ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following is discussed in more detail in other sections of the labeling:oSeizure [see Warnings and Precautions (5.1)]oPosterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.2)]oHypersensitivity [see Warnings and Precautions (5.3)]oIschemic Heart Disease [see Warnings and Precautions (5.4)]oFalls and Fractures [see Warnings and Precautions (5.5)]. oSeizure [see Warnings and Precautions (5.1)]. oPosterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.2)]. oHypersensitivity [see Warnings and Precautions (5.3)]. oIschemic Heart Disease [see Warnings and Precautions (5.4)]. oFalls 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 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 ChemotherapyAFFIRM 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 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 shows adverse reactions reported in AFFIRM that occurred at >= 2% higher frequency in the XTANDI arm compared to the placebo arm.Table 1. Adverse Reactions in AFFIRMXTANDI(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 Edema151.0130.8Musculoskeletal and Connective Tissue Disorders Back Pain265.3244.0 Arthralgia212.5171.8 Musculoskeletal Pain151.3120.3 Muscular Weakness9.81.56.81.8 Musculoskeletal Stiffness2.60.30.30.0Gastrointestinal Disorders Diarrhea221.1180.3Vascular Disorders Hot Flush200.0100.0 Hypertension6.42.12.81.3Nervous 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 Hypoesthesia4.00.31.80.0Infections 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. 8.52.44.81.3Psychiatric Disorders Insomnia8.80.06.00.5 Anxiety6.50.34.00.0Renal and Urinary Disorders Hematuria6.91.84.51.0 Pollakiuria4.80.02.50.0Injury, Poisoning and Procedural Complications Fall4.60.31.30.0 Non-pathologic Fractures 4.01.40.80.3Skin and Subcutaneous Tissue Disorders Pruritus3.80.01.30.0 Dry Skin3.50.01.30.0Respiratory Disorders Epistaxis3.30.11.30.3PREVAIL: XTANDI versus Placebo in Chemotherapy-naive Metastatic CRPCPREVAIL 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 includes adverse reactions reported in PREVAIL that occurred at >= 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in PREVAILXTANDI(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 Edema120.28.20.4Musculoskeletal and Connective Tissue Disorders Back Pain292.5223.0 Arthralgia211.6161.1Gastrointestinal Disorders Constipation230.7170.4 Diarrhea170.3140.4Vascular Disorders Hot Flush180.17.80.0 Hypertension147.24.12.3Nervous 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 Syndrome2.10.10.40.0Respiratory Disorders DyspneaIncludes dyspnea, exertional dyspnea, and dyspnea at rest. 110.68.50.6Infections 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. 7.91.54.71.1Psychiatric Disorders Insomnia8.20.15.70.0Renal and Urinary Disorders Hematuria8.81.35.81.3Injury, Poisoning and Procedural Complications Fall131.65.30.7 Non-Pathological Fracture8.82.13.01.1Metabolism and Nutrition Disorders Decreased Appetite190.3160.7Investigations Weight Decreased120.88.50.2Reproductive System and Breast Disorders Gynecomastia3.40.01.40.0TERRAIN: XTANDI versus Bicalutamide in Chemotherapy-naive Metastatic CRPCTERRAIN 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 shows overall and common adverse reactions (>= 10%) in XTANDI-treated patients.Table 3. Adverse Reactions in TERRAINXTANDI(N 183)Bicalutamide(N 189)Grade 1-4CTCAE 4(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Overall94399438General Disorders Asthenic ConditionsIncluding asthenia and fatigue. 321.6231.1Musculoskeletal and Connective Tissue Disorders Back Pain192.7181.6 Musculoskeletal PainIncluding musculoskeletal pain and pain in extremity. 161.1140.5Vascular Disorders Hot Flush150110 Hypertension147.17.44.2Gastrointestinal Disorders Nausea140180 Constipation131.1130.5 Diarrhea1209.01.1Infections and Infestations Upper Respiratory Tract InfectionIncluding nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 1206.30.5Investigational Weight Loss110.57.90.5PROSPER: XTANDI versus Placebo in Non-metastatic CRPC PatientsPROSPER 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 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 >= 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 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 shows adverse reactions reported in PROSPER that occurred at >= 2% higher frequency in the XTANDI arm than in the placebo arm.Table 4. Adverse Reactions in PROSPERXTANDI(N 930)Placebo(N 465)Grade 1-4CTCAE 4(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Metabolism and Nutrition Disorders Decreased Appetite9.60.23.90.2Nervous 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. 4.60.11.50Vascular Disorders Hot Flush130.17.70 Hypertension124.65.22.2Gastrointestinal Disorders Nausea110.38.60 Constipation9.10.26.90.4General Disorders and Administration Site Conditions Asthenic ConditionsIncludes asthenia and fatigue. 404.0200.9Investigations Weight Decreased5.90.21.50Injury, Poisoning and Procedural Complications Fall111.34.10.6 FracturesIncludes all osseous fractures from all sites. 9.82.04.91.7Psychiatric Disorders Anxiety2.80.20.40ARCHES: XTANDI versus Placebo in Metastatic CSPC PatientsARCHES randomized 1150 patients with mCSPC, of whom 1146 received at least one dose of study drug. All patients received either gonadotropin-releasing hormone (GnRH) analogue concurrently or had bilateral orchiectomy. Patients received either XTANDI at 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 >= 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 >= patients included heart disease (n=2) and sudden death (n=2). Grade 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 shows adverse reactions reported in ARCHES that occurred at >= 2% higher frequency in the XTANDI arm than in the placebo arm.Table 5. Adverse Reactions in ARCHESXTANDI(N 572)Placebo(N 574)Grade 1-4CTCAE 4.03.(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Metabolism and Nutrition Disorders Decreased Appetite4.90.22.60Nervous System Disorders Cognitive and Memory ImpairmentIncludes memory impairment, amnesia, cognitive disorder, dementia, disturbance in attention, transient global amnesia, dementia alzheimers type, mental impairment, senile dementia and vascular dementia.4.50.72.10 Restless Legs Syndrome2.400.30Vascular Disorders Hot Flush270.3220 Hypertension8.03.35.61.7General Disorders and Administration Site Conditions Asthenic conditionsIncludes asthenia and fatigue.241.7201.6Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain6.30.24.00.2Injury, Poisoning and Procedural Complications FracturesIncludes 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.6.51.04.21.0Laboratory Abnormalities Table 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 AbnormalitiesXTANDI(N 3173)Placebo(N 2282)Grade 1-4(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Hematology Neutrophil count decreased200.9170.4 White blood cell decreased170.49.80.2Chemistry Hyperglycemia833.2753.1 Hypermagnesemia160.1130 Hyponatremia131.48.61.5 Hypercalcemia6.80.14.50HypertensionIn 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. Decreased Appetite. Cognitive and Memory ImpairmentIncludes memory impairment, amnesia, cognitive disorder, dementia, disturbance in attention, transient global amnesia, dementia alzheimers type, mental impairment, senile dementia and vascular dementia.. Restless Legs Syndrome. Hot Flush. Hypertension. Asthenic conditionsIncludes asthenia and fatigue.. Musculoskeletal Pain. FracturesIncludes 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.. Neutrophil count decreased. White blood cell decreased. Hyperglycemia. Hypermagnesemia. Hyponatremia. Hypercalcemia. 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 population of uncertain size, it is not always possible to reliably estimate the frequency or establish causal relationship to drug exposure.Gastrointestinal Disorders: vomitingImmune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx)Neurological Disorders: posterior reversible encephalopathy syndrome (PRES), dysgeusiaSkin 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)).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 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 >= mg/kg/day (0.3 times the human exposure based on AUC).

CLINICAL PHARMACOLOGY SECTION.

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. 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 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.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 ElectrophysiologyAt 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 single dose. At steady-state, the mean (%CV) maximum concentration (Cmax) for enzalutamide and N-desmethyl enzalutamide are 16.6 ug/mL (23%) and 12.7 ug/mL (30%), respectively, and the mean (%CV) minimum concentrations (Cmin) are 11.4 ug/mL (26%) and 13.0 ug/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). AbsorptionThe median Tmax is hour (0.5 to hours) following single 160 mg dose of capsules and hours (0.5 to hours) following single 160 mg dose of tablets. Effect of FoodThere was no clinically meaningful effect on enzalutamide or N-desmethyl enzalutamide pharmacokinetics following the administration of XTANDI with 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 single oral dose is 110 (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 single dose is 0.56 L/h (0.33 to 1.02 L/h). The mean terminal half-life (t1/2) for enzalutamide after single oral dose is 5.8 days (2.8 to 10.2 days). The mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.MetabolismEnzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.Specific PopulationsNo 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 StudiesClinical StudiesEffect 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 Cmax. 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 Cmax. 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 Cmax. 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 Cmax by 77%.Coadministration of XTANDI 160 mg orally once daily with warfarin (a sensitive CYP2C9 substrate) decreased S-warfarin AUC by 56% and Cmax by 17%.Coadministration of XTANDI 160 mg orally once daily with omeprazole (a sensitive CYP2C19 substrate) decreased omeprazole AUC by 72% and Cmax by 62%.No clinically meaningful changes in exposure of pioglitazone (a sensitive CYP2C8 substrate), caffeine (a sensitive CYP1A2 substrate), or dextromethorphan (a sensitive CYP2D6 substrate) were observed following coadministration with XTANDI. In Vitro StudiesCytochrome 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. Enzalutamide and N-desmethyl enzalutamide are inhibitors of P-glycoprotein and BCRP. The major inactive carboxylic acid metabolite does not inhibit P-glycoprotein.

CLINICAL STUDIES SECTION.

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, total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either XTANDI orally at 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, skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with 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 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 and Figure 3).Table 7. Overall Survival of Patients Treated with Either XTANDI or Placebo in AFFIRMNR 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 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). < 0.0001 Hazard Ratio (95% CI)Hazard Ratio is derived from 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-naive Metastatic CRPCIn PREVAIL, 1717 chemotherapy-naive patients were randomized 1:1 to receive either XTANDI orally at dose of 160 mg once daily (N 872) or placebo orally once daily (N 845). Patients with visceral metastases, patients with history of mild to moderate heart failure (NYHA class or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with previous history of seizure or 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, skeletal-related event, or clinical progression) and the initiation of 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 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST 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 for 68% of patients, and 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 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 PREVAILNR Not reached.XTANDI (N 872)Placebo (N 845)Pre-specified Interim AnalysisThe 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-valueP-value is derived from an unstratified log-rank test. < 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 cut-off date is 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 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 PREVAILNR 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-valueP-value is derived from an unstratified log-rank test. < 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 median of 28.0 months for patients on the XTANDI arm versus median of 10.8 months for patients on the placebo arm [HR 0.35 (95% CI: 0.30, 0.40), < 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), < 0.0001]. 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-naive Metastatic CRPCTERRAIN was conducted in 375 chemotherapy-naive patients who were randomized 1:1 to receive either XTANDI orally at dose of 160 mg once daily (N 184) or bicalutamide orally at dose of 50 mg once daily (N 191). Patients with previous history of seizure or 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, 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 criteria and/or Response Evaluation Criteria in Solid Tumors (RECIST 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 for 74% of patients and 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 (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 TERRAINXTANDI (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 CRPCPROSPER enrolled 1401 patients with non-metastatic CRPC who were randomized 2:1 to receive either XTANDI orally at dose of 160 mg once daily (N 933) or placebo orally once daily (N 468). All patients in the PROSPER trial received gonadotropin-releasing hormone (GnRH) analog or had 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 PSA doubling time <= 10 months, PSA >= 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. majority of patients had Gleason score of 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 or 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. 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 (< months or >= months) and use of prior bone-targeting agent (yes or no). The efficacy results from PROSPER are summarized in Table 11, Figure 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 Cox regression model (with treatment as the only covariate) and p-value from log-rank test are stratified by PSA doubling time and prior or concurrent use of bone targeting agent. 0.29 (0.24, 0.35) P-value < 0.0001Overall 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-value = 0.0011Figure 7. Kaplan-Meier Curves of Metastasis-free Survival in PROSPER Figure 8. Kaplan-Meier Curves of Overall Survival in PROSPERThe primary efficacy outcome was also supported by 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], < 0.0001).ARCHES (NCT02677896): XTANDI versus Placebo in Metastatic CSPCARCHES enrolled 1150 patients with mCSPC who were randomized 1:1 to receive XTANDI orally at dose of 160 mg once daily (N=574) or placebo orally once daily (N=576). All patients in the trial received GnRH analog or had 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 prior cycles). High volume of disease is defined as metastases involving the viscera or, in the absence of visceral lesions, there must be or more bone lesions, at least of which must be in 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 Gleason score of >= 8. Thirty-seven percent (37%) of patients had low volume of disease and 63% of patients had high volume of disease. Eighty-two percent (82%) of patients had no prior docetaxel treatment; 2% of patients had to cycles of docetaxel and 16% of patients had 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 for 78% of patients and 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 or more new bone lesions on bone scan with confirmation (Prostate Cancer Working Group criteria) and/or progression in soft tissue disease. Time to new antineoplastic therapy was an additional efficacy endpoint.XTANDI demonstrated 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 reachedXTANDI(N 574)Placebo (N 576)Radiographic Progression-free Survival Number of events (%)89 (15.5)198 (34.4) Radiographic disease progression77 (13.4)185 (32.1) Death within 24 weeks after treatment discontinuation12 (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 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 stratified log-rank test by volume of disease (low vs high) and prior docetaxel use (yes or no). < 0.0001Figure 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 new antineoplastic therapy (HR 0.28 [95% CI: 0.20, 0.40]; < 0.0001).. Radiographic disease progression. Death within 24 weeks after treatment discontinuation. 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).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

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 C21H16F4N4O2S. The structural formula is:Enzalutamide is 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 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 & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. XTANDI 160 mg administered orally once daily. (2.1)Patients receiving XTANDI should also receive 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 patient experiences >= Grade or an intolerable adverse reaction, withhold XTANDI for one week or until symptoms improve to <= Grade 2, then resume at the same or 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 InhibitorsAvoid the coadministration of strong CYP2C8 inhibitors. If the coadministration of 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 InducersAvoid the coadministration of strong CYP3A4 inducers. If the coadministration of 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 gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

DOSAGE FORMS & STRENGTHS SECTION.

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 40.XTANDI 80 mg tablets are yellow, oval, film-coated and debossed with 80. Capsules: 40 mg (3)Tablets: 40 mg, 80 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oStrong CYP2C8 Inhibitors: Avoid strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI. (2.3, 7.1) oStrong CYP3A4 Inducers: Avoid strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI. (2.3, 7.1)oAvoid coadministration with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which 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). oStrong CYP2C8 Inhibitors: Avoid strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI. (2.3, 7.1) oStrong CYP3A4 Inducers: Avoid strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI. (2.3, 7.1). oAvoid coadministration with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which 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 InhibitorsThe 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 strong CYP2C8 inhibitor cannot be avoided, reduce the dosage of XTANDI [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. Strong CYP3A4 InducersThe coadministration of XTANDI with rifampin (a strong CYP3A4 inducer and 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 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 SubstratesXTANDI is strong CYP3A4 inducer and 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 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential ContraceptionMalesBased on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose of XTANDI [see Use in Specific Populations (8.1)].InfertilityMalesBased on animal studies, XTANDI may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

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 SECTION.

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:oBottles 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 40, and are available in the following package size: oBottles 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 80, and are available in the following package size: oBottles of 60 tablets with child resistant closures (NDC 0469-0725-60)Recommended storage: Store XTANDI capsules and tablets at 20C to 25C (68F to 77F) in dry place and keep the container tightly closed. Excursions permitted from 15C to 30C (59F to 86F).Swallow capsules or tablets whole. Do not chew, dissolve or open the capsules. Do not cut, crush, or chew the tablets.. oBottles of 120 capsules with child resistant closures (NDC 0469-0125-99) oBottles of 120 tablets with child resistant closures (NDC 0469-0625-99). oBottles of 60 tablets with child resistant closures (NDC 0469-0725-60).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. XTANDI(R) is indicated for the treatment of patients with:ocastration-resistant prostate cancer (CRPC)ometastatic castration-sensitive prostate cancer (mCSPC). ocastration-resistant prostate cancer (CRPC). ometastatic castration-sensitive prostate cancer (mCSPC). XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with:ocastration-resistant prostate cancer. (1)ometastatic castration-sensitive prostate cancer. (1). ocastration-resistant prostate cancer. (1). ometastatic castration-sensitive prostate cancer. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).SeizureoInform 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)oInform 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)].HypersensitivityoInform 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 DiseaseoInform 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 cardiovascular event occur [see Warnings and Precautions (5.4)].Falls and FracturesoInform 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)].HypertensionoInform patients that XTANDI is associated with an increased incidence of hypertension [see Adverse Reactions (6.1)].Dosing and AdministrationoInform 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.oInstruct 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.oInform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their healthcare provider.oInform patients that if they miss 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 oInform patients that XTANDI can be harmful to developing fetus and can cause loss of pregnancy. oAdvise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose of XTANDI. Advise male patients to use condom if having sex with pregnant woman [see Warnings and Precautions (5.6)].InfertilityoInform 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 60062Marketed by:Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10017316386-XTA-USA Rx Only(C) 2020-21 Astellas Pharma US, Inc.XTANDI is registered trademark of Astellas Pharma Inc. oInform 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)].. oInform 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)].. oInform 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.. oInform 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 cardiovascular event occur [see Warnings and Precautions (5.4)].. oInform 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)].. oInform patients that XTANDI is associated with an increased incidence of hypertension [see Adverse Reactions (6.1)].. oInform 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.. oInstruct 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.. oInform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their healthcare provider.. oInform patients that if they miss 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)].. oInform patients that XTANDI can be harmful to developing fetus and can cause loss of pregnancy. oAdvise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose of XTANDI. Advise male patients to use condom if having sex with pregnant woman [see Warnings and Precautions (5.6)].. oInform male patients that XTANDI may impair fertility [see Use in Specific Populations (8.3)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThe 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).DataFollowing single oral administration in lactating rats on postnatal day 14, enzalutamide and/or its metabolites were present in milk at Cmax that was times higher than concentrations in the plasma and occurred hours after administration.

MECHANISM OF ACTION SECTION.

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. 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 mouse prostate cancer xenograft model.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 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 >= mg/kg/day (0.3 times the human exposure based on AUC).

OVERDOSAGE SECTION.

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 dose escalation study, no seizures were reported at 240 mg daily, whereas seizures were reported, each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdosage.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL. NDC 0469-0125-99Rx OnlyXtandi(R) (enzalutamide)capsules40 mgSwallow capsules whole.Do not chew, dissolve, or open the capsules.120 CapsulesManufactured by Catalent Pharma Solutions, LLC for Astellas Pharma US, Inc., Northbrook, IL 60062111607-02 263374-XTA-USA. Xtandi (enzalutamide) capsules 40 mg label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

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.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 ElectrophysiologyAt the recommended dosage, XTANDI does not cause large mean increases (i.e., 20 msec) in the QT interval.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Enzalutamide achieves steady-state by Day 28 and its AUC accumulates approximately 8.3-fold relative to single dose. At steady-state, the mean (%CV) maximum concentration (Cmax) for enzalutamide and N-desmethyl enzalutamide are 16.6 ug/mL (23%) and 12.7 ug/mL (30%), respectively, and the mean (%CV) minimum concentrations (Cmin) are 11.4 ug/mL (26%) and 13.0 ug/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). AbsorptionThe median Tmax is hour (0.5 to hours) following single 160 mg dose of capsules and hours (0.5 to hours) following single 160 mg dose of tablets. Effect of FoodThere was no clinically meaningful effect on enzalutamide or N-desmethyl enzalutamide pharmacokinetics following the administration of XTANDI with 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 single oral dose is 110 (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 single dose is 0.56 L/h (0.33 to 1.02 L/h). The mean terminal half-life (t1/2) for enzalutamide after single oral dose is 5.8 days (2.8 to 10.2 days). The mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.MetabolismEnzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.Specific PopulationsNo 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 StudiesClinical StudiesEffect 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 Cmax. 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 Cmax. 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 Cmax. 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 Cmax by 77%.Coadministration of XTANDI 160 mg orally once daily with warfarin (a sensitive CYP2C9 substrate) decreased S-warfarin AUC by 56% and Cmax by 17%.Coadministration of XTANDI 160 mg orally once daily with omeprazole (a sensitive CYP2C19 substrate) decreased omeprazole AUC by 72% and Cmax by 62%.No clinically meaningful changes in exposure of pioglitazone (a sensitive CYP2C8 substrate), caffeine (a sensitive CYP1A2 substrate), or dextromethorphan (a sensitive CYP2D6 substrate) were observed following coadministration with XTANDI. In Vitro StudiesCytochrome 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. Enzalutamide and N-desmethyl enzalutamide are inhibitors of P-glycoprotein and BCRP. The major inactive carboxylic acid metabolite does not inhibit P-glycoprotein.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe 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). DataAnimal DataIn 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 pharmacokinetic study in pregnant rats with single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred hours after administration.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONXTANDI(R) (ex TAN dee)(enzalutamide)capsules and tabletsWhat is XTANDI(R)XTANDI is prescription medicine used to treat men with prostate cancer that:ono longer responds to hormone therapy or surgical treatment to lower testosterone ORohas spread to other parts of the body and responds to 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:ohave history of seizures, brain injury, stroke, or brain tumors.ohave history of heart disease.ohave high blood pressure.ohave abnormal amounts of fat or cholesterol in your blood (dyslipidemia).oare pregnant or plan to become pregnant. XTANDI can cause harm to your unborn baby and loss of pregnancy (miscarriage). ohave partner who is pregnant or may become pregnant. oMales who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with XTANDI and for months after the last dose of XTANDI. oMales must use condom during sex with pregnant female.oare 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 list of them with you to show your healthcare provider and pharmacist when you get new medicine.How should take XTANDIoTake XTANDI exactly as your healthcare provider tells you.oTake your prescribed dose of XTANDI time day, at the same time each day.oYour healthcare provider may change your dose if needed.oDo not change or stop taking your prescribed dose of XTANDI without talking with your healthcare provider first.oXTANDI can be taken with or without food.oSwallow XTANDI capsules or tablets whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets.oIf you are receiving gonadotropin-releasing hormone (GnRH) therapy, you should continue with this treatment during your treatment with XTANDI unless you have had surgery to lower the amount of testosterone in your body (surgical castration).oIf you miss 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 XTANDIXTANDI may cause serious side effects including:oSeizure. If you take XTANDI you may be at risk of having seizure. You should avoid activities where 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.oPosterior Reversible Encephalopathy Syndrome (PRES). If you take XTANDI you may be at risk of developing condition involving the brain called PRES. Tell your healthcare provider right away if you have seizure or quickly worsening symptoms such as headache, decreased alertness, confusion, reduced eyesight, blurred vision or other visual problems. Your healthcare provider will do test to check for PRES.oAllergic 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.oHeart 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.oFalls 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:oweakness or feeling more tired than usualoback painohot flashesoconstipationojoint painodecreased appetiteodiarrheaohigh blood pressureXTANDI 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 store XTANDIoXTANDI capsules and tablets come in child-resistant bottle. oStore XTANDI capsules and tablets between 68F to 77F (20C to 25C).oKeep XTANDI capsules and tablets dry and in 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 Patient Information leaflet. Do not use XTANDI for 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 XTANDIXTANDI capsulesActive ingredient: enzalutamideInactive ingredients: caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, black iron oxide.XTANDI 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 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10017 316386-XTA-USA (C) 2020-21 Astellas Pharma US, Inc. XTANDI is 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: January 2022. ono longer responds to hormone therapy or surgical treatment to lower testosterone ohas spread to other parts of the body and responds to hormone therapy or surgical treatment to lower testosterone.. ohave history of seizures, brain injury, stroke, or brain tumors.. ohave history of heart disease.. ohave high blood pressure.. ohave abnormal amounts of fat or cholesterol in your blood (dyslipidemia).. oare pregnant or plan to become pregnant. XTANDI can cause harm to your unborn baby and loss of pregnancy (miscarriage). ohave partner who is pregnant or may become pregnant. oMales who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with XTANDI and for months after the last dose of XTANDI. oMales must use condom during sex with pregnant female.. oMales who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with XTANDI and for months after the last dose of XTANDI. oMales must use condom during sex with pregnant female.. oare breastfeeding or plan to breastfeed. It is not known if XTANDI passes into your breast milk.. oTake XTANDI exactly as your healthcare provider tells you.. oTake your prescribed dose of XTANDI time day, at the same time each day.. oYour healthcare provider may change your dose if needed.. oDo not change or stop taking your prescribed dose of XTANDI without talking with your healthcare provider first.. oXTANDI can be taken with or without food.. oSwallow XTANDI capsules or tablets whole. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets.. oIf you are receiving gonadotropin-releasing hormone (GnRH) therapy, you should continue with this treatment during your treatment with XTANDI unless you have had surgery to lower the amount of testosterone in your body (surgical castration).. oIf you miss 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.. oSeizure. If you take XTANDI you may be at risk of having seizure. You should avoid activities where 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.. oPosterior Reversible Encephalopathy Syndrome (PRES). If you take XTANDI you may be at risk of developing condition involving the brain called PRES. Tell your healthcare provider right away if you have seizure or quickly worsening symptoms such as headache, decreased alertness, confusion, reduced eyesight, blurred vision or other visual problems. Your healthcare provider will do test to check for PRES.. oAllergic 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.. oHeart 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.. oFalls 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.. oweakness or feeling more tired than usual. oback pain. ohot flashes. oconstipation. ojoint pain. odecreased appetite. odiarrhea. ohigh blood pressure. oXTANDI capsules and tablets come in child-resistant bottle. oStore XTANDI capsules and tablets between 68F to 77F (20C to 25C).. oKeep XTANDI capsules and tablets dry and in tightly closed container.

SPL UNCLASSIFIED SECTION.

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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe 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). DataAnimal DataIn 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 pharmacokinetic study in pregnant rats with single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred hours after administration.. 8.2 Lactation. Risk SummaryThe 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).DataFollowing single oral administration in lactating rats on postnatal day 14, enzalutamide and/or its metabolites were present in milk at Cmax that was times higher than concentrations in the plasma and occurred hours after administration.. 8.3 Females and Males of Reproductive Potential ContraceptionMalesBased on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after the last dose of XTANDI [see Use in Specific Populations (8.1)].InfertilityMalesBased 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSeizure 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 seizure during treatment. (5.1) oPosterior reversible encephalopathy syndrome (PRES): Discontinue XTANDI. (5.2)oHypersensitivity: Discontinue XTANDI. (5.3)oIschemic Heart Disease: Optimize management of cardiovascular risk factors. Discontinue XTANDI for Grade 3-4 events. (5.4)oFalls 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)oEmbryo-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). oSeizure 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 seizure during treatment. (5.1) oPosterior reversible encephalopathy syndrome (PRES): Discontinue XTANDI. (5.2). oHypersensitivity: Discontinue XTANDI. (5.3). oIschemic Heart Disease: Optimize management of cardiovascular risk factors. Discontinue XTANDI for Grade 3-4 events. (5.4). oFalls 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). oEmbryo-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 single-arm trial designed to assess the risk of seizure in patients with pre-disposing factors for seizure, of 366 (2.2%) XTANDI-treated patients experienced seizure. Three of the patients experienced 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 Alzheimers disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, past history of seizure, presence of 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 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 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 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. 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: 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 pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for months after the last dose of XTANDI [see Use in Specific Populations (8.1, 8.3)].