Xtandi

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

4 CONTRAINDICATIONS None. None. ( 4 )

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

2 DOSAGE AND ADMINISTRATION XTANDI 160 mg administered orally once daily. ( 2.1 ) Patients receiving XTANDI should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.4 ) 2.1 Recommended Dosage The recommended dosage of XTANDI is 160 mg administered orally once daily 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. 2.2 Dosage Modifications for Adverse Reactions If a patient experiences a ≥ Grade 3 or an intolerable adverse reaction, withhold XTANDI 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 )] . 2.3 Dosage Modifications for Drug Interactions Strong CYP2C8 Inhibitors Avoid the coadministration of strong CYP2C8 inhibitors. If the coadministration of a strong CYP2C8 inhibitor cannot be avoided, reduce the XTANDI dosage to 80 mg once daily. If the coadministration of the strong inhibitor is discontinued, increase the XTANDI dosage to the dosage used prior to initiation of the strong CYP2C8 inhibitor [see Clinical Pharmacology ( 12.3 )]. Strong CYP3A4 Inducers Avoid the coadministration of strong CYP3A4 inducers. If the coadministration of a strong CYP3A4 inducer cannot be avoided, increase the XTANDI dosage from 160 mg to 240 mg orally once daily. If the coadministration of the strong CYP3A4 inducer is discontinued, decrease the XTANDI dosage to the dosage used prior to initiation of the strong CYP3A4 inducer [see Clinical Pharmacology ( 12.3 )]. 2.4 Important Administration Instructions Patients receiving XTANDI should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

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 )

10 OVERDOSAGE In the event of an overdosage, 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 overdosage.

7 DRUG INTERACTIONS • Strong CYP2C8 Inhibitors: Avoid strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI. ( 2.3 , 7.1 ) • Strong CYP3A4 Inducers: Avoid strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI. ( 2.3 , 7.1 ) • Avoid coadministration with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. In cases where active metabolites are formed, there may be increased exposure to the active metabolites. ( 7.2 ) 7.1 Effect of Other Drugs on XTANDI Strong CYP2C8 Inhibitors The coadministration of XTANDI with gemfibrozil (a strong CYP2C8 inhibitor) increases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may increase the incidence and severity of adverse reactions of XTANDI. Avoid the coadministration of XTANDI with strong CYP2C8 inhibitors. If the coadministration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dosage of XTANDI [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )]. Strong CYP3A4 Inducers The coadministration of XTANDI with rifampin (a strong CYP3A4 inducer and a moderate CYP2C8 inducer) decreases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may decrease the efficacy of XTANDI. Avoid the coadministration of XTANDI with strong CYP3A4 inducers. If the coadministration of XTANDI with a strong CYP3A4 inducer cannot be avoided, increase the dosage of XTANDI [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )]. 7.2 Effect of XTANDI on Other Drugs Certain CYP3A4, CYP2C9, or CYP2C19 Substrates XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. The coadministration of XTANDI decreases the concentrations of certain CYP3A4, CYP2C9, or CYP2C19 substrates [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of these substrates. Avoid the coadministration of XTANDI with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. If the coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

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 Once daily dosing of 160 mg enzalutamide in addition to ADT reduced PSA levels to undetectable levels (< 0.2 ng/mL) in 68% of patients with mCSPC (ARCHES). Based on the efficacy results of AFFIRM after once daily dosing of 160 mg enzalutamide, no exposure‑response relationship for the efficacy endpoint of overall survival could be identified. In addition, there was no clinically meaningful exposure-response relationship for adverse effects (e.g. fatigue, flushing, headache, or hypertension) within the limited exposure range for 160 mg/day. Cardiac Electrophysiology At the recommended dosage, XTANDI does not cause large mean increases (i.e., > 20 msec) in the QT interval. 12.3 Pharmacokinetics Enzalutamide achieves steady-state by Day 28 and its AUC accumulates approximately 8.3-fold relative to a single dose. At steady-state, the mean (%CV) maximum concentration (C max ) for enzalutamide and N-desmethyl enzalutamide are 16.6 µg/mL (23%) and 12.7 µg/mL (30%), respectively, and the mean (%CV) minimum concentrations (C min ) are 11.4 µg/mL (26%) and 13.0 µg/mL (30%), respectively. Enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 (0.2 times the approved recommended dosage) to 360 mg (2.25 times the approved recommended dosage). Absorption The median T max is 1 hour (0.5 to 3 hours) following a single 160 mg dose of capsules and 2 hours (0.5 to 6 hours) following a single 160 mg dose of tablets. Effect of Food There was no clinically meaningful effect on enzalutamide or N-desmethyl enzalutamide pharmacokinetics following the administration of XTANDI with a high‑fat meal (approximately 150 calories from protein, 250 calories from carbohydrates, and 500 to 600 calories from fat). Distribution The mean (%CV) volume of distribution after a single oral dose is 110 L (29%). Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. Elimination Enzalutamide is primarily eliminated by hepatic metabolism. The mean apparent clearance (CL/F) of enzalutamide after a single dose is 0.56 L/h (0.33 to 1.02 L/h). The mean terminal half-life (t 1/2 ) for enzalutamide after a single oral dose is 5.8 days (2.8 to 10.2 days). The mean terminal t 1/2 for N‑desmethyl enzalutamide is approximately 7.8 to 8.6 days. Metabolism Enzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite. Specific Populations No clinically meaningful differences in the pharmacokinetics of enzalutamide were observed based on age (41 to 92 years), race (White, Chinese, and Japanese), body weight (46 kg to 163 kg), mild to moderate renal impairment (CLcr ≥ 30 mL/min) and hepatic impairment (Child-Pugh A, B, and C). Severe renal impairment and end stage renal disease (CLcr < 30 mL/min) have not been studied. Drug Interaction Studies Clinical Studies Effect of CYP2C8 Inhibitors on XTANDI : The coadministration of XTANDI 160 mg with gemfibrozil (strong CYP2C8 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C max . Effect of CYP3A4 and CYP2C8 Inducers on XTANDI : The coadministration of XTANDI 160 mg after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer) decreased the AUC of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on C max . Effect of CYP3A4 Inhibitors on XTANDI : The coadministration of XTANDI 160 mg after multiple oral doses of itraconazole (strong CYP3A4 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on C max . Effect of XTANDI on Other Drugs: The coadministration of XTANDI 160 mg orally once daily with midazolam (a sensitive CYP3A4 substrate) decreased midazolam AUC by 86% and C max by 77%. Coadministration of XTANDI 160 mg orally once daily with warfarin (a sensitive CYP2C9 substrate) decreased S‑warfarin AUC by 56% and C max by 17%. Coadministration of XTANDI 160 mg orally once daily with omeprazole (a sensitive CYP2C19 substrate) decreased omeprazole AUC by 72% and C max by 62%. Coadministration of XTANDI 160 mg orally once daily with digoxin (a P-glycoprotein substrate) increased digoxin AUC by 33% and C max by 17%. No clinically meaningful changes in exposure of pioglitazone (a sensitive CYP2C8 substrate), caffeine (a sensitive CYP1A2 substrate), dextromethorphan (a sensitive CYP2D6 substrate), or rosuvastatin (a BCRP substrate) were observed following coadministration with XTANDI. In Vitro Studies Cytochrome P450 (CYP) Enzymes : Enzalutamide induces CYP2B6 at clinically achievable concentrations. Transporter Systems : Enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for P-glycoprotein or BCRP.

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 Once daily dosing of 160 mg enzalutamide in addition to ADT reduced PSA levels to undetectable levels (< 0.2 ng/mL) in 68% of patients with mCSPC (ARCHES). Based on the efficacy results of AFFIRM after once daily dosing of 160 mg enzalutamide, no exposure‑response relationship for the efficacy endpoint of overall survival could be identified. In addition, there was no clinically meaningful exposure-response relationship for adverse effects (e.g. fatigue, flushing, headache, or hypertension) within the limited exposure range for 160 mg/day. Cardiac Electrophysiology At the recommended dosage, XTANDI does not cause large mean increases (i.e., > 20 msec) in the QT interval.

12.3 Pharmacokinetics Enzalutamide achieves steady-state by Day 28 and its AUC accumulates approximately 8.3-fold relative to a single dose. At steady-state, the mean (%CV) maximum concentration (C max ) for enzalutamide and N-desmethyl enzalutamide are 16.6 µg/mL (23%) and 12.7 µg/mL (30%), respectively, and the mean (%CV) minimum concentrations (C min ) are 11.4 µg/mL (26%) and 13.0 µg/mL (30%), respectively. Enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 (0.2 times the approved recommended dosage) to 360 mg (2.25 times the approved recommended dosage). Absorption The median T max is 1 hour (0.5 to 3 hours) following a single 160 mg dose of capsules and 2 hours (0.5 to 6 hours) following a single 160 mg dose of tablets. Effect of Food There was no clinically meaningful effect on enzalutamide or N-desmethyl enzalutamide pharmacokinetics following the administration of XTANDI with a high‑fat meal (approximately 150 calories from protein, 250 calories from carbohydrates, and 500 to 600 calories from fat). Distribution The mean (%CV) volume of distribution after a single oral dose is 110 L (29%). Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. Elimination Enzalutamide is primarily eliminated by hepatic metabolism. The mean apparent clearance (CL/F) of enzalutamide after a single dose is 0.56 L/h (0.33 to 1.02 L/h). The mean terminal half-life (t 1/2 ) for enzalutamide after a single oral dose is 5.8 days (2.8 to 10.2 days). The mean terminal t 1/2 for N‑desmethyl enzalutamide is approximately 7.8 to 8.6 days. Metabolism Enzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite. Specific Populations No clinically meaningful differences in the pharmacokinetics of enzalutamide were observed based on age (41 to 92 years), race (White, Chinese, and Japanese), body weight (46 kg to 163 kg), mild to moderate renal impairment (CLcr ≥ 30 mL/min) and hepatic impairment (Child-Pugh A, B, and C). Severe renal impairment and end stage renal disease (CLcr < 30 mL/min) have not been studied. Drug Interaction Studies Clinical Studies Effect of CYP2C8 Inhibitors on XTANDI : The coadministration of XTANDI 160 mg with gemfibrozil (strong CYP2C8 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C max . Effect of CYP3A4 and CYP2C8 Inducers on XTANDI : The coadministration of XTANDI 160 mg after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer) decreased the AUC of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on C max . Effect of CYP3A4 Inhibitors on XTANDI : The coadministration of XTANDI 160 mg after multiple oral doses of itraconazole (strong CYP3A4 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on C max . Effect of XTANDI on Other Drugs: The coadministration of XTANDI 160 mg orally once daily with midazolam (a sensitive CYP3A4 substrate) decreased midazolam AUC by 86% and C max by 77%. Coadministration of XTANDI 160 mg orally once daily with warfarin (a sensitive CYP2C9 substrate) decreased S‑warfarin AUC by 56% and C max by 17%. Coadministration of XTANDI 160 mg orally once daily with omeprazole (a sensitive CYP2C19 substrate) decreased omeprazole AUC by 72% and C max by 62%. Coadministration of XTANDI 160 mg orally once daily with digoxin (a P-glycoprotein substrate) increased digoxin AUC by 33% and C max by 17%. No clinically meaningful changes in exposure of pioglitazone (a sensitive CYP2C8 substrate), caffeine (a sensitive CYP1A2 substrate), dextromethorphan (a sensitive CYP2D6 substrate), or rosuvastatin (a BCRP substrate) were observed following coadministration with XTANDI. In Vitro Studies Cytochrome P450 (CYP) Enzymes : Enzalutamide induces CYP2B6 at clinically achievable concentrations. Transporter Systems : Enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for P-glycoprotein or BCRP.

20220915

18

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. • Capsules: 40 mg ( 3 ) • Tablets: 40 mg, 80 mg ( 3 )

Xtandi enzalutamide ENZALUTAMIDE ENZALUTAMIDE white to off-white ENZ Xtandi enzalutamide ENZALUTAMIDE ENZALUTAMIDE E;40 Xtandi enzalutamide ENZALUTAMIDE ENZALUTAMIDE E;80 Xtandi enzalutamide ENZALUTAMIDE ENZALUTAMIDE white to off-white ENZ Xtandi enzalutamide ENZALUTAMIDE ENZALUTAMIDE E;40

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).

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).

NDA213674

Xtandi

enzalutamide

0469-1725

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0469-0125-99 Rx Only Xtandi ® (enzalutamide) capsules 40 mg Swallow capsules whole. Do not chew, dissolve, or open the capsules. 120 Capsules Manufactured by Catalent Pharma Solutions, LLC for Astellas Pharma US, Inc., Northbrook, IL 60062 111607-02 263374-XTA-USA Xtandi (enzalutamide) capsules 40 mg label

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 337921-XTA-USA Rx Only © 2012-2022 Astellas Pharma US, Inc. XTANDI is a registered trademark of Astellas Pharma Inc.

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% White, 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 1 ). 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 1. 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% White, 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 2 ). 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 cut-off 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 cut-off 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 2. 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 3 ). Table 9. Radiographic Progression-free Survival of Patients Treated with Either XTANDI or Placebo in PREVAIL NR = Not reached. Note: As of the cut-off 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 3. 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% White, 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 4 ). 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 4. 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% White, 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 5 and Figure 6 . 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 5. Kaplan-Meier Curves of Metastasis-free Survival in PROSPER Figure 6. 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% White, 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 and OS were additional efficacy endpoints. XTANDI demonstrated a statistically significant improvement in rPFS and OS 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. Efficacy results for rPFS and OS from ARCHES are summarized in Table 12 , Figure 7 and Figure 8 . Table 12. Efficacy Results in ARCHES (Intent-to-Treat Analysis) NR = Not reached. XTANDI (N = 574) Placebo (N = 576) Radiographic Progression-free Survival Based on BICR. 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 Overall Survival Number of events (%) 154 (26.8) 202 (35.1) Median, months (95% CI) NR (NR, NR) NR (49.7, NR) Hazard ratio (95% CI) 0.66 (0.53, 0.81) P-value p < 0.0001 Figure 7. Kaplan-Meier Curves of rPFS in ARCHES (Intent-to-Treat Analysis) Figure 8. Kaplan-Meier Curves of Overall Survival in ARCHES 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 1. Kaplan-Meier Curves of Overall Survival in AFFIRM Figure 2. Kaplan-Meier Curves of Overall Survival in PREVAIL Figure 3. Kaplan-Meier Curves of Radiographic Progression-free Survival in PREVAIL Figure 4. Kaplan-Meier Curves of Radiographic Progression-free Survival in TERRAIN Figure 5. Kaplan-Meier Curves of Metastasis-free Survival in PROSPER Figure 6. Kaplan-Meier Curves of Overall Survival in PROSPER Figure 7. Kaplan-Meier Curves of rPFS in ARCHES (Intent-to-Treat Analysis) Figure 8. Kaplan-Meier Curves of Overall Survival in ARCHES

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.

8.4 Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

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 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 Renal Impairment No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] ≥ 30 mL/min). XTANDI has not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment No dosage modification is recommended for patients with mild, moderate, or severe hepatic impairment [see Clinical Pharmacology ( 12.3 )].

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.