انزالوتامید

5 هشدارها و اقدامات احتیاطی

• تشنج در 0.6% بیماران دریافت کننده XTANDI رخ داد. در بیماران با عوامل مستعد کننده، تشنج در 2.2 درصد از بیماران گزارش شده است. در بیمارانی که در طول درمان دچار تشنج می شوند، XTANDI را برای همیشه قطع کنید. (5.1)
• سندرم انسفالوپاتی برگشت پذیر خلفی (PRES): XTANDI را قطع کنید. (5.2)
• حساسیت مفرط: XTANDI را قطع کنید. (5.3)
• بیماری ایسکمیک قلبی: مدیریت بهینه عوامل خطر قلبی عروقی. برای عوارض جانبی درجه 3-4، XTANDI را قطع کنید (5.4)
• افتادن و شکستگی: بیماران را از نظر خطر شکستگی و افتادن ارزیابی کنید و بیماران را با عوامل هدفمند استخوان بر اساس دستورالعمل های تعیین شده درمان کنید. (5.5)
• مسمومیت جنینی- جنینی: XTANDI می تواند باعث آسیب جنین و از بین رفتن بارداری شود. به مردان دارای شریک زن با پتانسیل باروری توصیه کنید که از روش های پیشگیری موثر از بارداری استفاده کنند. (5.6، 8.1، 8.3)
• دیسفاژی شدید یا خفگی مرتبط با اندازه محصول: در بیمارانی که در بلعیدن مشکل دارند، از قرص(های) کوچکتر XTANDI استفاده کنید. برای بیمارانی که نمی توانند کپسول یا قرص را قورت دهند، XTANDI را قطع کنید. (2.1، 5.7)
• تداخل با ایمونواسی اندازه گیری دیگوکسین: XTANDI می تواند با برخی از ایمونواسی های دیگوکسین تداخل داشته باشد که منجر به افزایش کاذب غلظت پلاسمایی دیگوکسین می شود. ( 5.8 , 7.3 )

5.1 تشنج تشنج در 0.6 درصد از بیماران دریافت کننده XTANDI در هشت کارآزمایی بالینی تصادفی شده رخ داد. در این کارآزمایی ها، بیمارانی که عوامل مستعد کننده تشنج داشتند، به طور کلی حذف شدند. تشنج از 13 تا 2250 روز پس از شروع XTANDI رخ داد. بیمارانی که تشنج را تجربه کرده بودند به طور دائم از درمان قطع شدند و تمام حوادث تشنج برطرف شد. در یک کارآزمایی تک دستی که برای ارزیابی خطر تشنج در بیماران دارای فاکتورهای پیش‌ساز تشنج طراحی شده است، 8 نفر از 366 (2.2%) بیماران تحت درمان با XTANDI تشنج را تجربه کردند. سه نفر از 8 بیمار در طول ادامه درمان با XTANDI پس از رفع اولین تشنج، تشنج دوم را تجربه کردند. مشخص نیست که آیا داروهای ضد صرع از تشنج با XTANDI جلوگیری می کند یا خیر. بیماران شرکت کننده در مطالعه دارای یک یا چند مورد از عوامل مستعد کننده زیر بودند: استفاده از داروهایی که ممکن است آستانه تشنج را کاهش دهند (54%)، سابقه ضربه مغزی یا ضربه مغزی (28%)، سابقه تصادف عروق مغزی یا حمله ایسکمیک گذرا (24%)، و بیماری آلزایمر، مننژیوم یا بیماری لپتومننژیال ناشی از سرطان پروستات، از دست دادن سابقه هوشیاری در 12 ماه گذشته. تشنج، وجود فضای اشغال شده ضایعه مغزی، سابقه ناهنجاری شریانی وریدی، یا سابقه عفونت مغزی (همه کمتر از 5 درصد). تقریباً 17 درصد از بیماران بیش از یک عامل خطر داشتند. بیماران را در مورد خطر ابتلا به تشنج در حین دریافت XTANDI و انجام هر گونه فعالیتی که از دست دادن ناگهانی هوشیاری می تواند آسیب جدی به خود یا دیگران وارد کند، آگاه کنید. در بیمارانی که در طول درمان دچار تشنج می شوند، XTANDI را برای همیشه قطع کنید.

5.2 سندرم انسفالوپاتی برگشت پذیر خلفی (PRES) گزارش هایی از سندرم انسفالوپاتی برگشت پذیر خلفی (PRES) در بیماران دریافت کننده XTANDI گزارش شده است [به واکنش های جانبی (6.2) مراجعه کنید]. PRES یک اختلال عصبی است که می تواند با علائم به سرعت در حال تکامل از جمله تشنج، سردرد، بی حالی، گیجی، کوری، و سایر اختلالات بینایی و عصبی، همراه یا بدون فشار خون همراه ظاهر شود. تشخیص PRES نیاز به تایید با تصویربرداری مغز، ترجیحا تصویربرداری تشدید مغناطیسی (MRI) دارد. مصرف XTANDI در بیماران مبتلا به PRES قطع شود.

5.3 حساسیت مفرط واکنش های حساسیت مفرط، از جمله ادم صورت (0.5%)، زبان (0.1%)، یا لب (0.1%) در هشت کارآزمایی بالینی تصادفی شده با انزالوتامید مشاهده شده است. ادم حلق در موارد پس از بازاریابی گزارش شده است. به بیمارانی که علائم حساسیت مفرط را تجربه می کنند توصیه کنید که به طور موقت مصرف XTANDI را قطع کرده و به سرعت به دنبال مراقبت های پزشکی باشند. برای واکنش های حساسیت مفرط جدی، XTANDI را برای همیشه قطع کنید.

5.4 بیماری ایسکمیک قلب در داده های ترکیبی پنج مطالعه بالینی تصادفی شده و کنترل شده با دارونما، بیماری ایسکمیک قلبی در بیمارانی که در بازوی XTANDI در مقایسه با بیمارانی که در بازوی دارونما استفاده می کردند، شایع تر بود (3.5٪ در مقابل 2٪). حوادث ایسکمیک درجه 3-4 در 1.8٪ از بیماران در بازوی XTANDI در مقایسه با 1.1٪ در بازوی دارونما رخ داد. حوادث ایسکمیک منجر به مرگ در 0.4٪ از بیماران در بازوی XTANDI در مقایسه با 0.1٪ در بازوی دارونما شد. علائم و نشانه های بیماری ایسکمیک قلبی را پایش کنید. مدیریت بهینه عوامل خطر قلبی عروقی، مانند فشار خون بالا، دیابت، یا دیس لیپیدمی. برای بیماری ایسکمیک قلبی درجه 3-4، XTANDI را قطع کنید.

5.5 افتادن و شکستگی افتادن و شکستگی در بیماران دریافت کننده XTANDI رخ داد. بیماران را از نظر خطر شکستگی و سقوط ارزیابی کنید. بیماران در معرض خطر شکستگی را بر اساس دستورالعمل‌های درمانی تعیین‌شده نظارت و مدیریت کنید و استفاده از عوامل هدفمند استخوان را در نظر بگیرید. در داده‌های ترکیبی پنج مطالعه بالینی تصادفی‌سازی‌شده و کنترل‌شده با دارونما، سقوط در 12 درصد از بیماران تحت درمان با XTANDI در مقایسه با 6 درصد از بیماران تحت درمان با دارونما رخ داد. افتادن با از دست دادن هوشیاری یا تشنج همراه نبود. شکستگی در 13 درصد از بیماران تحت درمان با XTANDI و در 6 درصد از بیماران تحت درمان با دارونما رخ داده است. شکستگی های درجه 3-4 در 3.4 درصد از بیماران تحت درمان با XTANDI و در 1.9 درصد از بیماران تحت درمان با دارونما رخ داده است. میانگین زمان شروع شکستگی 420 روز (محدوده: 1 تا 2348 روز) برای بیماران تحت درمان با XTANDI بود. ارزیابی روتین تراکم استخوان و درمان پوکی استخوان با عوامل هدفمند استخوان در مطالعات انجام نشد.

5.6 سمیت جنینی- جنینی ایمنی و اثربخشی XTANDI در زنان ثابت نشده است. بر اساس مطالعات تولیدمثلی حیوانی و مکانیسم اثر، XTANDI می تواند باعث آسیب جنین و از دست دادن بارداری در صورت تجویز به یک ماده باردار شود. به مردان دارای شرکای زن با پتانسیل باروری توصیه کنید که در طول درمان با XTANDI و به مدت 3 ماه پس از آخرین دوز XTANDI از پیشگیری موثر از بارداری استفاده کنند [به استفاده در جمعیت های خاص (8.1، 8.3) مراجعه کنید].

5.7 دیسفاژی یا خفگی دیسفاژی یا خفگی شدید، از جمله حوادثی که می‌تواند تهدیدکننده زندگی باشد و نیاز به مداخله پزشکی داشته باشد یا کشنده باشد، می‌تواند به دلیل اندازه محصول XTANDI رخ دهد. به بیماران توصیه کنید که هر کپسول یا قرص را به طور کامل با مقدار کافی آب مصرف کنند تا اطمینان حاصل شود که تمام داروها با موفقیت بلعیده شده اند. استفاده از یک قرص کوچکتر XTANDI را در بیمارانی که در بلع مشکل دارند در نظر بگیرید. برای بیمارانی که نمی توانند کپسول یا قرص را قورت دهند، XTANDI را قطع کنید.

5.8 تداخل با ایمونواسی اندازه‌گیری دیگوکسین XTANDI می‌تواند با برخی از روش‌های ایمنی دیگوکسین (مانند سنجش‌های ایمنی میکروذرات شیمی‌تابناک)، که منجر به افزایش کاذب غلظت پلاسمایی دیگوکسین می‌شود، تداخل ایجاد کند. به آزمایشگاهی که سنجش غلظت پلاسمایی دیگوکسین را انجام می دهد اطلاع دهید تا از روش مناسب در بیمارانی که XTANDI و دیگوکسین دریافت می کنند استفاده کند [به تداخلات دارویی (7.3) مراجعه کنید].

عوارض جانبی زیر با جزئیات بیشتر در بخش های دیگر برچسب مورد بحث قرار گرفته است:

• تشنج [به هشدارها و اقدامات احتیاطی (5.1) مراجعه کنید]
• سندرم انسفالوپاتی برگشت پذیر خلفی (PRES) [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید]
• حساسیت مفرط [به هشدارها و اقدامات احتیاطی (5.3) مراجعه کنید]
• بیماری ایسکمیک قلب [به هشدارها و اقدامات احتیاطی (5.4) مراجعه کنید]
• سقوط و شکستگی [به هشدارها و اقدامات احتیاطی (5.5) مراجعه کنید]
• اختلال بلع یا خفگی [به هشدارها و اقدامات احتیاطی (5.7) مراجعه کنید] شایع ترین عوارض جانبی (≥ 10٪) که بیشتر (≥ 2٪ بیش از دارونما) در بیماران تحت درمان با XTANDI رخ می دهد، درد عضلانی-اسکلتی، خستگی، گرگرفتگی، یبوست، تهوع، کاهش اشتها، تهوع، کاهش اشتها است. شکستگی و سردرد (6.1) برای گزارش واکنش‌های نامطلوب مشکوک، با Astellas Pharma US, Inc. به شماره 1-800-727-7003 یا FDA به شماره 1-800-FDA-1088 یا www.fda.gov/medwatch تماس بگیرید.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS and PRECAUTIONS reflect eight randomized, controlled trials [AFFIRM, PREVAIL, TERRAIN, PROSPER, ARCHES, EMBARK, Asian PREVAIL (NCT02294461), and STRIVE (NCT01664923)] that were pooled to conduct safety analyses in patients with CRPC (N = 3651), mCSPC (N = 754), or nmCSPC with high‑risk BCR (N = 707) treated with XTANDI. Patients received XTANDI 160 mg (N = 5112) or placebo orally once daily (N = 2829) or bicalutamide 50 mg orally once daily (N = 387). In these eight trials, the median duration of treatment was 22.1 months (range: < 0.1 to 95.0) in patients that received XTANDI. In five placebo-controlled trials (AFFIRM, PROSPER, PREVAIL, ARCHES, and EMBARK), the median duration of treatment was 19.4 months (range: < 0.1 to 90.4) in the XTANDI group [see Clinical Studies ( 14 )]. In these five trials, the most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture and headache. AFFIRM: XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy AFFIRM enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse reactions were reported for 16% of XTANDI-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in AFFIRM that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in AFFIRM XTANDI (N = 800) Placebo (N = 399) Grade 1-4 CTCAE v 4. (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) General Disorders Asthenic Conditions Includes asthenia and fatigue. 51 9 44 9 Peripheral Edema 15 1 13 0.8 Musculoskeletal and Connective Tissue Disorders Back Pain 26 5 24 4 Arthralgia 21 2.5 17 1.8 Musculoskeletal Pain 15 1.3 12 0.3 Muscular Weakness 10 1.5 7 1.8 Musculoskeletal Stiffness 2.6 0.3 0.3 0 Gastrointestinal Disorders Diarrhea 22 1.1 18 0.3 Vascular Disorders Hot Flush 20 0 10 0 Hypertension 6 2.1 2.8 1.3 Nervous System Disorders Headache 12 0.9 5 0 Dizziness Includes dizziness and vertigo. 9 0.5 7 0.5 Spinal Cord Compression and Cauda Equina Syndrome 7 7 4.5 3.8 Paresthesia 7 0 4.5 0 Mental Impairment Disorders Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 4.3 0.3 1.8 0 Hypoesthesia 4 0.3 1.8 0 Infections and Infestations Upper Respiratory Tract Infection Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 11 0 6 0.3 Lower Respiratory Tract and Lung Infection Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. 8 2.4 4.8 1.3 Psychiatric Disorders Insomnia 9 0 6 0.5 Anxiety 6 0.3 4 0 Renal and Urinary Disorders Hematuria 7 1.8 4.5 1 Pollakiuria 4.8 0 2.5 0 Injury, Poisoning and Procedural Complications Fall 4.6 0.3 1.3 0 Non-pathologic Fractures 4 1.4 0.8 0.3 Skin and Subcutaneous Tissue Disorders Pruritus 3.8 0 1.3 0 Dry Skin 3.5 0 1.3 0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 PREVAIL: XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC PREVAIL enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse reactions were reported for 6% of XTANDI-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in PREVAIL that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in PREVAIL XTANDI (N = 871) Placebo (N = 844) Grade 1-4 CTCAE v 4. (%) 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 0.4 Musculoskeletal and Connective Tissue Disorders Back Pain 29 2 22 3 Arthralgia 21 1.6 16 1.1 Gastrointestinal Disorders Constipation 23 0.7 17 0.4 Diarrhea 17 0.3 14 0.4 Vascular Disorders Hot Flush 18 0.1 8 0 Hypertension 14 7 4.1 2.3 Nervous System Disorders Dizziness Includes dizziness and vertigo. 11 0.3 7 0 Headache 11 0.2 7 0.4 Dysgeusia 8 0.1 3.7 0 Mental Impairment Disorders Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 6 0 1.3 0.1 Restless Legs Syndrome 2.1 0.1 0.4 0 Respiratory Disorders Dyspnea Includes dyspnea, exertional dyspnea, and dyspnea at rest. 11 0.6 8 0.6 Infections and Infestations Upper Respiratory Tract Infection Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 16 0 11 0 Lower Respiratory Tract And Lung Infection Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. 8 1.5 4.7 1.1 Psychiatric Disorders Insomnia 8 0.1 6 0 Renal and Urinary Disorders Hematuria 9 1.3 6 1.3 Injury, Poisoning and Procedural Complications Fall 13 1.6 5 0.7 Non-Pathological Fracture 9 2.1 3 1.1 Metabolism and Nutrition Disorders Decreased Appetite 19 0.3 16 0.7 Investigations Weight Decreased 12 0.8 8 0.2 Reproductive System and Breast Disorders Gynecomastia 3.4 0 1.4 0 TERRAIN: XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC TERRAIN enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with XTANDI and 5.8 months with bicalutamide. Discontinuations with an adverse reaction as the primary reason were reported for 8% of XTANDI-treated patients and 6% of bicalutamide-treated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDI-treated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse reactions (≥ 10%) in XTANDI-treated patients. Table 3. Adverse Reactions in TERRAIN XTANDI (N = 183) Bicalutamide (N = 189) Grade 1-4 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 7 4.2 Gastrointestinal Disorders Nausea 14 0 18 0 Constipation 13 1.1 13 0.5 Diarrhea 12 0 9 1.1 Infections and Infestations Upper Respiratory Tract Infection Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. 12 0 6 0.5 Investigation s Weight Loss 11 0.5 8 0.5 PROSPER: XTANDI versus Placebo in Non-metastatic CRPC Patients PROSPER enrolled 1401 patients with non-metastatic CRPC, of whom 1395 received at least one dose of study drug. Patients were randomized 2:1 and received either XTANDI at a dose of 160 mg once daily (N = 930) or placebo (N = 465). The median duration of treatment at the time of analysis was 18.4 months (range: 0.0 to 42 months) with XTANDI and 11.1 months (range: 0.0 to 43 months) with placebo. Overall, 32 patients (3.4%) receiving XTANDI died from adverse reactions. The reasons for death with ≥ 2 patients included coronary artery disorders (n = 7), sudden death (n = 2), cardiac arrhythmias (n = 2), general physical health deterioration (n = 2), stroke (n = 2), and secondary malignancy (n = 5; one each of acute myeloid leukemia, brain neoplasm, mesothelioma, small cell lung cancer, and malignant neoplasm of unknown primary site). Three patients (0.6%) receiving placebo died from adverse reactions of cardiac arrest (n = 1), left ventricular failure (n = 1), and pancreatic carcinoma (n = 1). Grade 3 or higher adverse reactions were reported among 31% of XTANDI-treated patients and 23% of placebo‑treated patients. Discontinuations with an adverse reaction as the primary reason were reported for 9% of XTANDI-treated patients and 6% of placebo-treated patients. Of these, the most common adverse reaction leading to treatment discontinuation was fatigue, which occurred in 1.6% of the XTANDI-treated patients compared to none of the placebo-treated patients. Table 4 shows adverse reactions reported in PROSPER that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm. Table 4. Adverse Reactions in PROSPER XTANDI (N = 930) Placebo (N = 465) Grade 1-4 CTCAE v 4. (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Metabolism and Nutrition Disorders Decreased Appetite 10 0.2 3.9 0.2 Nervous System Disorders Dizziness Includes dizziness and vertigo. 12 0.5 5 0 Headache 9 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 8 0 Hypertension 12 4.6 5 2.2 Gastrointestinal Disorders Nausea 11 0.3 9 0 Constipation 9 0.2 7 0.4 General Disorders and Administration Site Conditions Asthenic Conditions Includes asthenia and fatigue. 40 4 20 0.9 Investigations Weight Decreased 6 0.2 1.5 0 Injury, Poisoning and Procedural Complications Fall 11 1.3 4.1 0.6 Fractures Includes all osseous fractures from all sites. 10 2 4.9 1.7 Psychiatric Disorders Anxiety 2.8 0.2 0.4 0 ARCHES: XTANDI versus Placebo in Metastatic CSPC Patients ARCHES randomized 1150 patients with mCSPC, of whom 1146 received at least one dose of study drug. All patients received either a gonadotropin-releasing hormone (GnRH) analog concurrently or had bilateral orchiectomy. Patients received either XTANDI at a dose of 160 mg once daily (N = 572) or placebo (N = 574). The median duration of treatment was 12.8 months (range: 0.2 to 26.6 months) with XTANDI and 11.6 months (range: 0.2 to 24.6 months) with placebo. Overall, 10 patients (1.7%) receiving XTANDI died from adverse reactions. The reasons for death in ≥ 2 patients included heart disease (n = 3), sepsis (n = 2) and pulmonary embolism (n = 2). Eight patients (1.4%) receiving placebo died from adverse reactions. The reasons for death in ≥ 2 patients included heart disease (n = 2) and sudden death (n = 2). Grade 3 or higher adverse reactions were reported in 24% of patients treated with XTANDI. Permanent discontinuation due to adverse reactions as the primary reason was reported in 4.9% of XTANDI-treated patients and 3.7% of placebo-treated patients. The most common adverse reactions resulting in permanent discontinuation in XTANDI-treated patients were alanine aminotransferase increased, aspartate aminotransferase elevation, and seizure, each in 0.3%. The most common adverse reactions leading to permanent discontinuation in placebo-treated patients were arthralgia, and fatigue, each in 0.3%. Dose reductions due to an adverse reaction occurred in 4.4% of patients who received XTANDI. Fatigue/asthenia was the most frequent adverse reaction requiring dose reduction in 2.1% of XTANDI-treated patients and 0.7% of placebo-treated patients. Table 5 shows adverse reactions reported in ARCHES that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm. Table 5. Adverse Reactions in ARCHES XTANDI (N = 572) Placebo (N = 574) Grade 1-4 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 3.3 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 0.2 4 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 1.0 4.2 1 EMBARK: XTANDI versus Placebo in Non-metastatic CSPC Patients with High-Risk BCR EMBARK enrolled 1068 patients with high-risk BCR, of whom 1061 patients received at least one dose of study drug. Patients received XTANDI at a dose of 160 mg once daily concurrently with leuprolide (N = 353), XTANDI at a dose of 160 mg once daily as open‑label monotherapy (N = 354), or placebo concurrently with leuprolide (N = 354). At week 37, treatment was suspended for patients whose PSA values were undetectable (< 0.2 ng/mL) at week 36. Treatment was reinitiated when PSA values increased to ≥ 2.0 ng/mL for patients with prior prostatectomy or ≥ 5.0 ng/mL for patients without prior prostatectomy. For patients whose PSA values were detectable (≥ 0.2 ng/mL) at week 36, treatment continued without suspension until permanent treatment discontinuation criteria were met. Table 6 shows the total duration of treatment for the three treatment arms. Table 6. Drug Treatment and Suspension in EMBARK XTANDI + Leuprolide (N = 353) Placebo + Leuprolide (N = 354) XTANDI (N = 354) Total Duration of Treatment Inclusive of time receiving drug treatment plus any time during which drug treatment was suspended because of undetectable PSA levels. Median, months 60.6 55.6 60.4 Range, months 0.1 – 90.4 0.7 – 94.1 0.4 – 95.0 Duration Receiving Drug Treatment Median, months 32.4 35.4 45.9 Range, months 0.1 – 83.4 0.7 – 85.7 0.4 – 88.9 Duration of Suspension from Drug Treatment Median, months 18.0 16.6 9.4 Range, months 1.4 – 87.9 3.4 – 83.0 2.0 – 77.7 Patients who had Drug Treatment Suspended at Week 37 Number of Patients (%) 321 (90.9) 240 (67.8) 304 (85.9) Overall, deaths from adverse reactions during the total duration of treatment occurred in 6 patients (1.7%) receiving XTANDI plus leuprolide, 8 patients (2.3%) receiving XTANDI as a single agent, and 3 patients (0.8%) receiving placebo plus leuprolide. The reason for death in ≥ 2 patients receiving XTANDI plus leuprolide was infection (n = 2), and the reason for death in ≥ 2 patients receiving XTANDI as a single agent was arterial thromboembolism (n = 2). Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide. The most common adverse reactions resulting in permanent discontinuation included fatigue (3.4% of patients treated with XTANDI plus leuprolide, 3.7% of patients receiving XTANDI as a single agent, and 1.4% of patients receiving placebo plus leuprolide), hot flush (2% of patients treated with XTANDI plus leuprolide, 0% of patients receiving XTANDI as a single agent, and 1.1% of patients receiving placebo plus leuprolide), nausea (1.1% of patients treated with XTANDI plus leuprolide, 0.6% of patients receiving XTANDI as a single agent, and 0.3% of patients receiving placebo plus leuprolide), and cognitive disorder (1.1% of patients treated with XTANDI plus leuprolide, 1.4% of patients receiving XTANDI as a single agent, and 0.8% of patients receiving placebo plus leuprolide). Dose reductions due to an adverse reaction occurred in 7% of patients who received XTANDI plus leuprolide, 16% of patients who received XTANDI as a single agent, and 4.5% of patients who received placebo plus leuprolide. Fatigue was the most frequent adverse reaction requiring dose reduction in 3.1% of patients treated with XTANDI plus leuprolide, 10% of patients receiving XTANDI as a single agent, and 1.7% of patients receiving placebo plus leuprolide. Table 7 shows adverse reactions reported in EMBARK that occurred at a ≥ 5% (Grade 1-4) or ≥ 2% (Grade 3-4) higher frequency in either of the XTANDI arms than in the placebo arm. Table 7. Adverse Reactions in EMBARK XTANDI + Leuprolide (N = 353) Placebo + Leuprolide (N = 354) XTANDI (N = 354) Grade 1-4 CTCAE v 4.03. (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3‑4 (%) Grade 1-4 (%) Grade 3-4 (%) Nervous System Disorders Cognitive Disorder Includes multiple terms. 10 0.3 4.8 0.6 10 0.3 Syncope 4.8 4.2 2.3 1.7 2.5 2 Vascular Disorders Hot Flush 69 0.6 57 0.8 22 0.3 Hemorrhage 20 3.4 15 1.7 21 3.7 Gastrointestinal Disorders Diarrhea 15 0.6 9 0.8 14 0.3 Nausea 12 0.3 8 0.3 15 0.6 Investigations Weight Decreased 7 0.3 3.4 0 11 0.3 General Disorders and Administration Site Conditions Fatigue 50 4 38 1.7 54 4.8 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain 50 4.8 43 2.3 48 3.1 Osteoarthritis 6 2.8 4.2 0.6 5 0.6 Injury, Poisoning and Procedural Complications Fall 21 1.1 14 1.1 16 2 Fracture 18 4 13 2.5 11 2 Reproductive System and Breast Disorders Gynecomastia 9 0 10 0 49 0.8 Breast tenderness 5 0 2.8 0 35 0 Cardiac Disorders Ischemic Heart Disease 5 4 6 3.1 9 6 Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 7 include hypertension (XTANDI plus leuprolide, 25%; XTANDI as a single agent, 21%), angioedema (XTANDI plus leuprolide, 2.5%; XTANDI as a single agent, 2%), and seizure (XTANDI plus leuprolide, 1.1%; XTANDI as a single agent, 0.8%). Laboratory Abnormalities Table 8 shows laboratory abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies. Table 8. Laboratory Abnormalities XTANDI (N = 3526) Placebo (N = 2636) Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Hematology Hemoglobin decreased 50 1.8 47 1.5 Neutrophil count decreased 20 1 17 0.5 White blood cell decreased 18 0.5 11 0.2 Chemistry Hyperglycemia 86 3.7 78 4.3 Hypermagnesemia 17 0.1 14 0.3 Hyponatremia 14 1.6 9 1.4 Hypophosphatemia 10 1.4 7 0.8 Hypercalcemia 8 0.1 5 0.1 Hypertension In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14% of patients receiving XTANDI and 7% of patients receiving placebo. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of XTANDI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: vomiting, dysphagia (including choking related to XTANDI product size) Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx) Neurological Disorders: posterior reversible encephalopathy syndrome (PRES), dysgeusia Skin and Subcutaneous Tissue Disorders: rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP))

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.