دوپیلوماب

دوپیکسنت با تزریق زیر جلدی تجویز می شود. ( 2.1 ) دوز درماتیت آتوپیک در بزرگسالان (2.3): دوز توصیه شده دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) است که به دنبال آن 300 میلی گرم هر 2 هفته (Q2W) تجویز می شود. مقدار مصرف در کودکان 6 ماهه تا 5 ساله (2.3): وزن بدن دوز توصیه شده برای بیماران اطفال 6 ماهه تا 5 ساله، هیچ دوز بارگیری اولیه 5 تا کمتر از 15 کیلوگرم 200 میلی گرم (یک تزریق 200 میلی گرم کودک) هر 4 هفته (Q4W) 15 تا کمتر از 30 کیلوگرم، 300 میلی گرم (یک بار 300 میلی گرم در هفته، هر 4 هفته تزریق) توصیه نمی شود. سن تا 17 سال (2.3): وزن بدن دوز بارگیری اولیه دوز بعدی Q2W - هر 2 هفته. Q4W - هر 4 هفته 15 تا کمتر از 30 کیلوگرم، 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم Q4W 30 تا کمتر از 60 کیلوگرم، 400 میلی گرم (دو تزریق 200 میلی گرم) 200 میلی گرم Q2W 60 کیلوگرم یا بیشتر 600 میلی گرم (دو تزریق 30 میلی گرم در هر دوز Q4) بیماران بزرگسال و کودکان 12 سال و بالاتر (2.4): دوز بارگیری اولیه دوز بعدی 400 میلی گرم (دو تزریق 200 میلی گرم) 200 میلی گرم هر 2 هفته (Q2W) یا 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم هر 2 هفته (Q2W) دوز برای بیماران مبتلا به آسم وابسته به کورتیکواستروئید خوراکی با آسم همراه وابسته به کورتیکواستروئید خوراکی و یا آسم متوسط وابسته به AD. CRSwNP یا AFRS برای کودکان 12 سال تا 17 سال (≥60 کیلوگرم) و بزرگسالان با AFRS 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم هر 2 هفته (Q2W) دوز در کودکان 6 سال تا 11 سال (2.4): وزن بدن دوز توصیه شده برای بیماران اطفال 6 سال تا 11 سال، هیچ دوز بارگیری اولیه 15 تا کمتر از 30 کیلوگرم 300 میلی گرم هر 4 هفته (Q4W) 30 کیلوگرم یا بیشتر 200 میلی گرم هر 2 هفته (Q2W) برای کودکان 6 سال تا 11 سال با بیماری های اتومی همراه با بیماری توصیه نمی شود. درماتیت، دوز توصیه شده را مطابق جدول 2 که شامل مقدار اولیه است، دنبال کنید دوز بارگیری (2.3) رینوسینوزیت مزمن با پولیپ بینی (2.5): دوز توصیه شده برای بیماران بزرگسال و کودکان 12 سال و بالاتر 300 میلی گرم هر 2 هفته (Q2W) است. ازوفاژیت ائوزینوفیلیک (2.6): وزن بدن دوز توصیه شده در بزرگسالان و کودکان 1 سال و بالاتر، با وزن حداقل 15 کیلوگرم، 15 تا کمتر از 30 کیلوگرم، 200 میلی گرم هر 2 هفته (Q2W) 30 تا کمتر از 40 کیلوگرم، 300 میلی گرم هر 2 هفته (Q2W) 40 کیلوگرم یا بیشتر هر 2 هفته (Q2W یا بیشتر) ): دوز توصیه شده برای بیماران بزرگسال دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) است که به دنبال آن 300 میلی گرم هر 2 هفته (Q2W) تجویز می شود. بیماری مزمن انسدادی ریه (2.8): دوز توصیه شده برای بیماران بزرگسال 300 میلی گرم هر 2 هفته (Q2W) است. مقدار مصرف کهیر خودبخودی مزمن در بزرگسالان (2.9): دوز توصیه شده دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) است که به دنبال آن 300 میلی گرم هر 2 هفته (Q2W) تجویز می شود. مقدار مصرف در کودکان 2 سال تا 5 سال ( 2.9 ): وزن بدن دوز توصیه شده برای بیماران اطفال 2 سال تا 5 سال مبتلا به CSU، هیچ دوز بارگیری اولیه 5 تا کمتر از 15 کیلوگرم 200 میلی گرم (یک تزریق 200 میلی گرم) هر 4 هفته (Q4W) 15 تا کمتر از 30 کیلوگرم، 300 میلی گرم در هر 4 هفته تزریق (یک تزریق 300 میلی گرم در هفته) توصیه نمی شود. 6 سال تا 17 سال ( 2.9 ): وزن بدن دوز بارگیری اولیه دوز بعدی Q2W - هر 2 هفته. Q4W - هر 4 هفته 15 تا کمتر از 30 کیلوگرم، 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم Q4W 30 تا کمتر از 60 کیلوگرم، 400 میلی گرم (دو تزریق 200 میلی گرم) 200 میلی گرم Q2W 60 کیلوگرم یا بیشتر 600 میلی گرم (دو بار تزریق 300 میلی گرم) (2.10): دوز توصیه شده برای بیماران بزرگسال دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) است که به دنبال آن 300 میلی گرم یک هفته در میان (Q2W) تجویز می شود. از دوپیکسنت در ترکیب با یک دوره کاهشی کورتیکواستروئیدهای خوراکی استفاده کنید. دوز رینوسینوزیت قارچی آلرژیک در بزرگسالان (2.11): دوز توصیه شده 300 میلی گرم هر 2 هفته (Q2W) است. مقدار مصرف در کودکان 6 سال تا 17 سال ( 2.11 ) : وزن بدن دوز توصیه شده Q2W - هر 2 هفته. Q4W - هر 4 هفته 15 تا کمتر از 30 کیلوگرم 300 میلی گرم Q4W 30 تا کمتر از 60 کیلوگرم 200 میلی گرم Q2W 60 کیلوگرم یا بیشتر 300 میلی گرم Q2W 2.1 دستورالعمل مهم تجویز DUPIXENT با تزریق زیر جلدی تجویز می شود. DUPIXENT برای استفاده تحت راهنمایی یک ارائه دهنده مراقبت های بهداشتی در نظر گرفته شده است. آموزش مناسب به بیماران و/یا مراقبان در مورد تهیه و تجویز DUPIXENT قبل از استفاده طبق "دستورالعمل های استفاده" ارائه دهید. استفاده از قلم از پیش پر شده یا سرنگ از پیش پر شده قلم از پیش پر شده DUPIXENT برای استفاده در بیماران بزرگسال و کودکان بالای 2 سال است. سرنگ از پیش پر شده DUPIXENT برای استفاده در بیماران بزرگسال و کودکان 6 ماهه و بالاتر می باشد. یک مراقب یا بیمار 12 ساله و بالاتر ممکن است دوپیکسنت را با استفاده از سرنگ یا قلم از پیش پر شده تزریق کند. در کودکان 12 سال و بالاتر، داروی دوپیکسنت را زیر نظر یک بزرگسال تجویز کنید. در کودکان 6 ماهه تا کمتر از 12 سال، داروی دوپیکسنت را توسط یک مراقب تجویز کنید. دستورالعمل های تجویز برای بیماران مبتلا به AD، آسم، PN، CSU و BP که دوز اولیه 600 میلی گرم را دریافت می کنند، هر یک از دو تزریق 300 میلی گرم DUPIXENT را در محل های مختلف تزریق انجام دهید. برای بیماران مبتلا به AD، آسم و CSU که دوز اولیه 400 میلی گرم را دریافت می کنند، هر یک از دو تزریق 200 میلی گرم DUPIXENT را در محل های مختلف تزریق انجام دهید. تزریق زیر جلدی را در ران یا شکم انجام دهید، به جز 2 اینچ (5 سانتی متر) در اطراف ناف. در صورتی که یک مراقب تزریق را انجام دهد، می توان از قسمت بالایی بازو نیز استفاده کرد. با هر تزریق محل تزریق را بچرخانید. دوپیکسنت را به پوستی که حساس، آسیب دیده، کبود شده یا زخمی است تزریق نکنید. "دستورالعمل های استفاده" DUPIXENT حاوی دستورالعمل های دقیق تری در مورد تهیه و تجویز DUPIXENT است [به دستورالعمل های استفاده مراجعه کنید].

2.2 واکسیناسیون قبل از درمان، قبل از شروع درمان با DUPIXENT، تمام واکسیناسیون‌های مناسب سن را طبق دستورالعمل‌های ایمن‌سازی فعلی تکمیل کنید [به هشدارها و اقدامات احتیاطی (5.10) مراجعه کنید].

2.3 دوز توصیه شده برای درماتیت آتوپیک دوز در بزرگسالان دوز توصیه شده دوپیکسنت برای بیماران بزرگسال دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) است و سپس 300 میلی گرم هر 2 هفته (Q2W) تجویز می شود. مقدار مصرف در کودکان 6 ماهه تا 5 ساله دوز توصیه شده دوپیکسنت برای بیماران کودکان 6 ماه تا 5 سال در جدول 1 مشخص شده است. جدول 1: دوز دوپیکسنت در بیماران کودکان 6 ماه تا 5 سال مبتلا به درماتیت آتوپیک وزن بدن دوز توصیه شده برای بیماران اطفال 6 ماه تا 5 سال مبتلا به AD، هیچ دوز بارگیری اولیه توصیه نمی شود. 5 تا کمتر از 15 کیلوگرم 200 میلی گرم (یک تزریق 200 میلی گرم) هر 4 هفته (Q4W) 15 تا کمتر از 30 کیلوگرم 300 میلی گرم (یک تزریق 300 میلی گرم) هر 4 هفته (Q4W) دوز در بیماران اطفال 6 سال تا 17 سال سن دوز توصیه شده برای کودکان 6 سال سن تا 17 در جدول 2 مشخص شده است. جدول 2: دوز دوپیکسنت در بیماران اطفال 6 سال تا 17 سال مبتلا به درماتیت آتوپیک وزن بدن دوز بارگیری اولیه دوز بعدی 15 تا کمتر از 30 کیلوگرم 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم هر 4 هفته (4 هفته تا 40 کیلوگرم وزن بدن) 60 میلی گرم تزریقات) 200 میلی گرم هر 2 هفته (Q2W) 60 کیلوگرم یا بیشتر 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم هر 2 هفته (Q2W) همزمان موضعی درمان های DUPIXENT را می توان با یا بدون کورتیکواستروئیدهای موضعی استفاده کرد. ممکن است از مهارکننده های موضعی کلسینورین استفاده شود، اما باید فقط برای نواحی مشکل دار مانند صورت، گردن، نواحی بین تریجینی و تناسلی استفاده شود.

2.4 دوز توصیه شده برای دوز مصرفی آسم در بیماران بزرگسال و کودکان 12 سال و بالاتر دوز توصیه شده دوپیکسنت برای بیماران بزرگسال و کودکان 12 سال و بالاتر در جدول 3 مشخص شده است. جدول 3: دوز دوپیکسنت در بزرگسالان و کودکان 12 سال و مسن تر مبتلا به آسم دوز بارگیری اولیه دوز بعدی 400 میلی گرم (دو تزریق 200 میلی گرم) 200 میلی گرم هر 2 هفته (Q2W) یا 600 میلی گرم (دو میلی گرم 300 میلی گرم برای هر هفته تزریق هر 2 هفته) آسم وابسته به کورتیکواستروئید یا همراه با بیماری AD متوسط تا شدید، CRSwNP یا AFRS برای کودکان 12 سال تا 17 سن (≥60 کیلوگرم) و بزرگسالان با AFRS 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم هر 2 هفته (Q2W) دوز در کودکان 6 سال تا 11 سال دوز توصیه شده از DUPIXENT برای بیماران اطفال 6 سال تا 14 سال قابل تعیین در سن T4 است. دوز دوپیکسنت در کودکان 6 سال تا 11 سال مبتلا به آسم وزن بدن دوز توصیه شده برای بیماران کودکان 6 سال تا 11 سال مبتلا به آسم، هیچ دوز بارگیری اولیه توصیه نمی شود. 15 تا کمتر از 30 کیلوگرم. ] .

2.5 دوز توصیه شده برای رینوسینوزیت مزمن همراه با پولیپ بینی دوز توصیه شده دوپیکسنت برای بیماران بزرگسال و کودکان 12 سال و بالاتر 300 میلی گرم هر 2 هفته (Q2W) است.

2.6 دوز توصیه شده برای ازوفاژیت ائوزینوفیلیک دوز توصیه شده دوپیکسنت برای بیماران بزرگسال و کودکان 1 سال و بالاتر با وزن حداقل 15 کیلوگرم در جدول 5 مشخص شده است. جدول 5: دوز دوپیکسنت در بزرگسالان و بیماران اطفال 1 ساله و بزرگتر مبتلا به ازوفاژیت ائوزینوفیلیک وزن بدن دوز توصیه شده 15 تا کمتر از 30 کیلوگرم 200 میلی گرم هر 2 هفته (Q2W) 30 تا کمتر از 40 میلی گرم 300 میلی گرم وات هر 2 هفته Q4 یا بیشتر (Q2W)

2.7 دوز توصیه شده برای Prurigo Nodularis دوز توصیه شده DUPIXENT برای بیماران بزرگسال دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) و سپس 300 میلی گرم هر 2 هفته (Q2W) است.

2.8 دوز توصیه شده برای بیماری مزمن انسدادی ریه دوز توصیه شده دوپیکسنت برای بیماران بزرگسال 300 میلی گرم هر 2 هفته (Q2W) است.

2.9 دوز توصیه شده برای کهیر خودبخودی مزمن در بزرگسالان دوز توصیه شده دوپیکسنت برای بیماران بزرگسال دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) است و سپس 300 میلی گرم هر 2 هفته (Q2W) تجویز می شود. مقدار مصرف در کودکان 2 سال تا 5 سال دوز توصیه شده DUPIXENT برای بیماران کودکان 2 سال تا 5 سال در جدول 6 مشخص شده است. جدول 6: دوز دوپیکسنت در کودکان 2 سال تا 5 سال با کهیر مزمن خودبخودی وزن بدن دوز توصیه شده برای بیماران کودکان 2 سال تا 5 سال مبتلا به CSU، هیچ دوز بارگیری اولیه توصیه نمی شود. 5 تا کمتر از 15 کیلوگرم 200 میلی گرم (یک تزریق 200 میلی گرم) هر 4 هفته (Q4W) 15 تا کمتر از 30 کیلوگرم 300 میلی گرم (یک تزریق 300 میلی گرم) هر 4 هفته (Q4W) دوز در بیماران اطفال 6 سال تا 17 سال سن دوز توصیه شده برای کودکان 6 سال سن تا 17 در جدول 7 مشخص شده است. جدول 7: دوز دوپیکسنت در کودکان 6 سال تا 17 سال با کهیر مزمن خودبخودی وزن بدن دوز بارگیری اولیه دوز بعدی 15 تا کمتر از 30 کیلوگرم 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم 4 میلی گرم کمتر از 4 هفته (30 میلی گرم 4 کیلوگرم وزن بدن) (دو تزریق 200 میلی گرم) 200 میلی گرم هر 2 هفته (Q2W) 60 کیلوگرم یا بیشتر 600 میلی گرم (دو تزریق 300 میلی گرم) 300 میلی گرم هر 2 هفته (Q2W)

2.10 دوز توصیه شده برای پمفیگوئید بولوز دوز توصیه شده دوپیکسنت برای بیماران بزرگسال دوز اولیه 600 میلی گرم (دو تزریق 300 میلی گرم) و سپس 300 میلی گرم هر هفته در میان (Q2W) است. مصرف همزمان کورتیکواستروئیدهای خوراکی: از DUPIXENT در ترکیب با یک دوره کاهشی کورتیکواستروئیدهای خوراکی استفاده کنید. پس از کنترل بیماری، به تدریج کورتیکواستروئیدها را کاهش دهید و پس از آن دوپیکسنت را به عنوان تک درمانی ادامه دهید. در صورت عود، اگر از نظر پزشکی توصیه شود، ممکن است کورتیکواستروئیدها اضافه شود.

2.11 دوز توصیه شده برای رینوسینوزیت قارچی آلرژیک دوز در بزرگسالان دوز توصیه شده دوپیکسنت برای بیماران بزرگسال 300 میلی گرم است که هر دو هفته یکبار (Q2W) داده می شود. مقدار مصرف در کودکان 6 سال تا 17 سال دوز توصیه شده DUPIXENT برای بیماران کودکان 6 سال تا 17 سال در جدول 8 مشخص شده است. جدول 8: دوز دوپیکسنت در کودکان 6 سال تا 17 سال مبتلا به رینوسینوزیت قارچی آلرژیک وزن بدن دوز توصیه شده 15 تا کمتر از 30 کیلوگرم 300 میلی گرم هر 4 هفته (Q4W) 30 تا کمتر از 60 کیلوگرم 200 میلی گرم 200 میلی گرم هر 2 هفته (60 کیو 200 میلی گرم وزن بدن هر 2 هفته) (Q2W)

2.12 دوز فراموش شده اگر یک دوز هفتگی فراموش شد، دوز را در اسرع وقت تجویز کنید و یک برنامه هفتگی جدید را از تاریخ آخرین دوز تجویز شده شروع کنید. اگر یک نوبت 2 هفته ای فراموش شد، تزریق را ظرف 7 روز پس از فراموشی دوز انجام دهید و سپس برنامه اولیه بیمار را از سر بگیرید. اگر دوز فراموش شده در عرض 7 روز تجویز نشد، دوز را تجویز کنید و برنامه جدیدی را بر اساس این تاریخ شروع کنید. اگر یک نوبت 4 هفته ای فراموش شد، تزریق را ظرف 7 روز پس از فراموشی دوز انجام دهید و سپس برنامه اولیه بیمار را از سر بگیرید. اگر دوز فراموش شده در عرض 7 روز تجویز نشد، دوز را تجویز کنید و برنامه جدیدی را بر اساس این تاریخ شروع کنید.

2.13 آماده سازی برای استفاده قبل از تزریق، DUPIXENT را از یخچال خارج کنید و اجازه دهید DUPIXENT به دمای اتاق برسد (45 دقیقه برای سرنگ 300 میلی گرم در 2 میلی لیتر یا قلم از پیش پر شده و 30 دقیقه برای سرنگ 200 میلی گرم / 1.14 میلی لیتر بدون سرنگ از قبل پر شده یا سرنگ از قبل پر شده 30 دقیقه). پس از خارج کردن از یخچال، DUPIXENT باید ظرف 14 روز استفاده شود یا دور ریخته شود. قبل از مصرف، DUPIXENT را از نظر وجود ذرات معلق و تغییر رنگ بررسی کنید. دوپیکسنت یک محلول شفاف تا کمی مادی، بی رنگ تا زرد کم رنگ است. اگر مایع حاوی ذرات قابل مشاهده است، تغییر رنگ داده یا کدر است (به غیر از شفاف تا کمی مادی، بی رنگ تا زرد کم رنگ) استفاده نکنید. DUPIXENT حاوی مواد نگهدارنده نیست. بنابراین، هر محصول استفاده نشده باقی مانده در سرنگ یا قلم از پیش پر شده را دور بریزید.

5 هشدارها و اقدامات احتیاطی حساسیت مفرط: واکنش های حساسیت مفرط شامل آنافیلاکسی، پوسچولوز اگزانتماتوز عمومی حاد (AGEP)، بیماری سرمی، آنژیوادم، کهیر، بثورات پوستی، اریتم ندوزوم و اریتم مولتی فرم رخ داده است. در صورت بروز واکنش حساسیت، مصرف دوپیکسنت را قطع کنید. (5.1) ورم ملتحمه، کراتیت و بلفاریت: به بیماران توصیه کنید که فوراً شروع جدید یا بدتر شدن علائم چشمی را به ارائه دهنده مراقبت های بهداشتی خود گزارش دهند. اگر علائم ادامه یافت یا بدتر شد، قطع دوپیکسنت را در نظر بگیرید. در صورت لزوم معاینه چشم پزشکی را در نظر بگیرید. (5.2) شرایط ائوزینوفیلیک: نسبت به بثورات واسکولیتیک، بدتر شدن علائم ریوی، عوارض قلبی، آسیب کلیه و/یا نوروپاتی، به ویژه پس از کاهش کورتیکواستروئیدهای خوراکی، هوشیار باشید. (5.3) کاهش دوز کورتیکواستروئید: کورتیکواستروئیدهای سیستمیک، موضعی یا استنشاقی را به طور ناگهانی با شروع دوپیکسنت قطع نکنید. در صورت لزوم استروئیدها را به تدریج کاهش دهید. (5.5) پسوریازیس: به بیماران توصیه کنید علائم پسوریازیس تازه شروع شده را به ارائه دهنده مراقبت های بهداشتی خود گزارش کنند. اگر علائم باقی ماند یا بدتر شد، ارزیابی پوست و/یا قطع دوپیکسنت را در نظر بگیرید. (5.7) آرترالژی و آرتریت پسوریاتیک: به بیماران توصیه کنید که علائم مفصلی شروع شده جدید را به ارائه دهنده مراقبت های بهداشتی خود گزارش دهند. اگر علائم باقی ماند یا بدتر شد، ارزیابی روماتولوژیک و/یا قطع دوپیکسنت را در نظر بگیرید. (5.8) عفونت های انگلی (هلمینت): قبل از شروع DUPIXENT، عفونت های کرمی از قبل موجود را درمان کنید. اگر بیماران در حین دریافت دوپیکسنت دچار عفونت شدند و به درمان ضد هلمینت پاسخ ندادند، مصرف دوپیکسنت را تا رفع عفونت قطع کنید. (5.9) واکسیناسیون: از استفاده از واکسن های زنده خودداری کنید. (5.10)

5.1 حساسیت مفرط واکنش های حساسیت مفرط، از جمله آنافیلاکسی، پوسچولوز اگزانتماتوز عمومی حاد (AGEP)، بیماری سرمی یا واکنش های شبه بیماری سرمی، آنژیوادم، کهیر عمومی، بثورات پوستی، اریتم ندوزوم و اریتم مولتی فرم گزارش شده است. یک مورد AGEP در یک فرد بالغ که در برنامه توسعه پمفیگوئید بولوز شرکت کرده بود گزارش شد. اگر یک واکنش حساسیت بالینی قابل توجه رخ داد، درمان مناسب را آغاز کنید و دوپیکسنت را قطع کنید [به واکنش های جانبی (6.1، 6.2) و فارماکولوژی بالینی (12.6) مراجعه کنید.

5.2 ورم ملتحمه، کراتیت و بلفاریت کنژونکتیویت و عوارض جانبی کراتیت در کارآزمایی های بالینی گزارش شده است [به واکنش های جانبی (6.1) مراجعه کنید]. ورم ملتحمه و کراتیت در افراد مبتلا به AD که دوپیکسنت دریافت کردند در مقایسه با افرادی که دارونما دریافت کردند، بیشتر رخ داد. ورم ملتحمه شایع ترین اختلال چشمی گزارش شده بود. اکثر افراد مبتلا به ورم ملتحمه یا کراتیت در طول دوره درمان بهبود یافتند یا در حال بهبود بودند. در میان افراد مبتلا به آسم، فراوانی ورم ملتحمه و کراتیت بین دوپیکسنت و دارونما مشابه بود. در افراد بالغ مبتلا به CRSwNP، فراوانی ملتحمه در گروه DUPIXENT 2% در مقایسه با 1% در گروه دارونما در گروه ایمنی 24 هفته ای بود. این افراد بهبود یافتند. در میان افراد مبتلا به EoE، هیچ گزارشی از ورم ملتحمه و کراتیت در گروه DUPIXENT در کارآزمایی‌های کنترل‌شده با دارونما وجود نداشت. در افراد مبتلا به PN، فراوانی ملتحمه در گروه DUPIXENT 4% در مقایسه با 1% در گروه دارونما بود. این افراد در طول دوره درمان بهبود یافتند یا در حال بهبود بودند. در بین افراد مبتلا به COPD، فراوانی ملتحمه و کراتیت به ترتیب در گروه DUPIXENT 1.4% و 0.1% و در گروه دارونما 1% و 0% بود. در افراد مبتلا به CSU، فراوانی ورم ملتحمه بین دوپیکسنت و دارونما مشابه بود. در بین افراد مبتلا به BP، فراوانی ملتحمه و کراتیت به ترتیب در گروه DUPIXENT 7.5% و 3.8% و در گروه دارونما 0% و 0% بود. عوارض جانبی ملتحمه، کراتیت و بلفاریت نیز با دوپیکسنت در شرایط پس از فروش، عمدتاً در بیماران مبتلا به AD گزارش شده است. برخی از بیماران درجات مختلفی از اختلال بینایی گذرا یا مداوم از جمله کوری همراه با ورم ملتحمه، کراتیت یا بلفاریت را گزارش کردند که منجر به قطع دوپیکسنت و/یا مداخله جراحی شد. به بیماران یا مراقبان آنها توصیه کنید که فوراً شروع جدید یا بدتر شدن علائم چشمی را به ارائه دهنده مراقبت های بهداشتی خود گزارش دهند. قطع دوپیکسنت و معاینه فوری چشم‌پزشکی را برای بیمارانی که علائم و نشانه‌هایی مبنی بر کراتیت ایجاد می‌کنند، یا زمانی که ورم ملتحمه یا بلفاریت پس از درمان استاندارد برطرف نمی‌شوند، در نظر بگیرید. در بیماران مبتلا به بیماری خشکی چشم قابل توجه، سابقه ناهنجاری/جراحی های قابل توجه پلک، یا سابقه جراحی بینی اشکی با احتیاط مصرف شود [به واکنش های جانبی (6.1، 6.2) مراجعه کنید].

5.3 شرایط ائوزینوفیلیک بیماران تحت درمان برای آسم ممکن است با ویژگی های بالینی پنومونی ائوزینوفیلیک یا گرانولوماتوز ائوزینوفیلیک همراه با پلی آنژیت (EGPA) مراجعه کنند. این رویدادها ممکن است با کاهش درمان با کورتیکواستروئید خوراکی همراه باشد. ارائه دهندگان مراقبت های بهداشتی باید نسبت به بثورات واسکولیتیک، بدتر شدن علائم ریوی، عوارض قلبی، آسیب کلیوی و/یا نوروپاتی در بیماران مبتلا به ائوزینوفیلی هوشیار باشند. موارد پنومونی ائوزینوفیلیک در بزرگسالانی که در برنامه توسعه آسم شرکت کرده بودند گزارش شد. مواردی از EGPA با DUPIXENT در بزرگسالانی که در برنامه توسعه آسم شرکت کرده‌اند و همچنین در بزرگسالان مبتلا به آسم همراه در برنامه توسعه CRSwNP گزارش شده است. به بیماران توصیه کنید که علائم ذات الریه ائوزینوفیلیک و EGPA را به ارائه دهنده مراقبت های بهداشتی خود گزارش کنند. اگر مشکوک به ذات الریه ائوزینوفیلیک یا EGPA هستید، مصرف DUPIXENT را در نظر بگیرید.

5.4 علائم حاد آسم یا بیماری انسداد مزمن ریه یا بیماری حاد رو به وخامت DUPIXENT نباید برای درمان علائم حاد یا تشدید حاد آسم یا COPD استفاده شود. از دوپیکسنت برای درمان برونکواسپاسم حاد یا وضعیت آسم استفاده نکنید. اگر پس از شروع درمان با دوپیکسنت، آسم یا COPD کنترل نشده یا بدتر شد، بیماران باید به دنبال مشاوره پزشکی باشند.

5.5 خطر مرتبط با کاهش ناگهانی دوز کورتیکواستروئیدها کورتیکواستروئیدهای سیستمیک، موضعی یا استنشاقی را به طور ناگهانی با شروع درمان با دوپیکسنت قطع نکنید. کاهش دوز کورتیکواستروئید، در صورت لزوم، باید تدریجی باشد و تحت نظارت مستقیم یک ارائه دهنده مراقبت های بهداشتی انجام شود. کاهش دوز کورتیکواستروئید ممکن است با علائم محرومیت سیستمیک و/یا آشکار کردن شرایطی که قبلاً توسط درمان سیستمیک کورتیکواستروئید سرکوب شده‌اند همراه باشد.

5.6 بیماران مبتلا به آسم همزمان به بیماران مبتلا به آسم همراه توصیه کنید که درمان های آسم خود را بدون مشورت با پزشک خود تنظیم یا متوقف نکنند.

5.7 پسوریازیس مواردی از پسوریازیس با شروع جدید با استفاده از DUPIXENT برای درمان درماتیت آتوپیک و آسم گزارش شده است، از جمله در بیماران بدون سابقه خانوادگی پسوریازیس. در گزارش‌های پس از بازاریابی، شروع پسوریازیس از هفته‌ها تا ماه‌ها پس از اولین دوز دوپیکسنت متفاوت بود و منجر به رفع نسبی یا کامل پسوریازیس با قطع دوپیلوماب، با یا بدون استفاده از درمان تکمیلی پسوریازیس (محلی یا سیستمیک) شد. کسانی که دوپیلوماب را ادامه دادند، درمان تکمیلی پسوریازیس را برای بهبود علائم مرتبط دریافت کردند. به بیماران توصیه کنید علائم پسوریازیس تازه شروع شده را به ارائه دهنده مراقبت های بهداشتی خود گزارش کنند. اگر علائم باقی ماند یا بدتر شد، ارزیابی پوست و/یا قطع دوپیکسنت را در نظر بگیرید.

5.8 آرترالژی و آرتریت پسوریاتیک آرترالژی با استفاده از DUPIXENT در برخی از بیماران گزارش شده است که اختلالات راه رفتن یا کاهش تحرک مرتبط با علائم مفصلی را گزارش کرده اند. برخی از موارد منجر به بستری شدن در بیمارستان شد [به واکنش های نامطلوب (6.1) مراجعه کنید]. در گزارش‌های پس از بازاریابی، شروع آرترالژی متغیر بود و از روزها تا ماه‌ها پس از اولین دوز دوپیکسنت متغیر بود. مواردی از آرتریت پسوریاتیک با شروع جدید که نیاز به درمان سیستمیک دارند با استفاده از DUPIXENT گزارش شده است. علائم برخی از بیماران با ادامه درمان با دوپیکسنت برطرف شد و سایر بیماران پس از قطع دوپیکسنت بهبود یافتند یا در حال بهبود بودند. به بیماران توصیه کنید که شروع جدید یا بدتر شدن علائم مفصلی را به ارائه دهنده مراقبت های بهداشتی خود گزارش دهند. اگر علائم باقی ماند یا بدتر شد، ارزیابی روماتولوژیک و/یا قطع دوپیکسنت را در نظر بگیرید.

5.9 عفونت های انگلی (Helminth) بیماران مبتلا به عفونت های کرمی شناخته شده از شرکت در مطالعات بالینی حذف شدند. مشخص نیست که آیا DUPIXENT بر پاسخ ایمنی در برابر عفونت های کرمی تأثیر می گذارد یا خیر. قبل از شروع درمان با دوپیکسنت، بیماران مبتلا به عفونت های کرمی از قبل موجود را درمان کنید. اگر بیماران در حین درمان با دوپیکسنت دچار عفونت شدند و به درمان ضد کرمی پاسخ ندادند، درمان با دوپیکسنت را تا رفع عفونت قطع کنید. واکنش های نامطلوب عفونت های کرمی (5 مورد انتروبیازیس و 1 مورد آسکاریازیس) در کودکان 6 تا 11 ساله که در برنامه توسعه آسم کودکان شرکت کرده بودند گزارش شد [به واکنش های جانبی (6.1) مراجعه کنید].

5.10 واکسیناسیون، قبل از شروع درمان با DUPIXENT، تمام واکسیناسیون های متناسب با سن را طبق دستورالعمل های ایمن سازی فعلی تکمیل کنید. در طول درمان با دوپیکسنت از استفاده از واکسن های زنده خودداری کنید. مشخص نیست که آیا تجویز واکسن های زنده در طول درمان با دوپیکسنت بر ایمنی یا اثربخشی این واکسن ها تأثیر می گذارد یا خیر. اطلاعات محدودی در مورد مصرف همزمان دوپیکسنت با واکسن های غیر زنده در دسترس است [به فارماکولوژی بالینی (12.2) مراجعه کنید].

عوارض جانبی قابل توجه بالینی زیر در جای دیگری در برچسب توضیح داده شده است: حساسیت مفرط [به هشدارها و اقدامات احتیاطی (5.1) مراجعه کنید] ورم ملتحمه و کراتیت [نگاه کنید به هشدارها و اقدامات احتیاطی (5.2)] پسوریازیس [نگاه کنید به هشدارها و اقدامات احتیاطی (5.7)] آرترالژی و آرتریت پسوریاتیک [نگاه کنید به هشدارها و اقدامات احتیاطی(5.8) [به هشدارها و اقدامات احتیاطی (5.9) مراجعه کنید] شایع‌ترین عوارض جانبی عبارتند از: درماتیت آتوپیک (شیوع ≥1%): واکنش های محل تزریق، ورم ملتحمه، بلفاریت، تبخال دهان، کراتیت، خارش چشم، سایر عفونت های ویروس هرپس سیمپلکس، خشکی چشم و ائوزینوفیلی. (6.1) آسم (شیوع ≥1%): واکنش های محل تزریق، درد اوروفارنکس و ائوزینوفیلی. ( 6.1 ) رینوسینوزیت مزمن با پولیپ بینی ( بروز ≥1 %): واکنش های محل تزریق، ائوزینوفیلی، بی خوابی، دندان درد، گاستریت، آرترالژی و ورم ملتحمه. (6.1) ازوفاژیت ائوزینوفیلیک (بروز ≥2%): واکنش‌های محل تزریق، عفونت‌های دستگاه تنفسی فوقانی، آرترالژی و عفونت‌های ویروسی تبخال. (6.1) Prurigo Nodularis (بروز ≥2%): نازوفارنژیت، ورم ملتحمه، عفونت تبخال، سرگیجه، میالژی، و اسهال. (6.1) بیماری انسدادی مزمن ریه (شیوع ≥2%): عفونت ویروسی، سردرد، نازوفارنژیت، کمردرد، اسهال، آرترالژی، عفونت دستگاه ادراری، واکنش های تجویز موضعی، رینیت، ائوزینوفیلی، دندان درد و گاستریت. (6.1) کهیر خودبخودی مزمن (بروز ≥2%): واکنش های محل تزریق. (6.1) پمفیگوئید بولوز (بروز ≥2%): آرترالژی، ورم ملتحمه، تاری دید، عفونت های ویروسی تبخال، کراتیت. ( 6.1 ) رینوسینوزیت قارچی آلرژیک: مشابه واکنش های نامطلوب برای رینوسینوزیت مزمن با پولیپ بینی. (6.1) برای گزارش واکنش‌های نامطلوب مشکوک، با Regeneron با شماره 1-844-387-4936 یا FDA به شماره 1-800-FDA-1088 یا www.fda.gov/medwatch تماس بگیرید.

6.1 Clinical Trials 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. Atopic Dermatitis Adults with Atopic Dermatitis Three randomized, double-blind, placebo-controlled, multicenter trials (SOLO 1, SOLO 2, and CHRONOS) and one dose-ranging trial (AD-1021) evaluated the safety of DUPIXENT in subjects with moderate-to-severe atopic dermatitis (AD) [see Clinical Studies (14.1) ] . In terms of co-morbid conditions, 48% of the subjects had asthma, 49% had allergic rhinitis, 37% had food allergy, and 27% had allergic conjunctivitis. In these 4 trials, 1472 subjects were treated with subcutaneous injections of DUPIXENT, with or without concomitant topical corticosteroids (TCS). A total of 739 subjects were treated with DUPIXENT for at least 1 year in the development program for moderate-to-severe AD. SOLO 1, SOLO 2, and AD-1021 compared the safety of DUPIXENT monotherapy to placebo through Week 16. CHRONOS compared the safety of DUPIXENT + TCS to placebo + TCS through Week 52. AD-1225 is a multicenter, open-label extension (OLE) trial which assessed the long-term safety of repeat doses of DUPIXENT through 260 weeks of treatment in adults with moderate-to-severe AD who had previously participated in controlled trials of DUPIXENT or had been screened for SOLO 1 or SOLO 2. The safety data in AD-1225 reflect exposure to DUPIXENT 200 mg QW, 300 mg QW and 300 mg Q2W in 2677 subjects, including 2254 exposed for at least 52 weeks, 1224 exposed for at least 100 weeks, 561 exposed for at least 148 weeks and 179 exposed for at least 260 weeks. Weeks 0 to 16 (SOLO 1, SOLO 2, CHRONOS, and AD-1021) In DUPIXENT monotherapy trials (SOLO 1, SOLO 2, and AD-1021) through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 1.9% in both the DUPIXENT 300 mg Q2W and placebo groups. Table 9 summarizes the adverse reactions that occurred at a rate of at least 1% in the DUPIXENT 300 mg Q2W monotherapy groups, and in the DUPIXENT + TCS group, all at a higher rate than in their respective comparator groups during the first 16 weeks of treatment. Table 9: Adverse Reactions Occurring in ≥1% of the DUPIXENT Monotherapy Group or the DUPIXENT + TCS Group in the Atopic Dermatitis Trials through Week 16 Adverse Reaction DUPIXENT Monotherapy Pooled analysis of SOLO 1, SOLO 2, and AD-1021. DUPIXENT + TCS Analysis of CHRONOS where subjects were on background TCS therapy. DUPIXENT 300 mg Q2W DUPIXENT 600 mg at Week 0, followed by 300 mg every 2 weeks. Placebo DUPIXENT 300 mg Q2W + TCS Placebo + TCS N=529 n (%) N=517 n (%) N=110 n (%) N=315 n (%) Injection site reaction 51 (10) 28 (5) 11 (10) 18 (6) Conjunctivitis Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation. 51 (10) 12 (2) 10 (9) 15 (5) Blepharitis 2 (<1) 1 (<1) 5 (5) 2 (1) Oral herpes 20 (4) 8 (2) 3 (3) 5 (2) Keratitis Keratitis cluster includes keratitis, ulcerative keratitis, allergic keratitis, atopic keratoconjunctivitis, and ophthalmic herpes simplex. 1 (<1) 0 4 (4) 0 Eye pruritus 3 (1) 1 (<1) 2 (2) 2 (1) Other herpes simplex virus infection Other herpes simplex virus infection cluster includes herpes simplex, genital herpes, herpes simplex otitis externa, and herpes virus infection, but excludes eczema herpeticum. 10 (2) 6 (1) 1 (1) 1 (<1) Dry eye 1 (<1) 0 2 (2) 1 (<1) Safety through Week 52 (CHRONOS) In the DUPIXENT with concomitant TCS trial (CHRONOS) through Week 52, the proportion of subjects who discontinued treatment because of adverse events was 1.8% in DUPIXENT 300 mg Q2W + TCS group and 7.6% in the placebo + TCS group. Two subjects discontinued DUPIXENT because of adverse reactions: atopic dermatitis (1 subject) and exfoliative dermatitis (1 subject). The safety profile of DUPIXENT + TCS through Week 52 was generally consistent with the safety profile observed at Week 16. Safety through 260 Weeks (AD-1225) The long-term safety profile observed in this trial through 260 weeks was generally consistent with the safety profile of DUPIXENT observed in controlled studies. Pediatric Subjects 12 Years of Age and Older with Atopic Dermatitis The safety of DUPIXENT was assessed in a trial of 250 pediatric subjects 12 years of age and older with moderate-to-severe AD (AD-1526). The safety profile of DUPIXENT in these subjects through Week 16 was similar to the safety profile seen in adults with AD. The long-term safety of DUPIXENT was assessed in an open-label extension study in pediatric subjects 12 years of age and older with moderate-to-severe AD (AD-1434). The safety profile of DUPIXENT in subjects followed through Week 52 was similar to the safety profile observed at Week 16 in AD-1526. The long-term safety profile of DUPIXENT observed in pediatric subjects 12 years of age and older was consistent with that seen in adults with AD. Pediatric Subjects 6 to 11 Years of Age with Atopic Dermatitis The safety of DUPIXENT with concomitant TCS was assessed in a trial of 367 pediatric subjects 6 to 11 years of age with severe AD (AD-1652). The safety profile of DUPIXENT + TCS in these subjects through Week 16 was similar to the safety profile from trials in adult and pediatric subjects 12 years of age and older with AD. The long-term safety of DUPIXENT ± TCS was assessed in an open-label extension study of 368 pediatric subjects 6 to 11 years of age with AD (AD-1434). Among subjects who entered this study, 110 (30%) had moderate and 72 (20%) had severe AD at the time of enrollment in AD-1434. The safety profile of DUPIXENT ± TCS in subjects followed through Week 52 was similar to the safety profile observed through Week 16 in AD-1652. The long-term safety profile of DUPIXENT ± TCS observed in pediatric subjects 6 to 11 years of age was consistent with that seen in adult and pediatric subjects 12 years of age and older with AD. Pediatric Subjects 6 Months to 5 Years of Age with Atopic Dermatitis The safety of DUPIXENT with concomitant TCS was assessed in a trial of 161 pediatric subjects 6 months to 5 years of age with moderate-to-severe AD (AD-1539). The safety profile of DUPIXENT + TCS in these subjects through Week 16 was similar to the safety profile from trials in adults and pediatric subjects 6 years of age and older with AD. The long-term safety of DUPIXENT ± TCS was assessed in an open-label extension study of 180 pediatric subjects 6 months to 5 years of age with AD (AD-1434). The majority of subjects were treated with DUPIXENT 300 mg every 4 weeks. The safety profile of DUPIXENT ± TCS in subjects followed through Week 52 was similar to the safety profile observed through Week 16 in AD-1539. The long-term safety profile of DUPIXENT ± TCS observed in pediatric subjects 6 months to 5 years of age was consistent with that seen in adults and pediatric subjects 6 years of age and older with AD. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects treated with DUPIXENT ± TCS. These cases did not lead to study drug discontinuation. Atopic Dermatitis with Hand and/or Foot Involvement The safety of DUPIXENT was assessed in a 16-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial (Liberty-AD-HAFT) in 133 adult and pediatric subjects 12 to 17 years of age with atopic dermatitis with moderate-to-severe hand and/or foot involvement [see Clinical Studies (14) ] . In this trial 67 subjects received DUPIXENT, and 66 subjects received placebo. DUPIXENT-treated subjects received the recommended dosage based on their age and body weight [see Dosage and Administration (2.3) ] . The safety profile of DUPIXENT in these subjects through Week 16 was consistent with the safety profile from studies in adult and pediatric subjects 6 months of age and older with moderate-to-severe AD. Asthma Adults and Pediatric Subjects 12 Years of Age and Older with Asthma A total of 2888 adult and pediatric subjects 12 to 17 years of age with moderate-to-severe asthma (AS) were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks duration (DRI12544, QUEST, and VENTURE). Of these, 2678 had a history of 1 or more severe exacerbations in the year prior to enrollment despite regular use of medium to high-dose inhaled corticosteroids plus an additional controller(s) (DRI12544 and QUEST). A total of 210 subjects with oral corticosteroid-dependent asthma receiving high-dose inhaled corticosteroids plus up to two additional controllers were enrolled (VENTURE). The safety population (DRI12544 and QUEST) was 12-87 years of age, of which 63% were female, and 82% were White. DUPIXENT 200 mg or 300 mg was administered subcutaneously Q2W, following an initial dose of 400 mg or 600 mg, respectively. In DRI12544 and QUEST, the proportion of subjects who discontinued treatment due to adverse events was 4% of the placebo group, 3% of the DUPIXENT 200 mg Q2W group, and 6% of the DUPIXENT 300 mg Q2W group. Table 10 summarizes the adverse reactions that occurred at a rate of at least 1% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator groups in DRI12544 and QUEST. Table 10: Adverse Reactions Occurring in ≥1% of Adult and Pediatric Subjects 12 Years of Age and Older with Asthma in the DUPIXENT Groups in DRI12544 and QUEST and Greater than Placebo (6 Month Safety Pool) Adverse Reaction DRI12544 and QUEST DUPIXENT 200 mg Q2W DUPIXENT 300 mg Q2W Placebo N=779 n (%) N=788 n (%) N=792 n (%) Injection site reactions Injection site reactions cluster includes erythema, edema, pruritus, pain, and inflammation. 111 (14%) 144 (18%) 50 (6%) Oropharyngeal pain 13 (2%) 19 (2%) 7 (1%) Eosinophilia Eosinophilia = blood eosinophils ≥3,000 cells/mcL or deemed by the investigator to be an adverse event. None met the criteria for serious eosinophilic conditions [see Warnings and Precautions (5.3) ] . 17 (2%) 16 (2%) 2 (<1%) Injection site reactions were most common with the loading (initial) dose. The safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24. Pediatric Subjects 6 to 11 Years of Age with Asthma The safety of DUPIXENT was assessed in 405 pediatric subjects 6 to 11 years of age with moderate-to-severe asthma (VOYAGE). The safety profile of DUPIXENT in these subjects through Week 52 was similar to the safety profile from studies in adult and pediatric subjects 12 years of age and older with moderate-to-severe asthma with the addition of helminth infections. Helminth infections were reported in 2.2% (6 subjects) in the DUPIXENT group and 0.7% (1 subject) in the placebo group. The majority of cases were enterobiasis, reported in 1.8% (5 subjects) in the DUPIXENT group and none in the placebo group. There was one case of ascariasis in the DUPIXENT group. All helminth infection cases were mild to moderate and subjects recovered with anti-helminth treatment without DUPIXENT treatment discontinuation. Chronic Rhinosinusitis with Nasal Polyps A total of 722 adult subjects with chronic rhinosinusitis with nasal polyps (CRSwNP) were evaluated in 2 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks duration (SINUS-24 and SINUS-52). The safety pool consisted of data from the first 24 weeks of treatment from both studies. In the safety pool, the proportion of adult subjects who discontinued treatment due to adverse events was 5% of the placebo group and 2% of the DUPIXENT 300 mg Q2W group. Table 11 summarizes the adverse reactions that occurred at a rate of at least 1% in adult subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in SINUS-24 and SINUS-52. Table 11: Adverse Reactions Occurring in ≥1% of Adult Subjects with CRSwNP in the DUPIXENT Group in SINUS-24 and SINUS-52 and Greater than Placebo (24-Week Safety Pool) Adverse Reaction SINUS-24 and SINUS-52 DUPIXENT 300 mg Q2W Placebo N=440 n (%) N=282 n (%) Injection site reactions Injection site reactions cluster includes injection site reaction, pain, bruising and swelling. 28 (6%) 12 (4%) Conjunctivitis Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation. 7 (2%) 2 (1%) Arthralgia 14 (3%) 5 (2%) Gastritis 7 (2%) 2 (1%) Insomnia 6 (1%) 0 (<1%) Eosinophilia 5 (1%) 1 (<1%) Toothache 5 (1%) 1 (<1%) The safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24. Eosinophilic Esophagitis Adults and Pediatric Subjects 12 Years of Age and Older with EoE A total of 239 adult and pediatric subjects 12 years of age and older, weighing at least 40 kg, with eosinophilic esophagitis (EoE) were evaluated in a randomized, double-blind, parallel-group, multicenter, placebo-controlled trial, including two 24-week treatment periods (Study EoE-1 Parts A and B) and received either DUPIXENT 300 mg QW or placebo [see Clinical Studies (14.4) ] . The proportion of subjects who discontinued treatment due to adverse events was 2% of the placebo group and 2% of the DUPIXENT 300 mg QW group. Table 12 summarizes the adverse reactions that occurred at a rate of at least 2% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in Parts A and B. Table 12: Adverse Reactions Occurring in ≥2% of Adult and Pediatric Subjects 12 Years of Age and Older with EoE Treated with DUPIXENT in a Placebo-Controlled Trial (Study EoE-1 Parts A and B; 24-Week Safety Pool) Study EoE-1 Parts A and B Adverse Reaction DUPIXENT 300 mg QW N=122 n (%) Placebo N=117 n (%) Injection site reactions Injection site reactions are composed of several terms including, but not limited to, injection site swelling, pain, and bruising. 46 (38%) 39 (33%) Upper respiratory tract infections Upper respiratory tract infections are composed of several terms including, but not limited to, COVID-19, sinusitis, and upper respiratory tract infection. 22 (18%) 12 (10%) Arthralgia 3 (2%) 1 (1%) Herpes viral infections Herpes viral infections are composed of oral herpes and herpes simplex. 3 (2%) 1 (1%) The safety profile of DUPIXENT in 72 pediatric subjects 12 to 17 years of age, weighing at least 40 kg, and adults in Parts A and B was similar. Pediatric Subjects 1 to 11 Years of Age, Weighing at least 15 kg, with EoE A total of 61 pediatric subjects 1 to 11 years of age, weighing at least 15 kg, with EoE were evaluated in a randomized, blinded, parallel-group, multicenter trial, including an initial 16-week placebo-controlled treatment period (Study EoE-2 Part A) and a 36-week extended active treatment period (Study EoE-2 Part B). Subjects in Part A received a weight-based dosing regimen of DUPIXENT or placebo [see Clinical Studies (14.4) ] . All subjects in Part B completed Part A and received active treatment with weight-based dosing regimens of DUPIXENT in Part B (N=47). The safety profile of DUPIXENT through Week 16 of Study EoE-2 Part A was generally similar to the safety profile in adult and pediatric subjects 12 years of age and older with EoE. In Part B, a helminth infection was reported in one DUPIXENT-treated subject. Prurigo Nodularis A total of 309 adult subjects with prurigo nodularis (PN) were evaluated in two 24-week randomized, double-blind, placebo-controlled, multicenter trials (PRIME and PRIME2) [see Clinical Studies (14.5) ] . The safety pool included data from the 24-week treatment and 12-week follow-up periods from both trials. The proportion of subjects who discontinued treatment due to adverse events was 3% of the placebo group and 0% of the DUPIXENT 300 mg Q2W group. Subjects with co-morbid conditions included 43% of subjects with a history of atopy (defined as having a medical history of AD, allergic rhinitis/rhino conjunctivitis, asthma, or food allergy), 8% of subjects with a history of hypothyroidism and 9% of subjects with a history of diabetes mellitus type 2. Table 13 summarizes the adverse reactions that occurred at a rate of at least 2% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in PRIME and PRIME2. Table 13: Adverse Reactions Occurring in ≥2% of Adult Subjects with PN in the DUPIXENT Group in PRIME and PRIME2 and Greater than Placebo Adverse Reaction PRIME and PRIME2 DUPIXENT 300 mg Q2W Placebo N=152 n (%) N=157 n (%) Nasopharyngitis Nasopharyngitis includes pharyngitis 8 (5%) 3 (2%) Conjunctivitis Conjunctivitis includes conjunctivitis and allergic conjunctivitis. 6 (4%) 2 (1%) Herpes Infection Herpes infection includes oral herpes, genital herpes simplex, herpes zoster and ophthalmic herpes zoster 5 (3%) 0% Dizziness Dizziness includes dizziness postural, vertigo and vertigo positional 5 (3%) 2 (1%) Myalgia Myalgia includes musculoskeletal pain and musculoskeletal chest pain 5 (3%) 2 (1%) Diarrhea 4 (3%) 1 (1%) Chronic Obstructive Pulmonary Disease A total of 1874 adult subjects with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype were evaluated in two randomized, double-blind, multicenter, parallel-group, placebo-controlled trials with a 52-week treatment period (BOREAS and NOTUS) [see Clinical Studies (14.6) ] . Of those randomized, 1872 subjects received at least one dose of DUPIXENT 300 mg or placebo subcutaneously every 2 weeks (Q2W). The safety of DUPIXENT was assessed in the pooled safety population from BOREAS and NOTUS, which consisted of 938 adult subjects treated with DUPIXENT. Of the subjects treated with DUPIXENT, 98% utilized inhaled triple therapy at baseline (comprising of an inhaled corticosteroid, long-acting beta-agonist, and long-acting muscarinic antagonist), and 97% had chronic bronchitis. Table 14 summarizes the adverse reactions that occurred in at least 2% of subjects treated with DUPIXENT and at a higher rate than placebo in BOREAS and NOTUS trials. Table 14: Adverse Reactions That Occurred in ≥2% of Adult Subjects with COPD Treated with DUPIXENT in BOREAS and NOTUS Trials (Pooled Safety Population) and Greater than Placebo Adverse Reaction BOREAS and NOTUS DUPIXENT 300 mg Q2W Placebo N=938 n (%) N=934 n (%) Viral Infection Consists of multiple similar terms. 133 (14.2) 115 (12.3) Headache 73 (7.8) 62 (6.6) Nasopharyngitis 73 (7.8) 69 (7.4) Back Pain 42 (4.5) 29 (3.1) Diarrhea 35 (3.7) 30 (3.2) Arthralgia 29 (3.1) 25 (2.7) Urinary Tract Infection 28 (3.0) 18 (1.9) Local Administration Reaction 26 (2.8) 6 (0.6) Injection Site Reaction 11 (1.2) 2 (0.2) Rhinitis 24 (2.6) 17 (1.8) Eosinophilia Eosinophilia was defined as blood eosinophils ≥3,000 cells/mcL or deemed by the investigator to be an adverse event. None met the criteria for serious eosinophilic conditions. 22 (2.3) 7 (0.7) Toothache 20 (2.1) 11 (1.2) Gastritis 19 (2) 7 (0.7) Less Common Adverse Reaction in Subjects with COPD: Cholecystitis In adult subjects with COPD, cholecystitis was reported in 6 subjects (0.6%) in the DUPIXENT group compared to 1 subject (0.1%) in the placebo group. Among these subjects, serious cholecystitis was reported in 4 (0.4%) of the DUPIXENT group compared with 0% of the placebo group. Chronic Spontaneous Urticaria Adults and Pediatric Subjects 12 Years of Age and Older with CSU The pooled safety data below reflects the safety of DUPIXENT in adult and pediatric subjects 12 years of age and older with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment. A total of 392 adult and pediatric subjects 12 years of age and older with CSU were evaluated for safety in three randomized, double-blind, parallel-group, multicenter, placebo-controlled, studies, Study A, B, and C, conducted under a master protocol (CUPID) for 36 weeks [see Clinical Studies (14.7) ] . The pooled safety population received an initial dose of DUPIXENT 600 mg or 400 mg, followed by DUPIXENT 300 mg or 200 mg, respectively, or matching placebo, administered subcutaneously every 2 weeks (Q2W) [see Dosage and Administration (2.9) ] . Table 15 summarizes the adverse reactions that occurred in at least 2% in subjects treated with DUPIXENT and at a higher rate than placebo in CUPID Study A, B and C (pooled safety population). Table 15: Adverse Reactions That Occurred in ≥2% of Adult and Pediatric Subjects 12 Years of Age and Older with CSU Treated with DUPIXENT in CUPID Study A, B, and C (Pooled Safety Population) and Greater than Placebo Adverse Reaction CUPID Study A, B, and C DUPIXENT 200 mg Q2W or 300 mg Q2W Placebo N=195 n (%) N=197 n (%) Injection site reactions Injection site reactions cluster includes injection site dermatitis, injection site erythema, injection site hematoma, injection site induration, injection site pain, injection site pruritus, injection site reaction, injection site swelling 20 (10.3) 16 (8.1) Pediatric Subjects 2 to 11 Years of Age with CSU The safety of DUPIXENT was assessed in 18 subjects 2 to 11 years of age who received DUPIXENT based on weight [see Dosage and Administration (2.9) and Use in Specific Populations (8.4) ] . No new adverse reactions were identified in pediatric subjects aged 2 to 11 years who received DUPIXENT. Bullous Pemphigoid The safety of DUPIXENT was evaluated in a 52-week, randomized, double-blind, parallel-group, multicenter, placebo-controlled trial (ADEPT) in a total of 106 adult subjects with moderate-to-severe bullous pemphigoid (BP) [see Clinical Studies (14.8) ] . Of the 106 randomized subjects, all received at least one dose of DUPIXENT or placebo with a course of oral corticosteroids (OCS) with a prespecified taper. At the time of analysis, 87 subjects had completed Week 36 and 65 subjects had completed Week 52. Table 16 summarizes the adverse reactions that occurred in at least 2% of subjects treated with DUPIXENT and at a higher rate than placebo in the ADEPT trial. Table 16: Adverse Reactions Occurring in ≥2% of Adult Subjects with BP Treated with DUPIXENT in ADEPT and Greater than Placebo In combination with a tapering course of oral corticosteroids Adverse Reaction ADEPT DUPIXENT 300 mg Q2W + OCS Placebo + OCS N=53 n (%) N=53 n (%) Arthralgia 5 (9%) 3 (6%) Conjunctivitis 4 (8%) 0% Vision blurred 4 (8%) 0% Herpes viral infections Herpes viral infections include herpes simplex and herpes zoster 3 (6%) 0% Keratitis 2 (4%) 0% A case of AGEP was reported in 1 subject with BP treated with DUPIXENT compared with 0 subjects in the placebo group. Allergic Fungal Rhinosinusitis Adults and Pediatric Subjects 6 Years of Age and Older with AFRS A total of 62 adult and pediatric subjects 6 years of age and older with allergic fungal rhinosinusitis (AFRS) were evaluated in a randomized, double-blind, parallel-group, placebo-controlled trial (AIMS) with a 52-week treatment period [see Clinical Studies (14.9) ] . The adult subjects (n=30) received DUPIXENT 300 mg every 2 weeks and pediatric subjects aged 6 to 17 years (n=3) received DUPIXENT based on body weight [see Dosage and Administration (2.11) ] . The safety profile of DUPIXENT in patients with AFRS was similar to the safety profile of DUPIXENT in patients with CRSwNP (see Chronic Rhinosinusitis with Nasal Polyps ). Specific Adverse Reactions for AD, Asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS Conjunctivitis and Keratitis In adult subjects with AD, conjunctivitis was reported in 10% (34 per 100 patient-years) in the 300 mg Q2W dose group and in 2% of the placebo group (8 per 100 patient-years) during the 16-week treatment period of the monotherapy trials (SOLO 1, SOLO 2, and AD-1021). During the 52-week treatment period of concomitant therapy AD trial (CHRONOS), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 patient-years) and in 9% of the placebo + TCS group (10 per 100 patient-years). During the long-term OLE trial with data through 260 weeks (AD-1225), conjunctivitis was reported in 21% of the DUPIXENT group (12 per 100 patient-years). In DUPIXENT AD monotherapy trials (SOLO 1, SOLO 2, and AD-1021) through Week 16, keratitis was reported in <1% of the DUPIXENT group (1 per 100 patient-years) and in 0% of the placebo group (0 per 100 patient-years). In the 52-week DUPIXENT + topical corticosteroids (TCS) AD trial (CHRONOS), keratitis was reported in 4% of the DUPIXENT + TCS group (4 per 100 patient-years) and in 2% of the placebo + TCS group (2 per 100 patient-years). Conjunctivitis and keratitis occurred more frequently in AD subjects who received DUPIXENT. Conjunctivitis was the most frequently reported eye disorder. During the long-term OLE trial with data through 260 weeks (AD-1225), keratitis was reported in 3% of the DUPIXENT group (1 per 100 patient-years). Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period. Among subjects with asthma, the frequency of conjunctivitis and keratitis was similar between DUPIXENT and placebo. In adult subjects with CRSwNP, the frequency of conjunctivitis was 2% in the DUPIXENT group compared to 1% in the placebo group in the 24-week safety pool; these subjects recovered. In the 52-week CRSwNP study (SINUS-52), the frequency of conjunctivitis was 3% in the DUPIXENT adult subjects and 1% in the placebo subjects; all of these subjects recovered. Among subjects with EoE, there were no reports of conjunctivitis and keratitis in the DUPIXENT group in placebo-controlled trials. In the 36-week active treatment extension period of Study EoE-2 Part B, conjunctivitis was reported in 4% of DUPIXENT-treated pediatric subjects with EoE. Among subjects with PN, the frequency of conjunctivitis was 4% in the DUPIXENT group compared to 1% in the placebo group; all of these subjects recovered or were recovering during the treatment period. Among subjects with COPD, the frequency of conjunctivitis and keratitis was 1.4% and 0.1% in the DUPIXENT group and 1% and 0% in the placebo group, respectively. Among subjects with CSU in the pooled safety population, the frequency of conjunctivitis was similar between DUPIXENT and placebo. Among subjects with BP, the frequency of conjunctivitis and keratitis was 8% and 4% in the DUPIXENT group and 0% and 0% in the placebo group, respectively. Eczema Herpeticum and Herpes Zoster The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the AD trials. The rates remained stable through 260 weeks in the long-term OLE trial (AD-1225). Herpes zoster was reported in <1% of the DUPIXENT groups (1 per 100 patient-years) and in <1% of the placebo group (1 per 100 patient-years) in the 16-week AD monotherapy trials. In the 52-week DUPIXENT + TCS AD trial, herpes zoster was reported in 1% of the DUPIXENT + TCS group (1 per 100 patient-years) and 2% of the placebo + TCS group (2 per 100 patient-years). During the long-term OLE trial with data through 260 weeks (AD-1225), 2.0% of DUPIXENT-treated subjects reported herpes zoster (0.94 per 100 patient-years of follow up). Among asthma subjects the frequency of herpes zoster was similar between DUPIXENT and placebo. Among subjects with CRSwNP or EoE there were no reported cases of herpes zoster or eczema herpeticum. Among subjects with PN, herpes zoster and ophthalmic herpes zoster were each reported in <1% of the DUPIXENT group (1 per 100 patient-years) and 0% of the placebo group. Among subjects with COPD, herpes zoster was reported in 0.9% of the DUPIXENT group and 0.2% of the placebo group. Ophthalmic herpes zoster was reported in 0.1% of the DUPIXENT group and 0.2% of the placebo group. Among subjects with CSU in the pooled safety population, herpes zoster was reported in <1% of the DUPIXENT and placebo groups (1 per 100 patient-years). Among subjects with …

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DUPIXENT during pregnancy. Risk Summary Available data from case reports and case series with DUPIXENT use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, DUPIXENT may be transmitted from the mother to the developing fetus. There are adverse effects on maternal and fetal outcomes associated with asthma in pregnancy ( see Clinical Considerations ). In an enhanced pre- and post-natal developmental study, no adverse developmental effects were observed in offspring born to pregnant monkeys after subcutaneous administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα) during organogenesis through parturition at doses up to 10-times the maximum recommended human dose (MRHD) ( see Data ) . The background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-fetal Risk In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control. Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Therefore, DUPIXENT may be present in infants exposed in utero . The potential clinical impact of dupilumab exposure in infants exposed in utero should be considered. Data Animal Data In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of homologous antibody against IL-4Rα up to 10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from the beginning of organogenesis to parturition. No treatment-related adverse effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age.

8.2 Lactation Risk Summary There are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure to dupilumab on the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DUPIXENT and any potential adverse effects on the breastfed child from DUPIXENT or from the underlying maternal condition.

8.4 Pediatric Use Atopic Dermatitis The safety and effectiveness of DUPIXENT have been established in pediatric patients 6 months of age and older with moderate-to-severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Use of DUPIXENT in this age group is supported by data from the following clinical trials: AD-1526 which included 251 pediatric subjects 12 years of age and older with moderate-to-severe AD. Of the 251 subjects, 82 were treated with DUPIXENT 200 mg Q2W (<60 kg) or 300 mg Q2W (≥60 kg) and 85 were treated with matching placebo AD-1652 which included 367 pediatric subjects 6 to 11 years of age with severe AD. Of the 367 subjects, 120 were treated with DUPIXENT 300 mg Q4W + TCS (15 to <30 kg) or 200 mg Q2W + TCS (≥30 kg) and 123 were treated with matching placebo + TCS AD-1539 which included 162 pediatric subjects 6 months to 5 years of age with moderate-to-severe AD. Of the 162 subjects, 83 were treated with DUPIXENT 200 mg Q4W + TCS (5 to <15 kg) or 300 mg Q4W + TCS (15 to <30 kg) and 79 subjects were assigned to be treated with matching placebo + TCS AD-1434, an open-label extension study that enrolled 275 pediatric subjects 12 years of age and older treated with DUPIXENT ± TCS, 368 pediatric subjects 6 to 11 years of age treated with DUPIXENT ± TCS, and 180 pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS Liberty-AD-HAFT which included 27 pediatric subjects 12 years of age and older with atopic dermatitis with moderate-to-severe hand and/or foot involvement treated with DUPIXENT (N=14) or matching placebo (N=13) The safety and effectiveness were generally consistent between pediatric and adult patients. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS in AD-1434. These cases did not lead to study drug discontinuation [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 6 months of age with AD. Asthma The safety and effectiveness of DUPIXENT for an add-on maintenance treatment in patients with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma have been established in pediatric patients 6 years of age and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients 6 years and older [see Clinical Studies (14.2)] . Pediatric Subjects 12 to 17 Years of Age : A total of 107 pediatric subjects 12 to 17 years of age with moderate-to-severe asthma were enrolled in QUEST and received either 200 mg (N=21) or 300 mg (N=18) DUPIXENT (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) Q2W. Asthma exacerbations and lung function were assessed in both pediatric subjects 12 to 17 years of age and adults. For both the 200 mg and 300 mg Q2W doses, improvements in FEV 1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults. Dupilumab exposure was higher in pediatric subjects 12 to 17 years of age than that in adults at the respective dose level which was mainly accounted for by difference in body weight [see Clinical Pharmacology (12.3) ] . The adverse event profile in pediatric subjects 12 to 17 years of age was generally similar to the adults [see Adverse Reactions (6.1) ] . Pediatric Subjects 6 to 11 Years of Age : A total of 408 pediatric subjects 6 to 11 years of age with moderate-to-severe asthma were enrolled in VOYAGE, which evaluated doses of 100 mg Q2W or 200 mg Q2W. Improvement in asthma exacerbations and lung function were demonstrated [see Clinical Studies (14.2) ] . The effectiveness of DUPIXENT 300 mg Q4W in subjects 6 to 11 years of age with body weight 15 to <30 kg was extrapolated from efficacy of 100 mg Q2W in VOYAGE with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W [see Clinical Pharmacology (12.3) ] . Subjects who completed the treatment period of the VOYAGE study could participate in the open-label extension study (LTS14424). Eighteen subjects (≥15 to <30 kg) out of 365 subjects were exposed to 300 mg Q4W in this study, and the safety profile in these eighteen subjects was consistent with that seen in VOYAGE. Additional safety for DUPIXENT 300 mg Q4W is based upon available safety information from the pediatric AD indication [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 6 years of age with asthma. CRSwNP The safety and effectiveness of DUPIXENT for add-on maintenance treatment in patients with inadequately controlled CRSwNP have been established in pediatric patients aged 12 years and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies of DUPIXENT as add-on maintenance treatment in adults with inadequately controlled CRSwNP (SINUS-24 and SINUS-52) with the following additional data: Pharmacokinetic (PK) data from adult and pediatric patients aged 12 years and older with moderate-to-severe asthma and adult patients with inadequately controlled CRSwNP Safety data in pediatric patients aged 12 years and older with moderate-to-severe asthma [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ] Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 12 years of age with CRSwNP. EoE The safety and effectiveness of DUPIXENT for the treatment of EoE have been established in pediatric subjects 1 year of age and older, weighing at least 15 kg. Use of DUPIXENT in this population is supported by an adequate well-controlled study in adults and 72 pediatric subjects 12 to 17 years of age (Study EoE-1), a clinical study in 61 pediatric subjects 1 to 11 years of age (Study EoE-2), and pharmacokinetic data in adult and pediatric subjects 1 to 17 years of age. The safety of DUPIXENT in pediatric subjects 1 to 17 years of age was similar to adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.4) ] . Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 1 year of age, or weighing less than 15 kg, with EoE. Prurigo Nodularis Safety and effectiveness of DUPIXENT have not been established in pediatric patients with PN. Chronic Obstructive Pulmonary Disease The safety and effectiveness of DUPIXENT have not been established in pediatric patients with COPD. COPD is largely a disease of adult patients. Chronic Spontaneous Urticaria The safety and effectiveness of DUPIXENT for the treatment of CSU in patients who remain symptomatic despite H1 antihistamine treatment have been established in pediatric patients 2 years of age and older. Use of DUPIXENT in this indication is supported by evidence from two adequate and well-controlled studies in adults and pediatric patients aged 12 years and older [see Clinical Studies (14.7) ] with the following additional data: Pharmacokinetic (PK) data in 6 pediatric patients 12 to 17 years of age, PK data in 18 pediatric patients 2 to 11 years of age, and safety data in pediatric patients in other indications [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 2 years of age, and/or weighing less than 5 kg, with CSU. Bullous Pemphigoid The safety and effectiveness of DUPIXENT have not been established in pediatric patients with BP. BP is largely a disease of adult patients. Allergic Fungal Rhinosinusitis The safety and effectiveness of DUPIXENT for the treatment of AFRS in patients who have a history of sino-nasal surgery have been established in pediatric patients 6 years of age and older. Use of DUPIXENT in this indication is supported by evidence from an adequate and well-controlled study (AIMS) in adults and pediatric patients aged 12 years and older [see Clinical Studies (14.9) ] , with the following additional data: Pharmacokinetic (PK) data in 3 pediatric patients 12 years of age and older with AFRS [see Clinical Pharmacology (12.3) ] PK and safety data in pediatric patients 6 years to 11 years of age in other indications. [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] Safety and effectiveness in pediatric patients younger than 6 years of age with AFRS have not been established.

8.5 Geriatric Use Of the 1539 subjects with AD exposed to DUPIXENT in a dose-ranging study and placebo-controlled trials, 70 subjects were 65 years or older. Clinical trials of DUPIXENT in AD did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1977 subjects with asthma exposed to DUPIXENT, a total of 240 subjects were 65 years or older. Efficacy and safety in this age group were similar to the overall study population. Of the 440 subjects with CRSwNP exposed to DUPIXENT, a total of 79 subjects were 65 years or older. Efficacy and safety in this age group were similar to the overall study population. Clinical studies of DUPIXENT in EoE did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger adult subjects. Of the 152 subjects with PN exposed to DUPIXENT, a total of 37 were 65 years or older including 8 subjects 75 years or older. Clinical trials did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects. Of the 1874 subjects with COPD randomized in clinical trials of DUPIXENT, a total of 1072 were 65 years or older, while 244 subjects were 75 years or older. No overall differences in safety or effectiveness of DUPIXENT have been observed between subjects 65 years of age and older and younger adult subjects. Of the 198 subjects with CSU exposed to DUPIXENT, a total of 30 subjects were 65 years or older, including 7 subjects 75 years or older. Efficacy and safety in subjects 65 years or older were similar to the overall study population. Of the 53 subjects with BP exposed to DUPIXENT, a total of 40 were 65 years or older, including 22 subjects 75 years or older. Ten percent of subjects aged 65 years and older treated with DUPIXENT had an adverse reaction of vision blurred compared to zero in younger adult subjects. Clinical studies of DUPIXENT in AFRS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Atopic Dermatitis The safety and effectiveness of DUPIXENT have been established in pediatric patients 6 months of age and older with moderate-to-severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Use of DUPIXENT in this age group is supported by data from the following clinical trials: AD-1526 which included 251 pediatric subjects 12 years of age and older with moderate-to-severe AD. Of the 251 subjects, 82 were treated with DUPIXENT 200 mg Q2W (<60 kg) or 300 mg Q2W (≥60 kg) and 85 were treated with matching placebo AD-1652 which included 367 pediatric subjects 6 to 11 years of age with severe AD. Of the 367 subjects, 120 were treated with DUPIXENT 300 mg Q4W + TCS (15 to <30 kg) or 200 mg Q2W + TCS (≥30 kg) and 123 were treated with matching placebo + TCS AD-1539 which included 162 pediatric subjects 6 months to 5 years of age with moderate-to-severe AD. Of the 162 subjects, 83 were treated with DUPIXENT 200 mg Q4W + TCS (5 to <15 kg) or 300 mg Q4W + TCS (15 to <30 kg) and 79 subjects were assigned to be treated with matching placebo + TCS AD-1434, an open-label extension study that enrolled 275 pediatric subjects 12 years of age and older treated with DUPIXENT ± TCS, 368 pediatric subjects 6 to 11 years of age treated with DUPIXENT ± TCS, and 180 pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS Liberty-AD-HAFT which included 27 pediatric subjects 12 years of age and older with atopic dermatitis with moderate-to-severe hand and/or foot involvement treated with DUPIXENT (N=14) or matching placebo (N=13) The safety and effectiveness were generally consistent between pediatric and adult patients. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS in AD-1434. These cases did not lead to study drug discontinuation [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 6 months of age with AD. Asthma The safety and effectiveness of DUPIXENT for an add-on maintenance treatment in patients with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma have been established in pediatric patients 6 years of age and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients 6 years and older [see Clinical Studies (14.2)] . Pediatric Subjects 12 to 17 Years of Age : A total of 107 pediatric subjects 12 to 17 years of age with moderate-to-severe asthma were enrolled in QUEST and received either 200 mg (N=21) or 300 mg (N=18) DUPIXENT (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) Q2W. Asthma exacerbations and lung function were assessed in both pediatric subjects 12 to 17 years of age and adults. For both the 200 mg and 300 mg Q2W doses, improvements in FEV 1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults. Dupilumab exposure was higher in pediatric subjects 12 to 17 years of age than that in adults at the respective dose level which was mainly accounted for by difference in body weight [see Clinical Pharmacology (12.3) ] . The adverse event profile in pediatric subjects 12 to 17 years of age was generally similar to the adults [see Adverse Reactions (6.1) ] . Pediatric Subjects 6 to 11 Years of Age : A total of 408 pediatric subjects 6 to 11 years of age with moderate-to-severe asthma were enrolled in VOYAGE, which evaluated doses of 100 mg Q2W or 200 mg Q2W. Improvement in asthma exacerbations and lung function were demonstrated [see Clinical Studies (14.2) ] . The effectiveness of DUPIXENT 300 mg Q4W in subjects 6 to 11 years of age with body weight 15 to <30 kg was extrapolated from efficacy of 100 mg Q2W in VOYAGE with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W [see Clinical Pharmacology (12.3) ] . Subjects who completed the treatment period of the VOYAGE study could participate in the open-label extension study (LTS14424). Eighteen subjects (≥15 to <30 kg) out of 365 subjects were exposed to 300 mg Q4W in this study, and the safety profile in these eighteen subjects was consistent with that seen in VOYAGE. Additional safety for DUPIXENT 300 mg Q4W is based upon available safety information from the pediatric AD indication [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 6 years of age with asthma. CRSwNP The safety and effectiveness of DUPIXENT for add-on maintenance treatment in patients with inadequately controlled CRSwNP have been established in pediatric patients aged 12 years and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies of DUPIXENT as add-on maintenance treatment in adults with inadequately controlled CRSwNP (SINUS-24 and SINUS-52) with the following additional data: Pharmacokinetic (PK) data from adult and pediatric patients aged 12 years and older with moderate-to-severe asthma and adult patients with inadequately controlled CRSwNP Safety data in pediatric patients aged 12 years and older with moderate-to-severe asthma [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ] Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 12 years of age with CRSwNP. EoE The safety and effectiveness of DUPIXENT for the treatment of EoE have been established in pediatric subjects 1 year of age and older, weighing at least 15 kg. Use of DUPIXENT in this population is supported by an adequate well-controlled study in adults and 72 pediatric subjects 12 to 17 years of age (Study EoE-1), a clinical study in 61 pediatric subjects 1 to 11 years of age (Study EoE-2), and pharmacokinetic data in adult and pediatric subjects 1 to 17 years of age. The safety of DUPIXENT in pediatric subjects 1 to 17 years of age was similar to adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.4) ] . Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 1 year of age, or weighing less than 15 kg, with EoE. Prurigo Nodularis Safety and effectiveness of DUPIXENT have not been established in pediatric patients with PN. Chronic Obstructive Pulmonary Disease The safety and effectiveness of DUPIXENT have not been established in pediatric patients with COPD. COPD is largely a disease of adult patients. Chronic Spontaneous Urticaria The safety and effectiveness of DUPIXENT for the treatment of CSU in patients who remain symptomatic despite H1 antihistamine treatment have been established in pediatric patients 2 years of age and older. Use of DUPIXENT in this indication is supported by evidence from two adequate and well-controlled studies in adults and pediatric patients aged 12 years and older [see Clinical Studies (14.7) ] with the following additional data: Pharmacokinetic (PK) data in 6 pediatric patients 12 to 17 years of age, PK data in 18 pediatric patients 2 to 11 years of age, and safety data in pediatric patients in other indications [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 2 years of age, and/or weighing less than 5 kg, with CSU. Bullous Pemphigoid The safety and effectiveness of DUPIXENT have not been established in pediatric patients with BP. BP is largely a disease of adult patients. Allergic Fungal Rhinosinusitis The safety and effectiveness of DUPIXENT for the treatment of AFRS in patients who have a history of sino-nasal surgery have been established in pediatric patients 6 years of age and older. Use of DUPIXENT in this indication is supported by evidence from an adequate and well-controlled study (AIMS) in adults and pediatric patients aged 12 years and older [see Clinical Studies (14.9) ] , with the following additional data: Pharmacokinetic (PK) data in 3 pediatric patients 12 years of age and older with AFRS [see Clinical Pharmacology (12.3) ] PK and safety data in pediatric patients 6 years to 11 years of age in other indications. [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] Safety and effectiveness in pediatric patients younger than 6 years of age with AFRS have not been established.

12.1 مکانیسم اثر Dupilumab یک آنتی بادی مونوکلونال IgG4 انسانی است که سیگنال دهی اینترلوکین-4 (IL-4) و اینترلوکین-13 (IL-13) را با اتصال خاص به زیرواحد IL-4Rα مشترک توسط مجتمع های گیرنده IL-4 و IL-13 مهار می کند. دوپیلوماب سیگنال دهی IL-4 را از طریق گیرنده نوع I و هر دو سیگنالینگ IL-4 و IL-13 از طریق گیرنده نوع II را مهار می کند. التهاب ناشی از IL-4 و IL-13 یک جزء مهم در پاتوژنز آسم، AD، CRSwNP، EoE، PN، COPD، CSU، BP، و AFRS است. انواع سلول های متعددی که IL-4Rα را بیان می کنند (مانند ماست سل ها، بازوفیل ها، ائوزینوفیل ها، ماکروفاژها، لنفوسیت ها، سلول های اپیتلیال، سلول های جامی) و واسطه های التهابی (مانند هیستامین، ایکوزانوئیدها، لکوترین ها، سیتوکین ها) در التهاب نقش دارند. مسدود کردن IL-4Rα با دوپیلوماب، پاسخ‌های التهابی ناشی از سیتوکین‌های IL-4 و IL-13، از جمله آزادسازی سیتوکین‌های پیش التهابی، کموکاین‌ها، اکسید نیتریک و IgE را مهار می‌کند. مکانیسم اثر دوپیلوماب به طور قطعی مشخص نشده است.

12.2 Pharmacodynamics Consistent with inhibition of IL-4 and IL-13 signaling, dupilumab treatment decreased certain biomarkers of inflammation. In asthma subjects, fractional exhaled nitric oxide (FeNO) and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin were decreased relative to placebo. Reductions in these biomarkers were comparable for the 300 mg Q2W and 200 mg Q2W regimens. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment. The median percent reduction from baseline in total IgE concentrations with dupilumab treatments was 52% at Week 24 (DRI12544) and 70% at Week 52 (QUEST). For FeNO, the mean percent reduction from baseline at Week 2 was 35% and 24% in DRI12544 and QUEST, respectively, and in the overall safety population, the mean FeNO level decreased to 20 ppb. A continuous decline in total IgE in serum was observed in CSU trials. In AFRS subjects, total IgE concentrations showed a progressive decline with dupilumab treatment throughout the 52-week treatment period. Antibody Response to Non-Live Vaccines During DUPIXENT Treatment In a clinical study, adult subjects with AD were treated once weekly for 16 weeks with 300 mg of DUPIXENT (twice the recommended dosing frequency). After 12 weeks of administration, subjects received a Tdap vaccine and a meningococcal polysaccharide vaccine. Antibody responses to tetanus toxoid and serogroup C meningococcal polysaccharide were assessed 4 weeks later. Antibody responses to both tetanus toxoid and serogroup C meningococcal polysaccharide were similar in DUPIXENT-treated and placebo-treated subjects. Antibody responses to the other active components of both vaccines were not assessed. Antibody responses to other non-live vaccines were also not assessed.

12.3 Pharmacokinetics The pharmacokinetics of dupilumab is similar in subjects with AD, asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS. Absorption Following an initial subcutaneous (SC) dose of 600 mg, 400 mg, or 300 mg, dupilumab reached peak mean ± SD concentrations (C max ) of 70.1±24.1 mcg/mL, 41.8±12.4 mcg/mL, or 30.5±9.39 mcg/mL, respectively, by approximately 1 week post dose. Steady-state concentrations were achieved by Week 16 following the administration of 600 mg starting dose and 300 mg dose either weekly or Q2W, or 400 mg starting dose and 200 mg dose Q2W, or 300 mg Q2W without a loading dose. Across clinical trials, the mean ± SD steady-state trough concentrations ranged from 55.3±34.3 mcg/mL to 80.2±35.3 mcg/mL for 300 mg administered Q2W, from 173±75.9 mcg/mL to 195±71.7 mcg/mL for 300 mg administered weekly, and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg administered Q2W. The bioavailability of dupilumab following a SC dose is similar between AD, asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS subjects, ranging between 61% and 66%. Distribution The estimated total volume of distribution was approximately 4.8±1.3 L. Elimination The metabolic pathway of dupilumab has not been characterized. As a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. After the last steady-state dose of 300 mg QW, 300 mg Q2W, 200 mg Q2W, 300 mg Q4W, or 200 mg Q4W dupilumab, the median times to non-detectable concentration (<78 ng/mL) ranged from 9 to 13 weeks in adults and pediatric subjects 12 years of age and older. Population pharmacokinetic analyses indicate the median times to non-detectable concentration are approximately 1.5 times (up to 19 weeks) and 2.5 times (up to 32 weeks) longer in pediatric subjects 6 to 11 years of age and pediatric subjects 6 months to 5 years of age, respectively. Dose Linearity Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures increasing in a greater than dose-proportional manner. The systemic exposure increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 75 mg to 600 mg (i.e., 0.25-times to 2-times the recommended dose). Weight Dupilumab trough concentrations were lower in subjects with higher body weight. Immunogenicity Development of antibodies to dupilumab was associated with lower serum dupilumab concentrations. A few subjects who had high antibody titers also had no detectable serum dupilumab concentrations. Specific Populations Age Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and in pediatric subjects 6 to 17 years of age. In pediatric subjects 6 months to 5 years of age, clearance increased with age. Geriatric Patients No overall differences in the pharmacokinetics of dupilumab were observed between elderly and younger adult subjects. Pediatric Patients Atopic Dermatitis For pediatric subjects 12 years of age and older with AD receiving every 2 week dosing (Q2W) with either 200 mg (<60 kg) or 300 mg (≥60 kg), the mean ± SD steady-state trough concentration of dupilumab was 54.5±27.0 mcg/mL. For pediatric subjects 6 to 11 years of age with AD receiving every 2 week dosing (Q2W) with 200 mg (≥30 kg) or every 4 week dosing (Q4W) with 300 mg (<30 kg), mean ± SD steady-state trough concentration was 86.0±34.6 mcg/mL and 98.7±33.2 mcg/mL, respectively. For pediatric subjects 6 months to 5 years of age with AD receiving every 4 week dosing (Q4W) with 300 mg (≥15 to <30 kg) or 200 mg (≥5 to <15 kg), the mean ± SD steady-state trough concentration was 110±42.8 mcg/mL and 109±50.8 mcg/mL, respectively. Asthma A total of 107 pediatric subjects 12 to 17 years of age with asthma were enrolled in QUEST. The mean ± SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9 mcg/mL, respectively, for 300 mg or 200 mg administered Q2W. In VOYAGE, dupilumab pharmacokinetics was investigated in 270 subjects with moderate-to-severe asthma following subcutaneous administration of either 100 mg Q2W (for 91 pediatric subjects weighing <30 kg) or 200 mg Q2W (for 179 pediatric subjects weighing ≥30 kg). The mean ± SD steady-state trough concentration was 58.4±28.0 mcg/mL and 85.1±44.9 mcg/mL, respectively. Simulation of a 300 mg Q4W subcutaneous dose in pediatric subjects 6 to 11 years of age with body weight of ≥15 to <30 kg resulted in predicted steady-state trough concentrations (98.7±41.0 mcg/mL) and average concentrations higher than the observed trough concentrations and average concentrations of 100 mg Q2W (<30 kg). CRSwNP Clinical studies have not been conducted in pediatric patients aged 12 years and older with CRSwNP. Dupilumab exposures are expected to be comparable between adults and pediatric patients aged 12 years and older at the recommended dosage for CRSwNP (300 mg every 2 weeks). Eosinophilic Esophagitis In Study EoE-1, dupilumab pharmacokinetics were investigated in 35 pediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE, receiving 300 mg QW. The mean ± SD steady-state trough concentration of dupilumab was 227±95.3 mcg/mL. In Study EoE-2 Part A, dupilumab pharmacokinetics were investigated in 20 pediatric subjects 1 to 11 years of age with EoE receiving the following weight-based dosing regimens: ≥15 to <30 kg (200 mg Q2W) and ≥30 to <40 kg (300 mg Q2W). At Week 16, the mean ± SD steady-state trough concentration of dupilumab was 174±66.2 mcg/mL. The systemic exposure in pediatric subjects 1 to 11 years of age with a body weight ≥40 kg receiving 300 mg QW is expected to be comparable to adult and pediatric subjects 12 years and older with a body weight ≥40 kg. The systemic exposure in pediatric subjects 12 to 17 years of age with a body weight <40 kg receiving 300 mg Q2W is expected to be comparable to pediatric subjects 6 to 11 years of age. Chronic Spontaneous Urticaria A total of 12 pediatric subjects 12 to 17 years of age with CSU were enrolled in CUPID (Study A, B, and C), including 6 subjects who received DUPIXENT 200 mg Q2W (≥30 to <60 kg) and 300 mg Q2W (≥60 kg). At week 24, the mean ± SD observed steady-state trough concentration was 53.6 ± 19.4 mcg/mL, which was within the range of steady-state trough concentrations in adult subjects with CSU who received DUPIXENT 300 mg Q2W. A total of 20 pediatric subjects 2 to 11 years of age with CSU were enrolled in clinical trials and pharmacokinetic Study PKM16982, including 18 subjects who received DUPIXENT 200 mg Q4W (≥5 to <15 kg), 300 mg Q4W (≥15 to <30 kg), or 200 mg Q2W (≥30 to <60 kg). At week 24, the mean ± SD steady-state trough concentration was 91.1 ± 39.4 mcg/mL. Allergic Fungal Rhinosinusitis A total of 6 pediatric subjects 6 to 17 years of age with AFRS were enrolled in AIMS, including 3 subjects who received DUPIXENT 200 mg Q2W (≥30 to <60 kg) and 300 mg Q2W (≥60 kg). At week 52, the mean ± SD observed steady-state trough concentration was 72.3 ± 28.8 mcg/mL, which was within the range of steady-state trough concentrations in adult subjects with AFRS who received DUPIXENT 300 mg Q2W. Drug Interaction Studies An effect of dupilumab on the PK of co-administered medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on DUPIXENT pharmacokinetics in subjects with moderate-to-severe asthma. Cytochrome P450 Substrates The effects of dupilumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), metoprolol (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in a study with 12-13 evaluable subjects with AD (a SC loading dose of 600 mg followed by 300 mg SC weekly for six weeks). No clinically significant changes in AUC were observed. The largest effect was observed for metoprolol (CYP2D6) with an increase in AUC of 29%.

12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the trials described below with the incidence of anti-drug antibodies in other trials, including those of DUPIXENT or of other dupilumab products. The anti-drug antibody (ADA) and neutralizing antibody (NAb) incidence rates in subjects treated with DUPIXENT are presented in Table 17. Table 17: Anti-drug Antibody and Neutralizing Antibody Incidence in Subjects Treated with DUPIXENT Indication and Population Dose and Duration of Treatment Anti-drug Antibody (ADA) Neutralizing Antibody NAb Neutralizing potential is assessed only for ADA-positive samples. The NAb incidence is reported as a percentage of subjects with positive ADA response. Positive ADA Positive ADA: Includes subjects with a treatment-emergent response, defined as a negative or missing result at baseline with at least 1 positive post-baseline result in the ADA assay, and subjects with a treatment-boosted response, defined as a post-baseline ADA-positive result that is ≥ 4-fold higher than baseline titer levels, when baseline results are positive Persistent ADA Persistent ADA: A treatment-emergent ADA positive response with 2 or more consecutive ADA positive samples separated by a greater than 12-week period (>84 days), with no ADA negative result in between. Atopic Dermatitis Adult 300 mg Q2W for 52 weeks 7/105 (7%) 2/105 (2%) 1/7 (14%) 12 to 17 years of age 300 mg or 200 mg Q2W for 16 weeks 13/81 (16%) 2/81 (3%) 4/13 (31%) 6 to 11 years of age 200 mg Q2W or 300 mg Q4W for 16 weeks 3/171 (2%) 0/171 (0%) 1/3 (33%) 6 months to 5 years of age 200 mg Q4W, or 300 mg Q4W for 16 weeks 1/74 (1%) 0/74 (0%) 0/1 (0%) Asthma Adult and 12 years of age or older 300 mg Q2W for 52 weeks 33/626 (5%) 13/626 (2%) 14/33 (42%) 200 mg Q2W for 52 weeks 58/625 (9%) 26/625 (4%) 27/58 (47%) 6 to 11 years of age 100 mg Q2W or 200 mg Q2W up to 52 weeks 17/269 (6%) 9/269 (3%) 6/17 (35%) Chronic Rhinosinusitis with Nasal Polyps Adult 300 mg Q2W for 52 weeks 8/148 (5%) 3/148 (2%) 5/8 (63%) Eosinophilic Esophagitis Adult and 12 years of age or older 300 mg QW for 52 weeks 1/108 (1%) 0/108 (0%) 0/1 (0%) 1 to 11 years of age 200 mg Q2W or 300 mg Q2W for 52 weeks Immunogenicity was reported on pooled data for pediatric subjects 1 to 11 years of age with EoE receiving SC dupilumab 100 mg Q2W (in subjects weighing ≥5 kg to <15kg), 200 mg Q2W (in subjects weighing ≥15 kg to <30 kg), 300 mg Q2W (in subjects weighing ≥30 kg to <60 kg), and 300 mg QW (in subjects weighing ≥60 kg). 1/37 (3%) 0/37 (0%) 0/1 (0%) One subject 1 to 11 years of age with EoE with pre-existing immunoreactivity that was positive for neutralizing antibodies was excluded from the NAb positive subjects. Prurigo Nodularis Adult 300 mg Q2W for 24 weeks 11/143 (8%) 2/143 (1%) 4/11 (36%) Chronic Obstructive Pulmonary Disease Adult 300 mg Q2W for 52 weeks 78/923 (8%) 24/922 (3%) 28/78 (36%) Chronic Spontaneous Urticaria Adult and 12 years of age or older 200 mg Q2W or 300 mg Q2W through 24 weeks 9/193 (5%) 1/193 (1%) 2/9 (22%) 2 to 11 years of age 200 mg Q4W or 300 mg Q4W or 200 mg Q2W for 24 weeks 0/15 (0%) 0/15 (0%) 0/0 (0%) Bullous Pemphigoid Adult 300 mg Q2W up to 52 weeks 2/52 (4%) 0/52 (0%) 2/2 (100%) Allergic Fungal Rhinosinusitis Adult and 6 years of age or older 300 mg Q2W or 200 mg Q2W for 52 weeks 2/22 (9%) 1/22 (4.5%) 0/2 (0%) Two adult subjects with AD who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy [see Warnings and Precautions (5.1) ] . The antibody titers detected in subjects who received DUPIXENT were mostly low. In subjects who received DUPIXENT, development of high titer antibodies to DUPIXENT was associated with lower serum dupilumab concentrations [see Clinical Pharmacology (12.3) ] .

The pharmacokinetics of dupilumab is similar in subjects with AD, asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS. Absorption Following an initial subcutaneous (SC) dose of 600 mg, 400 mg, or 300 mg, dupilumab reached peak mean ± SD concentrations (C max ) of 70.1±24.1 mcg/mL, 41.8±12.4 mcg/mL, or 30.5±9.39 mcg/mL, respectively, by approximately 1 week post dose. Steady-state concentrations were achieved by Week 16 following the administration of 600 mg starting dose and 300 mg dose either weekly or Q2W, or 400 mg starting dose and 200 mg dose Q2W, or 300 mg Q2W without a loading dose. Across clinical trials, the mean ± SD steady-state trough concentrations ranged from 55.3±34.3 mcg/mL to 80.2±35.3 mcg/mL for 300 mg administered Q2W, from 173±75.9 mcg/mL to 195±71.7 mcg/mL for 300 mg administered weekly, and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg administered Q2W. The bioavailability of dupilumab following a SC dose is similar between AD, asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS subjects, ranging between 61% and 66%. Distribution The estimated total volume of distribution was approximately 4.8±1.3 L. Elimination The metabolic pathway of dupilumab has not been characterized. As a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. After the last steady-state dose of 300 mg QW, 300 mg Q2W, 200 mg Q2W, 300 mg Q4W, or 200 mg Q4W dupilumab, the median times to non-detectable concentration (<78 ng/mL) ranged from 9 to 13 weeks in adults and pediatric subjects 12 years of age and older. Population pharmacokinetic analyses indicate the median times to non-detectable concentration are approximately 1.5 times (up to 19 weeks) and 2.5 times (up to 32 weeks) longer in pediatric subjects 6 to 11 years of age and pediatric subjects 6 months to 5 years of age, respectively. Dose Linearity Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures increasing in a greater than dose-proportional manner. The systemic exposure increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 75 mg to 600 mg (i.e., 0.25-times to 2-times the recommended dose). Weight Dupilumab trough concentrations were lower in subjects with higher body weight. Immunogenicity Development of antibodies to dupilumab was associated with lower serum dupilumab concentrations. A few subjects who had high antibody titers also had no detectable serum dupilumab concentrations. Specific Populations Age Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and in pediatric subjects 6 to 17 years of age. In pediatric subjects 6 months to 5 years of age, clearance increased with age. Geriatric Patients No overall differences in the pharmacokinetics of dupilumab were observed between elderly and younger adult subjects. Pediatric Patients Atopic Dermatitis For pediatric subjects 12 years of age and older with AD receiving every 2 week dosing (Q2W) with either 200 mg (<60 kg) or 300 mg (≥60 kg), the mean ± SD steady-state trough concentration of dupilumab was 54.5±27.0 mcg/mL. For pediatric subjects 6 to 11 years of age with AD receiving every 2 week dosing (Q2W) with 200 mg (≥30 kg) or every 4 week dosing (Q4W) with 300 mg (<30 kg), mean ± SD steady-state trough concentration was 86.0±34.6 mcg/mL and 98.7±33.2 mcg/mL, respectively. For pediatric subjects 6 months to 5 years of age with AD receiving every 4 week dosing (Q4W) with 300 mg (≥15 to <30 kg) or 200 mg (≥5 to <15 kg), the mean ± SD steady-state trough concentration was 110±42.8 mcg/mL and 109±50.8 mcg/mL, respectively. Asthma A total of 107 pediatric subjects 12 to 17 years of age with asthma were enrolled in QUEST. The mean ± SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9 mcg/mL, respectively, for 300 mg or 200 mg administered Q2W. In VOYAGE, dupilumab pharmacokinetics was investigated in 270 subjects with moderate-to-severe asthma following subcutaneous administration of either 100 mg Q2W (for 91 pediatric subjects weighing <30 kg) or 200 mg Q2W (for 179 pediatric subjects weighing ≥30 kg). The mean ± SD steady-state trough concentration was 58.4±28.0 mcg/mL and 85.1±44.9 mcg/mL, respectively. Simulation of a 300 mg Q4W subcutaneous dose in pediatric subjects 6 to 11 years of age with body weight of ≥15 to <30 kg resulted in predicted steady-state trough concentrations (98.7±41.0 mcg/mL) and average concentrations higher than the observed trough concentrations and average concentrations of 100 mg Q2W (<30 kg). CRSwNP Clinical studies have not been conducted in pediatric patients aged 12 years and older with CRSwNP. Dupilumab exposures are expected to be comparable between adults and pediatric patients aged 12 years and older at the recommended dosage for CRSwNP (300 mg every 2 weeks). Eosinophilic Esophagitis In Study EoE-1, dupilumab pharmacokinetics were investigated in 35 pediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE, receiving 300 mg QW. The mean ± SD steady-state trough concentration of dupilumab was 227±95.3 mcg/mL. In Study EoE-2 Part A, dupilumab pharmacokinetics were investigated in 20 pediatric subjects 1 to 11 years of age with EoE receiving the following weight-based dosing regimens: ≥15 to <30 kg (200 mg Q2W) and ≥30 to <40 kg (300 mg Q2W). At Week 16, the mean ± SD steady-state trough concentration of dupilumab was 174±66.2 mcg/mL. The systemic exposure in pediatric subjects 1 to 11 years of age with a body weight ≥40 kg receiving 300 mg QW is expected to be comparable to adult and pediatric subjects 12 years and older with a body weight ≥40 kg. The systemic exposure in pediatric subjects 12 to 17 years of age with a body weight <40 kg receiving 300 mg Q2W is expected to be comparable to pediatric subjects 6 to 11 years of age. Chronic Spontaneous Urticaria A total of 12 pediatric subjects 12 to 17 years of age with CSU were enrolled in CUPID (Study A, B, and C), including 6 subjects who received DUPIXENT 200 mg Q2W (≥30 to <60 kg) and 300 mg Q2W (≥60 kg). At week 24, the mean ± SD observed steady-state trough concentration was 53.6 ± 19.4 mcg/mL, which was within the range of steady-state trough concentrations in adult subjects with CSU who received DUPIXENT 300 mg Q2W. A total of 20 pediatric subjects 2 to 11 years of age with CSU were enrolled in clinical trials and pharmacokinetic Study PKM16982, including 18 subjects who received DUPIXENT 200 mg Q4W (≥5 to <15 kg), 300 mg Q4W (≥15 to <30 kg), or 200 mg Q2W (≥30 to <60 kg). At week 24, the mean ± SD steady-state trough concentration was 91.1 ± 39.4 mcg/mL. Allergic Fungal Rhinosinusitis A total of 6 pediatric subjects 6 to 17 years of age with AFRS were enrolled in AIMS, including 3 subjects who received DUPIXENT 200 mg Q2W (≥30 to <60 kg) and 300 mg Q2W (≥60 kg). At week 52, the mean ± SD observed steady-state trough concentration was 72.3 ± 28.8 mcg/mL, which was within the range of steady-state trough concentrations in adult subjects with AFRS who received DUPIXENT 300 mg Q2W. Drug Interaction Studies An effect of dupilumab on the PK of co-administered medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on DUPIXENT pharmacokinetics in subjects with moderate-to-severe asthma. Cytochrome P450 Substrates The effects of dupilumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), metoprolol (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in a study with 12-13 evaluable subjects with AD (a SC loading dose of 600 mg followed by 300 mg SC weekly for six weeks). No clinically significant changes in AUC were observed. The largest effect was observed for metoprolol (CYP2D6) with an increase in AUC of 29%.