_package_insert_table":["no longer responds to a hormone therapy or surgical treatment to lower testosteroneORhas spread to other parts of the body and responds to a hormone therapy or surgical treatment to lower testosterone.It is not known if XTANDI is safe and effective in females. It is not known if XTANDI is safe and effective in children.have a history of seizures, brain injury, stroke, or brain tumors.have a history of heart disease.have high blood pressure.have abnormal amounts of fat or cholesterol in your blood (dyslipidemia).are pregnant or plan to become pregnant. XTANDI can cause harm to your unborn baby and loss of pregnancy (miscarriage). have a partner who is pregnant or may become pregnant. Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with XTANDI and for 3 months after the last dose of XTANDI. Males must use a condom during sex with a pregnant female.are breastfeeding or plan to breastfeed. It is not known if XTANDI passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XTANDI may affect the way other medicines work, and other medicines may affect how XTANDI works.You should not start or stop any medicine before you talk with the healthcare provider that prescribed XTANDI.Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.Take XTANDI exactly as your healthcare provider tells you.Take your prescribed dose of XTANDI 1 time a day, at the same time each day.Your healthcare provider may change your dose if needed.Do not change or stop taking your prescribed dose of XTANDI without talking with your healthcare provider first.XTANDI can be taken with or without food.Swallow XTANDI capsules or tablets whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets.If you are receiving gonadotropin-releasing hormone (GnRH) therapy, you should continue with this treatment during your treatment with XTANDI unless you have had a surgery to lower the amount of testosterone in your body (surgical castration).If you miss a dose of XTANDI, take your prescribed dose as soon as you remember that day. If you miss your daily dose, take your prescribed dose at your regular time the next day. Do not take more than your prescribed dose of XTANDI each day.If you take too much XTANDI, call your healthcare provider or go to the nearest emergency room right away. You may have an increased risk of seizure if you take too much XTANDI.Seizure. If you take XTANDI you may be at risk of having a seizure. You should avoid activities where a sudden loss of consciousness could cause serious harm to yourself or others. Tell your healthcare provider right away if you have loss of consciousness or seizure.Posterior Reversible Encephalopathy Syndrome (PRES). If you take XTANDI you may be at risk of developing a condition involving the brain called PRES. Tell your healthcare provider right away if you have a seizure or quickly worsening symptoms such as headache, decreased alertness, confusion, reduced eyesight, blurred vision or other visual problems. Your healthcare provider will do a test to check for PRES.Allergic Reactions. Allergic reactions have happened in people who take XTANDI. Stop taking XTANDI and get medical help right away if you develop swelling of the face, tongue, lip or throat.Heart disease. Blockage of the arteries in the heart (ischemic heart disease) that can lead to death has happened in some people during treatment with XTANDI. Your healthcare provider will monitor you for signs and symptoms of heart problems during your treatment with XTANDI. Call your healthcare provider or go to the nearest emergency room right away if you get chest pain or discomfort at rest or with activity or shortness of breath during your treatment with XTANDI.Falls and fractures. XTANDI treatment may increase your risk for falls and fractures. Falls were not caused by loss of consciousness (fainting) or seizures. Your healthcare provider will monitor your risks for falls and fractures during treatment with XTANDI.Your healthcare provider will stop treatment with XTANDI if you have serious side effects.The most common side effects of XTANDI include:weakness or feeling more tired than usualback painhot flashesconstipationjoint paindecreased appetitediarrheahigh blood pressureXTANDI capsules and tablets come in a child-resistant bottle. Store XTANDI capsules and tablets between 68°F to 77°F (20°C to 25°C).Keep XTANDI capsules and tablets dry and in a tightly closed container.Keep XTANDI and all medicines out of the reach of children.
PATIENT INFORMATIONXTANDI® (ex TAN dee)(enzalutamide)capsules and tablets
What is XTANDI®?XTANDI is a prescription medicine used to treat men with prostate cancer that:
• •
Before taking XTANDI, tell your healthcare provider about all your medical conditions, including if you:
••••••oo•
How should I take XTANDI?
••••••••
What are the possible side effects of XTANDI?XTANDI may cause serious side effects including:
•••••
•••••
•••
XTANDI may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility.These are not all the possible side effects of XTANDI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store XTANDI?
•••
General information about the safe and effective use of XTANDI.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XTANDI for a condition for which it was not prescribed. Do not give XTANDI to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about XTANDI that is written for health professionals.
What are the ingredients in XTANDI?XTANDI capsulesActive ingredient: enzalutamideInactive ingredients: caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, black iron oxideXTANDI tabletsActive ingredient: enzalutamideInactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. The tablet film-coat contains hypromellose, talc, polyethylene glycol, titanium dioxide, and ferric oxide. Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10017280168-XTA-USA © 2020 Astellas Pharma US, Inc.XTANDI® is a registered trademark of Astellas Pharma Inc. For more information go to www.Xtandi.com or call 1-800-727-7003.
"],"spl_product_data_elements":["Xtandi enzalutamide ENZALUTAMIDE ENZALUTAMIDE E;40 Xtandi enzalutamide ENZALUTAMIDE ENZALUTAMIDE E;80"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary 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. There are no human data on the use of XTANDI in pregnant females. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose (see Data). Data Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a C max that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration. 8.2 Lactation Risk Summary The safety and efficacy of XTANDI have not been established in females. There is no information available on the presence of XTANDI in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Enzalutamide and/or its metabolites were present in milk of lactating rats (see Data) . Data Following a single oral administration in lactating rats on postnatal day 14, enzalutamide and/or its metabolites were present in milk at a C max that was 4 times higher than concentrations in the plasma and occurred 4 hours after administration. 8.3 Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of XTANDI [see Use in Specific Populations ( 8.1 )] . Infertility Males Based on animal studies, XTANDI may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. 8.5 Geriatric Use Of 4081 patients who received XTANDI in seven randomized, controlled clinical trials, 78% were 65 and over, while 35% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology ( 12.3 )] . 8.7 Patients with Hepatic Impairment Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment [see Clinical Pharmacology ( 12.3 )]."],"version":"2","warnings_and_cautions":["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 )]."]}