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5 هشدارها و اقدامات احتیاطی

• سمیت کبدی: علائم و نشانه های هشدار دهنده سمیت کبدی را به بیماران اطلاع دهید. در صورت تداوم یا بدتر شدن آزمایشات غیرطبیعی کبد یا در صورت بروز علائم و نشانه های بالینی بیماری کبد، آن را متوقف کنید. (5.3)
• پرفشاری خون: بیمارانی که برخی از داروهای ضد فشار خون مصرف می کنند ممکن است در هنگام مصرف NSAID ها پاسخ به این درمان ها را مختل کنند. فشار خون را کنترل کنید. ( 5.4 , 7 )
• نارسایی قلبی و ادم: از مصرف قرص‌های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به نارسایی شدید قلبی خودداری کنید، مگر اینکه انتظار می‌رود مزایای آن بیشتر از خطر بدتر شدن نارسایی قلبی باشد. (5.5)
• سمیت کلیوی: عملکرد کلیه را در بیماران مبتلا به نارسایی کلیوی یا کبدی، نارسایی قلبی، کم آبی یا هیپوولمی کنترل کنید. از مصرف قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به بیماری کلیوی پیشرفته خودداری کنید، مگر اینکه انتظار می رود مزایای آن بیشتر از خطر بدتر شدن عملکرد کلیه باشد. (5.6)
• واکنش های آنافیلاکسی: در صورت بروز واکنش آنافیلاکسی، به دنبال کمک اضطراری باشید. (5.7)
• تشدید آسم مرتبط با حساسیت به آسپرین: قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به آسم حساس به آسپرین منع مصرف دارند. بیماران مبتلا به آسم قبلی (بدون حساسیت به آسپرین) را تحت نظر بگیرید. (5.8)
• واکنش های جدی یا شدید پوستی: در اولین ظاهر بثورات پوستی یا سایر علائم حساسیت مفرط، مصرف قرص ناپروکسن و اسموپرازول منیزیم تاخیری را قطع کنید و ارزیابی های بیشتری را در نظر بگیرید. (5.9)
• واکنش دارویی با ائوزینوفیلی و علائم سیستمیک (DRESS): قطع و ارزیابی بالینی (5.10)
• مسمومیت جنینی: به دلیل خطر الیگوهیدرآمنیوس/اختلال عملکرد کلیه جنین، استفاده از NSAID ها، از جمله ناپروکسن و قرص های منیزیم اسموپرازول را بین هفته های 20 تا 30 بارداری محدود کنید. به دلیل خطرات الیگوهیدرآمنیوس/اختلال کلیه جنین و بسته شدن زودرس مجرای شریانی جنین، در حدود هفته 30 بارداری و بعد از آن در بارداری از مصرف NSAIDها در زنان اجتناب کنید (5.11، 8.1).
• مسمومیت هماتولوژیک: هموگلوبین یا هماتوکریت را در بیمارانی که علائم کم خونی دارند کنترل کنید. ( 5.12 , 7 )
• پوشاندن التهاب و تب: بالقوه برای کاهش کاربرد علائم تشخیصی در تشخیص عفونت. (5.13)
• مانیتورینگ آزمایشگاهی: در طول درمان به صورت دوره ای CBC و مشخصات شیمی را دریافت کنید. در بیماران تحت درمان طولانی مدت که مقدار اولیه آنها 10 گرم یا کمتر است، به طور دوره ای هموگلوبین را کنترل کنید. (5.14)
• خونریزی فعال: در بیمارانی که خونریزی فعال و بالینی قابل توجهی را تجربه می کنند، درمان را متوقف کنید. (5.15)
• مصرف همزمان NSAID ها: از استفاده از قرص های ناپروکسن و اسموپرازول منیزیم با تاخیر رهش با سایر محصولات حاوی ناپروکسن یا سایر NSAID های غیر آسپرین خودداری کنید. (5.16)
• بدخیمی معده: در بزرگسالان، پاسخ علامتی به اسموپرازول مانع از وجود بدخیمی معده نمی شود. پیگیری و آزمایشات تشخیصی اضافی را در نظر بگیرید. (5.17)
• نفریت توبولو اینترستیشیال حاد: درمان را قطع کرده و بیماران را ارزیابی کنید. (5.18)
• اسهال مرتبط با کلستریدیوم دیفیسیل: درمان با PPI ممکن است با افزایش خطر اسهال مرتبط با کلستریدیوم دیفیسیل همراه باشد. (5.19)
• شکستگی استخوان: درمان طولانی مدت و روزانه با دوزهای متعدد PPI ممکن است با افزایش خطر شکستگی های مرتبط با پوکی استخوان لگن، مچ دست یا ستون فقرات همراه باشد. (5.20)
• لوپوس اریتماتوز جلدی و سیستمیک: عمدتاً پوستی، شروع جدید یا تشدید بیماری موجود. مصرف قرص ناپروکسن و اسموپرازول منیزیم تاخیری را قطع کنید و برای ارزیابی به متخصص مراجعه کنید. (5.21)
• تداخل با کلوپیدوگرل: از مصرف همزمان خودداری کنید. ( 5.22 , 7 )
• کمبود سیانوکوبالامین (ویتامین B-12): استفاده طولانی مدت روزانه (به عنوان مثال، بیش از 3 سال) ممکن است منجر به سوء جذب یا کمبود سیانوکوبالامین شود. (5.23)
• هیپومنیزیمی و متابولیسم مواد معدنی: به ندرت با درمان طولانی مدت با PPI گزارش شده است. (5.24)
• تداخل با مخمر سنت جان یا ریفامپین: از مصرف همزمان خودداری کنید. ( 5.25 , 7 )
• تداخل با تحقیقات تشخیصی تومورهای نورواندوکرین: افزایش pH داخل معده ممکن است منجر به هیپرگاسترینمی، هیپرپلازی سلولی شبه انتروکرومافین و افزایش سطح کروموگرانین A شود که ممکن است در تحقیقات تشخیصی تومورهای نورواندوکرین اختلال ایجاد کند. (5.26)
• تداخل با متوترکسات: مصرف همزمان با PPI ها ممکن است غلظت سرمی متوترکسات و/یا متابولیت آن را افزایش و/یا طولانی کند که احتمالاً منجر به سمیت می شود. ( 5.27 , 7 )
• پولیپ غدد بنیادی: با استفاده طولانی مدت از PPI، به ویژه بیش از یک سال، خطر افزایش می یابد. از کوتاه ترین مدت درمان استفاده کنید. (5.28)

5.1 رویدادهای ترومبوتیک قلبی عروقی کارآزمایی‌های بالینی چندین NSAID انتخابی و غیرانتخابی COX-2 با مدت حداکثر تا سه سال، افزایش خطر حوادث ترومبوتیک قلبی عروقی (CV) جدی، از جمله انفارکتوس میوکارد (MI) و سکته مغزی را نشان داده‌اند که می‌تواند کشنده باشد. بر اساس داده های موجود، مشخص نیست که خطر حوادث ترومبوتیک CV برای همه NSAID ها مشابه است. به نظر می رسد افزایش نسبی حوادث ترومبوتیک جدی CV نسبت به سطح پایه ناشی از استفاده از NSAID در مواردی که دارای بیماری شناخته شده CV یا عوامل خطر بیماری CV هستند و بدون آن مشابه باشد. با این حال، بیماران مبتلا به بیماری CV شناخته شده یا عوامل خطر، به دلیل افزایش نرخ پایه، بروز مطلق حوادث ترومبوتیک بیش از حد جدی CV داشتند. برخی از مطالعات مشاهده ای نشان دادند که این افزایش خطر حوادث ترومبوتیک جدی CV از همان اوایل هفته های اول درمان شروع شد. افزایش خطر ترومبوتیک CV به طور مداوم در دوزهای بالاتر مشاهده شده است. برای به حداقل رساندن خطر احتمالی یک رویداد نامطلوب CV در بیماران تحت درمان با NSAID، از کمترین دوز موثر برای کوتاه ترین مدت ممکن استفاده کنید. پزشکان و بیماران باید در طول کل دوره درمان، حتی در غیاب علائم CV قبلی، نسبت به بروز چنین رویدادهایی هوشیار باشند. بیماران باید در مورد علائم حوادث CV جدی و اقداماتی که در صورت بروز آنها باید انجام دهند، مطلع شوند. شواهد ثابتی وجود ندارد که نشان دهد مصرف همزمان آسپرین خطر افزایش حوادث ترومبوتیک CV مرتبط با استفاده از NSAID را کاهش می دهد. استفاده همزمان از آسپرین و یک NSAID، مانند ناپروکسن، خطر حوادث جدی گوارشی (GI) را افزایش می دهد [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید]. وضعیت پس از جراحی بای پس عروق کرونر (CABG) دو کارآزمایی بالینی کنترل شده و بزرگ یک NSAID انتخابی COX-2 برای درمان درد در 10 روز تا 14 روز اول پس از جراحی CABG افزایش بروز سکته قلبی و سکته را نشان داد. NSAID ها در تنظیم CABG منع مصرف دارند [به موارد منع مصرف (4) مراجعه کنید]. بیماران پس از MI مطالعات مشاهده ای انجام شده در ثبت ملی دانمارک نشان داده است که بیماران تحت درمان با NSAID در دوره پس از MI در معرض افزایش خطر انفارکتوس مجدد، مرگ ناشی از CV و مرگ و میر ناشی از همه علل از هفته اول درمان بودند. در همین گروه، بروز مرگ در سال اول پس از MI در بیماران تحت درمان با NSAID 20 در هر 100 سال بود در حالی که در بیماران غیر در معرض NSAID 12 در هر 100 سال بود. اگرچه میزان مطلق مرگ تا حدودی پس از سال اول پس از MI کاهش یافت، افزایش خطر نسبی مرگ در مصرف کنندگان NSAID حداقل تا چهار سال بعد از پیگیری ادامه داشت. از مصرف قرص‌های ناپروکسن و اسموپرازول منیزیم تأخیری در بیماران مبتلا به MI اخیر خودداری کنید، مگر اینکه انتظار می‌رود فواید آن بیشتر از خطر حوادث ترومبوتیک مکرر CV باشد. اگر از قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به MI اخیر استفاده می شود، بیماران را از نظر علائم ایسکمی قلبی تحت نظر بگیرید.

5.2 خونریزی، زخم و سوراخ شدن دستگاه گوارش NSAID ها، از جمله ناپروکسن، می توانند عوارض جانبی جدی گوارشی (GI) از جمله التهاب، خونریزی، زخم، و سوراخ شدن مری، معده، روده کوچک یا روده بزرگ ایجاد کنند که می تواند کشنده باشد. این عوارض جانبی جدی می تواند در هر زمانی، با یا بدون علائم هشدار دهنده، در بیماران تحت درمان با NSAID رخ دهد. تنها یک نفر از هر پنج بیمار مبتلا به عارضه جانبی جدی دستگاه گوارش فوقانی در درمان NSAID علامتدار است. زخم گوارشی فوقانی، خونریزی شدید یا سوراخ شدن ناشی از NSAIDها در تقریباً 1٪ از بیمارانی که به مدت 3 ماه تا 6 ماه تحت درمان قرار گرفتند و در حدود 2٪ تا 4٪ از بیمارانی که به مدت یک سال تحت درمان قرار گرفتند، رخ داد. با این حال، حتی درمان کوتاه مدت NSAID بدون خطر نیست. عوامل خطر برای خونریزی دستگاه گوارش، زخم، و سوراخ شدن بیماران با سابقه قبلی بیماری زخم پپتیک و/یا خونریزی دستگاه گوارش که از NSAID استفاده می کردند، در مقایسه با بیمارانی که این عوامل خطر را نداشتند، بیش از 10 برابر افزایش خطر ابتلا به خونریزی دستگاه گوارش داشتند. سایر عواملی که خطر خونریزی دستگاه گوارش را در بیماران تحت درمان با NSAID افزایش می‌دهند عبارتند از طول مدت طولانی‌تر درمان با NSAID. مصرف همزمان کورتیکواستروئیدهای خوراکی، آسپرین، داروهای ضد انعقاد، یا مهارکننده های انتخابی بازجذب سروتونین (SSRIs)؛ سیگار کشیدن؛ استفاده از الکل؛ سن بالاتر؛ و وضعیت سلامت عمومی ضعیف است. بیشتر گزارش‌های پس از بازاریابی در مورد حوادث گوارشی کشنده در بیماران مسن یا ناتوان است. علاوه بر این، بیماران مبتلا به بیماری پیشرفته کبدی و/یا انعقاد در خطر افزایش خونریزی دستگاه گوارش هستند. راهبردهایی برای به حداقل رساندن خطرات دستگاه گوارش در بیماران تحت درمان با NSAID:

• از کمترین دوز موثر برای کوتاه ترین مدت ممکن استفاده کنید.
• از تجویز بیش از یک NSAID در یک زمان خودداری کنید.
• از مصرف در بیمارانی که در معرض خطر بالاتری هستند خودداری کنید، مگر اینکه انتظار می رود مزایای آن بیشتر از افزایش خطر خونریزی باشد. برای بیمارانی مانند بیمارانی که خونریزی دستگاه گوارش فعال دارند، درمان های جایگزینی غیر از NSAID ها را در نظر بگیرید.
• در طول درمان با NSAID نسبت به علائم و نشانه های زخم دستگاه گوارش و خونریزی هوشیار باشید.
• در صورت مشکوک شدن به یک عارضه جانبی جدی GI، به سرعت ارزیابی و درمان را آغاز کنید و تا زمانی که یک عارضه جانبی جدی GI رد شود، مصرف قرص های ناپروکسن و اسموپرازول منیزیم تاخیری رهش را قطع کنید.
• در شرایط استفاده همزمان از آسپرین با دوز پایین برای پروفیلاکسی قلبی، بیماران را برای شواهد خونریزی گوارشی با دقت بیشتری تحت نظر بگیرید [به تداخلات دارویی (7) مراجعه کنید. NSAID ها باید با احتیاط به بیماران دارای سابقه بیماری التهابی روده (کولیت اولسراتیو، بیماری کرون) داده شوند زیرا ممکن است وضعیت آنها تشدید شود.

5.3 سمیت کبدی افزایش ALT یا AST (سه بار یا بیشتر از حد بالای نرمال [ULN]) در تقریباً 1٪ از بیماران تحت درمان با NSAID در آزمایشات بالینی گزارش شده است. علاوه بر این موارد نادر و گاهی کشنده آسیب شدید کبدی از جمله زردی و هپاتیت برق آسای کشنده، نکروز کبد و نارسایی کبدی گزارش شده است. افزایش ALT یا AST (کمتر از سه برابر ULN) ممکن است در 15٪ از بیماران تحت درمان با NSAID ها از جمله ناپروکسن رخ دهد. علائم و نشانه های هشدار دهنده سمیت کبدی (مانند حالت تهوع، خستگی، بی حالی، اسهال، خارش، یرقان، حساسیت ربع فوقانی راست، و علائم «شبیه آنفولانزا») را به بیماران اطلاع دهید. اگر علائم و نشانه‌های بالینی منطبق با بیماری کبدی ایجاد شد، یا اگر تظاهرات سیستمیک رخ داد (مانند ائوزینوفیلی، بثورات پوستی و غیره)، مصرف قرص‌های تأخیری منیزیم ناپروکسن و اسموپرازول را فورا قطع کنید و یک ارزیابی بالینی از بیمار انجام دهید. در بیماران مبتلا به نارسایی شدید کبدی باید از مصرف قرص های ناپروکسن و اسموپرازول منیزیم با تأخیر رهش اجتناب شود [به دوز و نحوه تجویز (2)، مصرف در جمعیت های خاص (8.6)، و فارماکولوژی بالینی (12.3) مراجعه کنید.

5.4 فشار خون بالا NSAID ها، از جمله ناپروکسن و قرص های با رهش تأخیری منیزیم اسموپرازول، می توانند منجر به شروع جدید پرفشاری خون یا بدتر شدن فشار خون قبلی شوند، که هر یک ممکن است در افزایش بروز حوادث CV نقش داشته باشد. بیمارانی که از مهارکننده‌های آنزیم مبدل آنژیوتانسین (ACE)، دیورتیک‌های تیازیدی یا دیورتیک‌های لوپ استفاده می‌کنند، ممکن است در هنگام مصرف NSAID‌ها در پاسخ به این درمان‌ها اختلال ایجاد کنند [به تداخلات دارویی (7) مراجعه کنید]. فشار خون (BP) را در طول شروع درمان با NSAID و در طول دوره درمان کنترل کنید.

5.5 نارسایی قلبی و ادم متاآنالیز همکاری کوکسیب و کارآزمایی‌های NSAID سنتی در کارآزمایی‌های تصادفی‌سازی‌شده و کنترل‌شده، افزایش تقریباً دو برابری بستری شدن در بیمارستان برای نارسایی قلبی را در بیماران تحت درمان انتخابی COX-2 و بیماران غیرانتخابی تحت درمان با NSAID در مقایسه با بیماران تحت درمان با دارونما نشان داد. در یک مطالعه ثبت ملی دانمارک بر روی بیماران مبتلا به نارسایی قلبی، استفاده از NSAID خطر MI، بستری شدن در بیمارستان به دلیل نارسایی قلبی و مرگ را افزایش داد. علاوه بر این، احتباس مایعات و ادم در برخی از بیماران تحت درمان با NSAID مشاهده شده است. استفاده از ناپروکسن ممکن است اثرات CV چندین عامل درمانی مورد استفاده برای درمان این شرایط پزشکی (مانند دیورتیک‌ها، مهارکننده‌های ACE یا مسدودکننده‌های گیرنده آنژیوتانسین [ARBs]) را کاهش دهد [به تداخلات دارویی (7) مراجعه کنید]. از مصرف قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به نارسایی شدید قلبی خودداری کنید، مگر اینکه انتظار می رود مزایای آن بیشتر از خطر بدتر شدن نارسایی قلبی باشد. اگر از قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به نارسایی شدید قلبی استفاده می شود، بیماران را از نظر علائم و نشانه های بدتر شدن نارسایی قلبی تحت نظر قرار دهید.

5.6 سمیت کلیوی و هیپرکالمی مسمومیت کلیوی تجویز طولانی مدت NSAID ها منجر به نکروز پاپیلاری کلیه و سایر آسیب های کلیوی شده است. سمیت کلیوی در بیمارانی که پروستاگلاندین های کلیوی نقش جبرانی در حفظ پرفیوژن کلیوی دارند نیز دیده شده است. در این بیماران، تجویز یک NSAID ممکن است باعث کاهش وابسته به دوز در تشکیل پروستاگلاندین و ثانیاً در جریان خون کلیوی شود، که ممکن است باعث جبران خسارت آشکار کلیوی شود. بیمارانی که در معرض بیشترین خطر این واکنش قرار دارند، بیمارانی با اختلال عملکرد کلیه، کم آبی بدن، هیپوولمی، نارسایی قلبی، اختلال عملکرد کبد، کسانی که دیورتیک ها و مهارکننده های ACE یا ARB مصرف می کنند و افراد مسن هستند. قطع درمان با NSAID معمولاً با بهبودی به وضعیت قبل از درمان دنبال می شد. هیچ اطلاعاتی از مطالعات بالینی کنترل شده در مورد استفاده از قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به بیماری کلیوی پیشرفته در دسترس نیست. اثرات کلیوی قرص های ناپروکسن و اسموپرازول منیزیم تاخیری ممکن است پیشرفت اختلال عملکرد کلیوی را در بیماران مبتلا به بیماری کلیوی از قبل موجود تسریع کند. وضعیت صحیح حجم در بیماران کم آب یا هیپوولمیک قبل از شروع مصرف قرص تأخیری منیزیم ناپروکسن و اسموپرازول. عملکرد کلیه را در بیماران مبتلا به نارسایی کلیوی یا کبدی، نارسایی قلبی، کم آبی یا هیپوولمی در طول استفاده از قرص های تأخیری منیزیم ناپروکسن و اسموپرازول کنترل کنید [به تداخلات دارویی (7) مراجعه کنید]. از مصرف قرص ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به بیماری کلیوی پیشرفته خودداری کنید، مگر اینکه انتظار می رود فواید آن بیشتر از خطر بدتر شدن نارسایی کلیوی باشد. اگر از قرص‌های ناپروکسن و اسموپرازول منیزیم تأخیری در بیماران مبتلا به بیماری کلیوی پیشرفته استفاده می‌شود، بیماران را از نظر علائم بدتر شدن عملکرد کلیه تحت نظر بگیرید. هیپرکالمی افزایش غلظت پتاسیم سرم، از جمله هیپرکالمی، با استفاده از NSAIDها حتی در برخی از بیماران بدون نارسایی کلیوی گزارش شده است. در بیماران با عملکرد کلیوی طبیعی، این اثرات به حالت هیپورنیمیک-هیپوآلدوسترونیسم نسبت داده شده است.

5.7 واکنش های آنافیلاکتیک ناپروکسن با واکنش های آنافیلاکتیک در بیماران با و بدون حساسیت مفرط شناخته شده به ناپروکسن و در بیماران مبتلا به آسم حساس به آسپرین [نگاه کنید به موارد منع مصرف (4) و هشدارها و اقدامات احتیاطی (5.8)] مرتبط است. در صورت بروز واکنش آنافیلاکتیک، به دنبال کمک اضطراری باشید.

5.8 تشدید آسم مرتبط با حساسیت به آسپرین گروهی از بیماران مبتلا به آسم ممکن است آسم حساس به آسپرین داشته باشند که ممکن است شامل رینوسینوزیت مزمن باشد که با پولیپ بینی پیچیده شده است. برونکواسپاسم شدید و بالقوه کشنده؛ و/یا عدم تحمل آسپرین و سایر NSAID ها. از آنجایی که واکنش متقاطع بین آسپرین و سایر NSAID ها در بیماران حساس به آسپرین گزارش شده است، قرص های ناپروکسن و اسموپرازول منیزیم با رهش تأخیری در بیماران با این نوع حساسیت به آسپرین منع مصرف دارند [به موارد منع مصرف (4) مراجعه کنید]. هنگامی که از قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در بیماران مبتلا به آسم قبلی (بدون حساسیت شناخته شده به آسپرین) استفاده می شود، بیماران را از نظر تغییرات در علائم و نشانه های آسم تحت نظر قرار دهید.

5.9 واکنش های جدی یا شدید پوستی NSAID های ناپروکسن، از جمله ناپروکسن، می توانند عوارض جانبی جدی پوستی مانند درماتیت لایه بردار، سندرم استیونز-جانسون (SJS) و نکرولیز اپیدرمی سمی (TEN) ایجاد کنند که می تواند کشنده باشد. NSAID ها همچنین می توانند باعث فوران دارویی ثابت (FDE) شوند. FDE ممکن است به عنوان یک نوع شدیدتر شناخته شده به عنوان فوران دارویی ثابت بولوس عمومی (GBFDE) ظاهر شود که می تواند تهدید کننده زندگی باشد. این حوادث جدی ممکن است بدون هشدار رخ دهد. PPI های اسومپرازول می توانند عوارض جانبی شدید پوستی، از جمله SJS، TEN، و پوسچولوز اگزانتماتوز عمومی حاد (AGEP) ایجاد کنند [به واکنش های جانبی (6.2) مراجعه کنید]. قرص های ناپروکسن و اسومپرازول با تاخیر رهش منیزیم بیماران را در مورد علائم و نشانه های واکنش های جدی یا شدید پوستی آگاه کنید و در اولین ظاهر شدن بثورات پوستی یا هر نشانه دیگری از حساسیت، استفاده از قرص های ناپروکسن و اسموپرازول منیزیم تاخیری را قطع کنید و ارزیابی های بیشتری را در نظر بگیرید. قرص‌های ناپروکسن و اسموپرازول منیزیم تأخیری در بیمارانی که قبلاً واکنش‌های جدی پوستی به NSAID دارند، منع مصرف دارند [به موارد منع مصرف (4) مراجعه کنید.

5.10 واکنش دارویی با ائوزینوفیلی و علائم سیستمیک (DRESS) واکنش دارویی با ائوزینوفیلی و علائم سیستمیک (DRESS) در بیمارانی که از NSAID و PPIها مانند قرص های ناپروکسن و اسموپرازول منیزیم با رهش تاخیری استفاده می کنند، گزارش شده است. برخی از این حوادث کشنده یا تهدید کننده زندگی بوده اند. لباس معمولاً، اگرچه نه منحصراً، با تب، بثورات پوستی، لنفادنوپاتی و/یا تورم صورت تظاهر می‌کند. سایر تظاهرات بالینی ممکن است شامل هپاتیت، نفریت، ناهنجاری های خونی، میوکاردیت یا میوزیت باشد. گاهی اوقات علائم DRESS ممکن است شبیه یک عفونت حاد ویروسی باشد. ائوزینوفیلی اغلب وجود دارد. از آنجایی که این اختلال در تظاهرات آن متغیر است، سایر سیستم های اندامی که در اینجا ذکر نشده اند ممکن است درگیر باشند. توجه به این نکته ضروری است که تظاهرات اولیه حساسیت مفرط، مانند تب یا لنفادنوپاتی، ممکن است وجود داشته باشد، حتی اگر بثورات آشکار نباشد. در صورت وجود چنین علائم یا نشانه‌هایی، مصرف قرص ناپروکسن و اسموپرازول منیزیم تاخیری را قطع کنید و بیمار را فوراً ارزیابی کنید [همچنین به هشدارها و اقدامات احتیاطی (5.9) مراجعه کنید].

5.11 مسمومیت جنینی بسته شدن زودرس مجرای شریانی جنین: از مصرف NSAID ها، از جمله قرص ناپروکسن و اسموپرازول منیزیم تاخیری، در زنان باردار در حدود هفته 30 بارداری و بعد خودداری کنید. NSAID ها، از جمله ناپروکسن و قرص های با رهش تأخیری منیزیم اسموپرازول، خطر بسته شدن زودرس مجرای شریانی جنین را تقریباً در این سن حاملگی افزایش می دهند. الیگوهیدرآمنیوس/نارسایی کلیه نوزادان: استفاده از NSAIDها، از جمله ناپروکسن و قرص‌های تأخیری منیزیم اسموپرازول، در حدود هفته 20 بارداری یا بعد از آن ممکن است باعث اختلال عملکرد کلیه جنین شود که منجر به الیگوهیدرآمنیوس و در برخی موارد، نارسایی کلیوی نوزادان شود. این پیامدهای نامطلوب به طور متوسط ​​پس از روزها تا هفته‌ها درمان مشاهده می‌شوند، اگرچه الیگوهیدرآمنیوس به ندرت 48 ساعت پس از شروع NSAID گزارش شده است. الیگوهیدرآمنیوس اغلب، اما نه همیشه، با قطع درمان قابل برگشت است. برای مثال، عوارض الیگوهیدرآمنیوس طولانی مدت ممکن است شامل انقباض اندام و تاخیر در بلوغ ریه باشد. در برخی موارد پس از بازاریابی اختلال در عملکرد کلیه نوزادان، اقدامات تهاجمی مانند تعویض خون یا دیالیز مورد نیاز بود. اگر درمان NSAID بین حدود 20 هفته تا 30 هفته بارداری ضروری است، استفاده از قرص های ناپروکسن و اسموپرازول منیزیم تاخیری رهش را به کمترین دوز موثر و کوتاه ترین مدت ممکن محدود کنید. در صورت نیاز به درمان با قرص تأخیری منیزیم با ناپروکسن و اسموپرازول در یک زن باردار، نظارت سونوگرافی مایع آمنیوتیک را در نظر بگیرید. در صورت بروز الیگوهیدرآمنیوس، مصرف قرص‌های ناپروکسن و اسموپرازول منیزیم تأخیری را قطع کنید و طبق عملکرد بالینی پیگیری کنید [به استفاده در جمعیت‌های خاص (8.1) مراجعه کنید].

5.12 کم خونی سمیت خونی در بیماران تحت درمان با NSAID رخ داده است. این ممکن است به دلیل از دست دادن خون مخفی یا شدید، احتباس مایعات، یا یک اثر ناقص بر روی اریتروپویزیس باشد. اگر بیمار تحت درمان با ناپروکسن و قرص‌های تأخیری منیزیم اسموپرازول دارای علائم یا نشانه‌های کم خونی است، هموگلوبین یا هماتوکریت را کنترل کنید. NSAID ها، از جمله ناپروکسن و قرص های منیزیم اسموپرازول با رهش تاخیری، ممکن است خطر بروز خونریزی را افزایش دهند. شرایط همراه مانند اختلالات انعقادی یا مصرف همزمان وارفارین و سایر داروهای ضد انعقاد، عوامل ضد پلاکتی (مانند آسپرین)، و مهارکننده‌های بازجذب سروتونین (SSRIs) و مهارکننده‌های بازجذب نوراپی نفرین سروتونین (SNRIs) ممکن است خطر را افزایش دهند. این بیماران را از نظر علائم خونریزی تحت نظر بگیرید [به تداخلات دارویی (7) مراجعه کنید.

5.13 پوشاندن التهاب و تب فعالیت دارویی قرص های ناپروکسن و اسموپرازول منیزیم تاخیری در کاهش التهاب و احتمالاً تب، ممکن است کاربرد علائم تشخیصی را در تشخیص عفونت کاهش دهد.

5.14 نظارت آزمایشگاهی از آنجایی که خونریزی جدی دستگاه گوارش، سمیت کبدی و آسیب کلیوی می تواند بدون علائم یا علائم هشدار دهنده رخ دهد، بیماران تحت درمان طولانی مدت NSAID را با CBC و مشخصات شیمی به صورت دوره ای تحت نظر قرار دهید [به هشدارها و اقدامات احتیاطی (5.2، 5.3، 5.6) مراجعه کنید. بیماران با مقادیر اولیه هموگلوبین 10 گرم یا کمتر که قرار است درمان طولانی مدت دریافت کنند، باید مقادیر هموگلوبین را به صورت دوره ای تعیین کنند.

5.15 خونریزی فعال هنگامی که خونریزی فعال و از نظر بالینی قابل توجه از هر منبعی در بیماران دریافت کننده قرص تأخیری منیزیم ناپروکسن و اسموپرازول رخ دهد، درمان باید قطع شود.

5.16 استفاده همزمان از NSAID قرص ناپروکسن و اسموپرازول منیزیم با رهش تأخیری حاوی ناپروکسن به عنوان یکی از مواد فعال آن است. نباید با سایر محصولات حاوی ناپروکسن استفاده شود زیرا همه آنها به عنوان آنیون ناپروکسن در پلاسما گردش می کنند. به دلیل احتمال افزایش خطر عوارض جانبی، باید از مصرف همزمان ناپروکسن و اسمومپرازول منیزیم قرص تأخیری با هر دوزی از NSAID غیر آسپرین اجتناب شود.

5.17 وجود بدخیمی معده در بزرگسالان، پاسخ به علائم معده با قرص های ناپروکسن و اسموپرازول منیزیم تاخیری مانع از وجود بدخیمی معده نمی شود. پیگیری بیشتر دستگاه گوارش و آزمایشات تشخیصی را در بیماران بزرگسالی که در طول درمان با قرص ناپروکسن و اسموپرازول منیزیم با تأخیر رهش منیزیم دچار علائم معده می شوند یا پس از اتمام درمان دچار عود علامتی می شوند، در نظر بگیرید. در بیماران مسن تر، آندوسکوپی را نیز در نظر بگیرید.

5.18 نفریت حاد توبولو بینابینی نفریت حاد توبولوینترستیشیال (TIN) در بیمارانی که PPI مصرف می کنند مشاهده شده است و ممکن است در هر نقطه از درمان با PPI رخ دهد. بیماران ممکن است با علائم و نشانه‌های متفاوتی از واکنش‌های حساسیت مفرط علامتی گرفته تا علائم غیراختصاصی کاهش عملکرد کلیه (مانند بی‌حالی، حالت تهوع، بی‌اشتهایی) مراجعه کنند. در سری موارد گزارش شده، برخی از بیماران در بیوپسی و در غیاب تظاهرات خارج کلیوی (مانند تب، راش یا آرترالژی) تشخیص داده شدند. مصرف قرص ناپروکسن و اسموپرازول منیزیم تاخیری را قطع کنید و بیماران مشکوک به TIN حاد را ارزیابی کنید [به موارد منع مصرف (4) مراجعه کنید].

5.19 اسهال مرتبط با کلستریدیوم دیفیسیل مطالعات مشاهده ای منتشر شده نشان می دهد که درمان با مهارکننده پمپ پروتون (PPI) مانند قرص های ناپروکسن و اسموپرازول منیزیم تاخیر رهش ممکن است با افزایش خطر اسهال مرتبط با کلستریدیوم دیفیسیل، به ویژه در بیماران بستری در بیمارستان مرتبط باشد. این تشخیص باید برای اسهالی که بهبود نمی یابد در نظر گرفته شود [به واکنش های نامطلوب (6.2) مراجعه کنید]. بیماران باید از کمترین دوز و کوتاه ترین مدت درمان با PPI مناسب با شرایط تحت درمان استفاده کنند [دوز و نحوه تجویز (2) را ببینید].

5.20 شکستگی استخوان چندین مطالعه مشاهده ای منتشر شده نشان می دهد که درمان با PPI ممکن است با افزایش خطر شکستگی های مرتبط با پوکی استخوان لگن، مچ دست یا ستون فقرات مرتبط باشد. خطر شکستگی در بیمارانی که دوز بالا، که به عنوان دوزهای متعدد روزانه تعریف شده بود، و درمان طولانی مدت PPI (یک سال یا بیشتر) دریافت کردند، افزایش یافت. بیماران باید از کمترین دوز و کوتاه ترین مدت درمان PPI مناسب با شرایط تحت درمان استفاده کنند. بیمارانی که در معرض خطر شکستگی‌های مرتبط با پوکی استخوان هستند باید بر اساس دستورالعمل‌های درمانی تثبیت‌شده مدیریت شوند [به دوز و نحوه تجویز (2)، عوارض جانبی (6.2) مراجعه کنید]. قرص‌های ناپروکسن و اسموپرازول منیزیم تأخیری (یک ترکیب PPI/NSAID) برای استفاده دو بار در روز تأیید شده‌اند و اجازه تجویز دوز روزانه کمتر از PPI را نمی‌دهند [به دوز و نحوه تجویز (2) مراجعه کنید].

5.21 لوپوس اریتماتوی پوستی و سیستمیک لوپوس اریتماتوز جلدی (CLE) و لوپوس اریتماتوی سیستمیک (SLE) در بیمارانی که PPI از جمله اسموپرازول مصرف می کنند گزارش شده است. این رویدادها هم به عنوان شروع جدید و هم به عنوان تشدید بیماری خودایمنی موجود رخ داده اند. اکثر موارد لوپوس اریتماتوز ناشی از PPI CLE بودند. شایع‌ترین شکل CLE گزارش شده در بیماران تحت درمان با PPI، CLE تحت حاد (SCLE) بود و طی هفته‌ها تا سال‌ها پس از درمان مداوم دارویی در بیماران بستری از نوزادان تا افراد مسن رخ داد. به طور کلی، یافته های بافت شناسی بدون درگیری اندام مشاهده شد. SLE کمتر از CLE در بیماران دریافت کننده PPI گزارش می شود. SLE مرتبط با PPI معمولاً خفیف‌تر از SLE ناشی از دارو است. شروع SLE معمولاً در طی چند روز تا سالها پس از شروع درمان، عمدتاً در بیمارانی از بزرگسالان جوان تا افراد مسن رخ می دهد. اکثر بیماران با راش مراجعه کردند. با این حال، آرترالژی و سیتوپنی نیز گزارش شده است. از مصرف PPIها برای مدت طولانی‌تر از آنچه که از نظر پزشکی مشخص شده است خودداری کنید. اگر در بیمارانی که قرص‌های تأخیری منیزیم ناپروکسن و اسموپرازول دریافت می‌کنند، علائم یا نشانه‌های منطبق با CLE یا SLE مشاهده شد، دارو را قطع کرده و بیمار را برای ارزیابی به متخصص مربوطه ارجاع دهید. اکثر بیماران با قطع PPI به تنهایی در 4 تا 12 هفته بهبود می یابند. آزمایش‌های سرولوژیکی (مانند ANA) ممکن است مثبت باشد و بهبود نتایج آزمایش‌های سرولوژیکی ممکن است بیشتر از تظاهرات بالینی طول بکشد.

5.22 تداخل با کلوپیدوگرل از مصرف همزمان اسموپرازول با کلوپیدوگرل خودداری کنید. کلوپیدوگرل یک پیش دارو است. مهار تجمع پلاکتی توسط کلوپیدوگرل کاملاً به دلیل یک متابولیت فعال است. متابولیسم کلوپیدوگرل به متابولیت فعال آن می تواند با مصرف همزمان با داروهایی مانند اسموپرازول که فعالیت CYP2C19 را مهار می کند، مختل شود. مصرف همزمان کلوپیدوگرل با 40 میلی گرم اسموپرازول باعث کاهش فعالیت دارویی کلوپیدوگرل می شود. هنگام استفاده از اسموپرازول، جزء ناپروکسن و قرص‌های تأخیری منیزیم اسموپرازول، درمان جایگزین ضد پلاکتی را در نظر بگیرید [به تداخلات دارویی (7)، فارماکولوژی بالینی (12.3) مراجعه کنید.

5.23 کمبود سیانوکوبالامین (ویتامین B-12) درمان روزانه با هر گونه داروهای سرکوب کننده اسید در مدت زمان طولانی (مثلاً بیش از 3 سال) ممکن است منجر به سوء جذب سیانوکوبالامین (ویتامین B-12) ناشی از هیپو یا آکلرهدری شود. گزارش های نادری از کمبود سیانوکوبالامین که با درمان سرکوب کننده اسید اتفاق می افتد در ادبیات گزارش شده است. در صورت مشاهده علائم بالینی مطابق با کمبود سیانوکوبالامین، این تشخیص باید در نظر گرفته شود.

5.24 هیپومنیزیمی و متابولیسم مواد معدنی هیپومنیزیمی، علامت دار و بدون علامت، به ندرت در بیماران تحت درمان با PPI برای حداقل سه ماه، در بیشتر موارد پس از یک سال درمان، گزارش شده است. عوارض جانبی جدی شامل کزاز، آریتمی و تشنج است. هیپومنیزیمی ممکن است منجر به هیپوکلسمی و/یا هیپوکالمی شود و ممکن است هیپوکلسمی زمینه ای را در بیماران در معرض خطر تشدید کند. در اکثر بیماران، درمان هیپومنیزیمی نیاز به جایگزینی منیزیم و قطع PPI داشت. برای بیمارانی که انتظار می‌رود تحت درمان طولانی‌مدت باشند یا PPI را با داروهایی مانند دیگوکسین یا داروهایی که ممکن است باعث هیپومنیزیمی شوند (مثلاً دیورتیک‌ها) مصرف می‌کنند، متخصصان مراقبت‌های بهداشتی ممکن است قبل از شروع درمان PPI و به صورت دوره‌ای سطح منیزیم را تحت نظر داشته باشند [به واکنش‌های نامطلوب (6.2) مراجعه کنید]. نظارت بر سطوح منیزیم و کلسیم را قبل از شروع مصرف قرص های ناپروکسن و اسموپرازول منیزیم تأخیری و به طور دوره ای در حین درمان در بیماران با خطر قبلی هیپوکلسمی (مانند کم کاری پاراتیروئید) در نظر بگیرید. در صورت لزوم با منیزیم و/یا کلسیم مکمل کنید. اگر هیپوکلسمی نسبت به درمان مقاوم است، مصرف قرص ناپروکسن و اسموپرازول منیزیم تاخیری را در نظر بگیرید.

5.25 مصرف همزمان خار مریم یا ریفامپین با ناپروکسن و قرص‌های منیزیم اسومپرازول با تاخیر رهش داروهایی که CYP2C19 یا CYP3A4 را القا می‌کنند (مانند خارمریم یا ریفامپین) می‌توانند غلظت اسومپرازول را به میزان قابل توجهی کاهش دهند. از مصرف همزمان ناپروکسن و اسموپرازول منیزیم قرص تاخیری رهش با خار مریم یا ریفامپین خودداری کنید [به تداخلات دارویی (7) مراجعه کنید].

5.26 تداخلات با تحقیقات تشخیصی برای تومورهای نورواندوکرین سطوح کروموگرانین A (CgA) سرم ثانویه به کاهش اسیدیته معده ناشی از دارو افزایش می یابد. افزایش سطح CgA ممکن است باعث نتایج مثبت کاذب در تحقیقات تشخیصی تومورهای عصبی غدد شود. ارائه دهندگان باید به طور موقت درمان با اسموپرازول را حداقل 14 روز قبل از ارزیابی قطع کنند.

جدول 3 و جدول 4 را برای تداخلات دارویی مهم و تداخلات با تشخیص با ناپروکسن و اسموپرازول منیزیم ببینید. جدول 3: تداخلات دارویی مهم بالینی با ناپروکسن و اسومپرازول منیزیم - داروهای مؤثر بر داروهای تجویز شده همزمان با قرص‌های تأخیری منیزیم ناپروکسن و اسومپرازول و تداخلات با عوامل تشخیصی تأثیر بالینی: ناپروکسن

• ناپروکسن و داروهای ضد انعقاد مانند وارفارین اثر هم افزایی بر خونریزی دارند. مصرف همزمان ناپروکسن و داروهای ضد انعقاد در مقایسه با استفاده از هر دو دارو به تنهایی، خطر خونریزی جدی را افزایش داده است.
• ترشح سروتونین توسط پلاکت ها نقش مهمی در هموستاز دارد. مطالعات مورد شاهدی و همگروهی اپیدمیولوژیک نشان داد که مصرف همزمان داروهایی که با بازجذب سروتونین تداخل دارند و یک NSAID ممکن است خطر خونریزی را بیش از یک NSAID به تنهایی، اسمومپرازول منیزیم، تشدید کند.
• افزایش INR و زمان پروترومبین در بیمارانی که همزمان با PPIها از جمله اسموپرازول و وارفارین درمان می‌شوند. افزایش INR و زمان پروترومبین ممکن است منجر به خونریزی غیرطبیعی و حتی مرگ شود.
• مصرف همزمان اسموپرازول 40 میلی گرم منجر به کاهش غلظت پلاسمایی متابولیت فعال کلوپیدوگرل و کاهش مهار پلاکتی شد [به فارماکولوژی بالینی (12.3) مراجعه کنید.
• هیچ مطالعه ترکیبی کافی در مورد دوز کمتر اسموپرازول یا دوز بالاتر کلوپیدوگرل در مقایسه با دوز تایید شده کلوپیدوگرل وجود ندارد. مداخله: بیماران با مصرف همزمان ناپروکسن و قرص‌های تأخیری منیزیم اسموپرازول را با داروهای ضد انعقاد (مانند وارفارین)، داروهای ضد پلاکتی (مانند آسپرین)، مهارکننده‌های انتخابی بازجذب سروتونین (SSRIs) و سروتونین نوراپی‌نفرین‌ها برای نشانه‌های جدید کنترل کنید. [به هشدارها و اقدامات احتیاطی (5.14) مراجعه کنید]. کلوپیدوگرل: از مصرف همزمان کلوپیدوگرل با ناپروکسن و اسموپرازول منیزیم قرص تاخیری رهش خودداری کنید. استفاده از درمان جایگزین ضد پلاکتی را در نظر بگیرید [به هشدارها و اقدامات احتیاطی (5.22) مراجعه کنید]. تاثیر بالینی آسپرین: یک مطالعه فارماکودینامیک (PD) تداخلی را نشان داده است که در آن ناپروکسن با دوز پایین (220 میلی‌گرم در روز یا 220 میلی‌گرم دو بار در روز) با اثر ضد پلاکتی آسپرین با دوز کم رهش فوری تداخل می‌کند، با این تداخل که در طول دوره شستشوی ناپروکسن بیشتر مشخص می‌شود. دلیلی وجود دارد که انتظار داشته باشیم این تداخل با دوزهای تجویزی ناپروکسن یا آسپرین با دوز پایین با پوشش روده وجود داشته باشد. با این حال، اوج تداخل با عملکرد آسپرین ممکن است دیرتر از آنچه در مطالعه PD مشاهده شد، به دلیل طولانی‌تر بودن دوره شستشو باشد. مطالعات بالینی کنترل شده نشان داد که استفاده همزمان از NSAID ها و دوزهای ضد درد آسپرین هیچ اثر درمانی بیشتری نسبت به استفاده از NSAID ها به تنهایی ایجاد نمی کند. در یک مطالعه بالینی، استفاده همزمان از یک NSAID و آسپرین با افزایش قابل توجهی از بروز عوارض جانبی GI در مقایسه با استفاده از NSAID به تنهایی همراه بود [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید]. مداخله: از آنجایی که ممکن است به دنبال قطع ناپروکسن به دلیل تداخل با اثر ضد پلاکتی آسپرین در طول دوره شستشو، خطر بروز حوادث قلبی عروقی افزایش یابد، برای بیمارانی که آسپرین با دوز پایین برای محافظت از قلب مصرف می‌کنند و به مسکن‌های متناوب نیاز دارند، استفاده از یک NSAID را در نظر بگیرید که با اثر ضد پلاکتی، ضد پلاکتی یا غیرناسپیرین تداخل نداشته باشد. مسکن ها در صورت لزوم مصرف همزمان ناپروکسن و قرص‌های تأخیری منیزیم اسموپرازول و دوزهای ضددرد آسپرین معمولاً به دلیل افزایش خطر خونریزی توصیه نمی‌شود [به هشدارها و اقدامات احتیاطی (5.12) مراجعه کنید]. قرص های ناپروکسن و اسموپرازول منیزیم با رهش تاخیری جایگزین آسپرین با دوز پایین برای محافظت از قلب و عروق نیستند. تأثیر بالینی مهارکننده‌های ACE، مسدودکننده‌های گیرنده آنژیوتانسین و مسدودکننده‌های بتا:
• NSAIDها ممکن است اثر ضد فشار خون مهارکننده‌های آنزیم مبدل آنژیوتانسین (ACE)، مسدودکننده‌های گیرنده آنژیوتانسین (ARBs)، یا مسدودکننده‌های بتا (از جمله پروپرانولول) را کاهش دهند.
• در بیماران مسن، کاهش حجم (از جمله کسانی که تحت درمان با دیورتیک هستند)، یا دارای نارسایی کلیوی هستند، تجویز همزمان یک NSAID با مهارکننده های ACE یا ARBs ممکن است منجر به بدتر شدن عملکرد کلیه، از جمله نارسایی حاد کلیوی شود. این اثرات معمولا برگشت پذیر هستند. مداخله:
• در طول مصرف همزمان ناپروکسن و قرص‌های تأخیری منیزیم اسموپرازول و مهارکننده‌های ACE، ARBs یا مسدودکننده‌های بتا، فشار خون را کنترل کنید تا مطمئن شوید که فشار خون مورد نظر به دست می‌آید.
• During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6 )]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5.6 )]. Antiretrovirals Clinical Impact: The effect of esomeprazole magnesium on antiretroviral drugs is variable. The clinical importance and mechanisms behind these interactions are not always known.
• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with esomeprazole magnesium may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3 )].
• Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole magnesium may increase toxicity [see Clinical Pharmacology ( 12.3 )].
• There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole magnesium. Intervention: Rilpivirine-containing products: Concomitant use with naproxen and esomeprazole magnesium delayed-release tablets is contraindicated [see Contraindications ( 4 )]. A tazanavir: See prescribing information for atazanavir for dosing information. N elfinavir: Avoid concomitant use with naproxen and esomeprazole magnesium delayed-release tablets. S aquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretro virals: See prescribing information of specific drugs. Cilostazol Clinical Impact: Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) when coadministered with omeprazole magnesium, the racemate of esomeprazole [see Clinical Pharmacology ( 12.3 )]. Intervention: Consider reducing the dose of cilostazol to 50 mg twice daily. Digoxin Clinical Impact: Naproxen
• The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Esomeprazole Magnesium
• Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3 )]. Intervention: Monitor digoxin concentrations during concomitant use of naproxen and esomeprazole magnesium delayed-release tablets. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. Lithium Clinical Impact: NSAIDs have produced elevations of plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Naproxen
• Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Esomeprazole Magnesium
• Concomitant use of esomeprazole magnesium with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and Precautions ( 5.27 )] . Intervention: During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity. A temporary withdrawal of naproxen and esomeprazole magnesium delayed-release tablets may be considered in some patients receiving high-dose methotrexate. Cyclosporine Clinical Impact: Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function. Tacrolimus Clinical Impact: Concomitant use of esomeprazole magnesium and tacrolimus may increase exposure of tacrolimus Intervention: During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and tacrolimus, monitor tacrolimus whole blood concentrations. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2 )]. Intervention: The concomitant use of naproxen and esomeprazole magnesium delayed-release tablets with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 mL/min to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, mycophenoloate mofetil, ketoconazole) Clinical Impact: Esomeprazole magnesium can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole magnesium is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole and MMF. Use naproxen and esomeprazole magnesium delayed-release tablets with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3 )] . See the prescribing information for other drugs dependent on gastric pH for absorption. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.26 ), Clinical Pharmacology ( 12.2 )] . Intervention: Temporarily stop naproxen and esomeprazole magnesium delayed-release tablets treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology ( 12.3 )]. Intervention: Monitor patients for increased sedation and adjust the dose of diazepam as needed. Table 4: Clinically Significant Interactions with Esomeprazole Magnesium --Affecting Co-Administered Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of esomeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3 )]. Intervention: St. John’s Wort, rifampin: Avoid concomitant use with naproxen and esomeprazole magnesium delayed-release tablets [see Warnings and Precautions ( 5.25 )]. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology ( 12.3 )]. Intervention: Voriconazole: Avoid concomitant use with naproxen and esomeprazole magnesium delayed-release tablets. See full prescribing information for a list of clinically important drug interactions. ( 7 )

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events [see Warnings and Precautions ( 5.1 )]
• GI Bleeding, Ulceration and Perforations [see Warnings and Precautions ( 5.2 )]
• Hepatotoxicity [see Warnings and Precautions ( 5.3 )]
• Hypertension [see Warnings and Precautions ( 5.4 )]
• Heart Failure and Edema [see Warnings and Precautions ( 5.5 )]
• Renal Toxicity and Hyperkalemia [see Warnings and Precautions ( 5.6 )]
• Anaphylactic Reactions [see Warnings and Precautions ( 5.7 )]
• Serious or Severe Skin Reactions [see Warnings and Precautions ( 5.9 )]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.10 )]
• Fetal Toxicity [see Warnings and Precautions ( 5.11 )]
• Hematologic Toxicity [see Warnings and Precautions ( 5.12 )]
• Active Bleeding [see Warnings and Precautions ( 5.15 )]
• Acute Tubulointerstitial Nephritis [see Warnings and Precautions ( 5.18 )]
• Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.19 )]
• Bone Fracture [see Warnings and Precautions ( 5.20 )]
• Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.21 )]
• Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions ( 5.23 )]
• Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions ( 5.24 )]
• Fundic Gland Polyps [see Warnings and Precautions ( 5.28 )] Most common adverse reactions in clinical trials (greater than 5%) are gastritis and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Clinical Trials Experience with Naproxen and Esomeprazole Magnesium Delayed-Release Tablets Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions reported below are specific to the clinical trials with naproxen and esomeprazole magnesium delayed-release tablets. The safety of naproxen and esomeprazole magnesium delayed-release tablets was evaluated in clinical studies involving 2,317 patients (aged 27 years to 90 years) and ranging from 3 months to 12 months. Patients received either 500 mg/20 mg of naproxen and esomeprazole magnesium delayed-release tablets twice daily (n=1,157), 500 mg of enteric-coated naproxen twice daily (n=426), or placebo (n=246). The average number of naproxen and esomeprazole magnesium delayed-release tablets doses taken over 12 months was 69 6 +44. The table below lists all adverse reactions, regardless of causality, occurring in greater than 2% of patients receiving naproxen and esomeprazole magnesium delayed-release tablets and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than control from two clinical studies (Study 1 and Study 2). Both of these studies were randomized, multi-center, double-blind, parallel studies. The majority of patients were female (67%), white (86%). The majority of patients were 50 years to 69 years of age (83%). Approximately one quarter were on low-dose aspirin. Table 1: Adverse Reactions* in Study 1 and Study 2 (endoscopic studies) *reported in greater than 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than control Preferred term Naproxen and Esomeprazole Magnesium Delayed-Release Tablets 500 mg/20 mg twice daily (n=428) % EC-Naproxen 500 mg twice daily (n=426) % Gastritis 17 14 Diarrhea 6 5 Upper respiratory tract infection 5 4 Flatulence 4 3 Headache 3 1 Urinary tract infection 2 1 Dysgeusia 2 1 In Study 1 and Study 2, patients taking naproxen and esomeprazole magnesium delayed-release tablets had fewer premature discontinuations due to adverse reactions compared to patients taking enteric-coated naproxen alone (7.9% vs. 12.5% respectively). The most common reasons for discontinuations due to adverse events in the naproxen and esomeprazole magnesium delayed-release tablets treatment group were upper abdominal pain (1.2%, n=5), duodenal ulcer (0.7%, n=3) and erosive gastritis (0.7%, n=3). Among patients receiving enteric-coated naproxen, the most common reasons for discontinuations due to adverse events were duodenal ulcer 5.4% (n=23), dyspepsia 2.8% (n=12) and upper abdominal pain 1.2% (n=5). The proportion of patients discontinuing treatment due to any upper gastrointestinal adverse events (including duodenal ulcers) in patients treated with naproxen and esomeprazole magnesium delayed-release tablets was 4% compared to 12% for patients taking enteric-coated naproxen. The table below lists all adverse reactions, regardless of causality, occurring in greater than 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than placebo from 2 clinical studies conducted in patients with osteoarthritis of the knee (Study 3 and Study 4). Table 2: Adverse Reactions* in Study 3 and Study 4 *reported in greater than 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than placebo Preferred term Naproxen and Esomeprazole Magnesium Delayed-Release Tablets 500 mg/20 mg twice daily (n=490) % Placebo (n=246) % Diarrhea 6 4 Abdominal Pain Upper 4 3 Constipation 4 1 Dizziness 3 2 Peripheral edema 3 1 The percentage of subjects who withdrew from the naproxen and esomeprazole magnesium delayed-release tablets treatment group in these studies due to treatment-emergent adverse events was 7%. There were no preferred terms in which more than 1% of subjects withdrew from any treatment group. The long-term safety of naproxen and esomeprazole magnesium delayed-release tablets was evaluated in an open-label clinical trial of 239 patients, of which 135 patients received 500 mg/20 mg of naproxen and esomeprazole magnesium delayed-release tablets for 12 months. There were no differences in frequency or types of adverse reactions seen in the long-term safety study compared to shorter-term treatment in the randomized controlled studies. Clinical Trials Experience with Naproxen and Other NSAIDs In patients taking naproxen in clinical trials, the most frequent reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal : heartburn, nausea, dyspepsia, stomatitis Central Nervous System: drowsiness, lightheadedness, vertigo Dermatologic: pruritus, skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: palpitations General: dyspnea, thirst In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal: gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in less than 1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes In patients taking NSAIDs, the following adverse experiences have also been reported in less than 1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremor, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria Clinical Trials Experience with Esomeprazole Magnesium Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium with an incidence of less than 1% are listed below by body system: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, malaise, pain, rigors Cardiovascular: flushing, hypertension, tachycardia Endocrine: goiter Gastrointestinal: dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting Hearing: earache, tinnitus Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia Hepatic : bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect Reproductive: dysmenorrhea, menstrual disorder, vaginitis Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria Special Senses: otitis media, parosmia, taste loss Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria Visual: conjunctivitis, vision abnormal The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium, were reported in less than or equal to 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine. Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of naproxen and esomeprazole magnesium delayed-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Naproxen and Esomeprazole Magnesium Delayed-Release Tablets Body as a Whole: gait disturbance Gastrointestinal: abdominal distension, abdominal pain, gastroesophageal reflux, hematochezia Injury, Poisoning and Procedural Complications: contusion, fall Musculoskeletal and Connective Tissue: joint swelling, muscle spasms Urogenital: renal tubular necrosis Naproxen Body as a Whole: angioneurotic edema, menstrual disorders Cardiovascular: congestive heart failure, vasculitis, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, and obstruction of the upper or lower gastrointestinal tract, esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) Hepatobiliary: hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis Dermatologic: alopecia, urticaria, toxic epidermal necrolysis (TEN), erythema multiforme, erythema nodosum, fixed drug eruption (FDE), lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE), photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female) : infertility Esomeprazole Magnesium Blood and Lymphatic: agranulocytosis Eye: blurred vision Gastrointestinal: pancreatitis, microscopic colitis, fundic gland polyps Hepatobiliary: hepatic failure, hepatitis with or without jaundice Immune System: anaphylactic reaction/shock, systemic lupus erythematosus Infections and Infestations: GI candidiasis, Clostridium difficile associated diarrhea Metabolism and Nutritional Disorders: hypomagnesemia, hypocalcemia, hypokalemia [see Warnings and Precautions ( 5.24 )] ,hyponatremia Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture Nervous System: hepatic encephalopathy Psychiatric: aggression, agitation, hallucination Renal and Urinary: interstitial nephritis Reproductive System and Breast: gynecomastia, erectile dysfunction Respiratory, Thoracic, and Mediastinal: bronchospasm Skin and Subcutaneous Tissue: alopecia, erythema multiforme, photosensitivity, SJS, TEN (some fatal), DRESS, AGEP, cutaneous lupus erythematosus

• Females and Males of Reproductive Potential: NSAIDs are associated with reversible infertility. Consider withdrawal of naproxen and esomeprazole magnesium delayed-release tablets in women who have difficulties conceiving. ( 8.3 )

8.1 Pregnancy Risk Summary Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal and renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of naproxen and esomeprazole magnesium delayed-release tablets use between about 20 weeks and 30 weeks of gestation and avoid naproxen and esomeprazole magnesium delayed-release tablets use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data) . Premature Closure of the Fetal Ductus Arteriosus Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Naproxen and esomeprazole magnesium delayed-release tablets contain naproxen and esomeprazole magnesium. Esomeprazole is the S-isomer of omeprazole. Naproxen Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, naproxen administered during organogenesis to rats and rabbits at doses less than the maximum recommended human daily dose of 1500 mg/day showed no evidence of harm to the fetus (see Data) . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen resulted in increased pre-and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Esomeprazole There are no human data for esomeprazole. However, available epidemiologic data for omeprazole (esomeprazole is the S-isomer of omeprazole) fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use (see Data) . In animal studies with administration of oral esomeprazole magnesium in rats, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data] . The estimated background risks of major birth defects and miscarriage for the indicated population 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 Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If naproxen and esomeprazole magnesium delayed-release tablets treatment is needed in pregnant women, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue naproxen and esomeprazole magnesium delayed-release tablets and follow up according to clinical practice (see Data) . Labor or Delivery There are no studies on the effects of naproxen and esomeprazole magnesium delayed-release tablets during labor or delivery. In animal studies, NSAIDs, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Naproxen When used to delay preterm labor, inhibitors of prostaglandin synthesis, including NSAIDs such naproxen, may increase the risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Esomeprazole Esomeprazole is the S-isomer of omeprazole. Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H 2 -receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H 2 -blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H 2 -blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data There are no reproduction studies in animals with naproxen and esomeprazole magnesium delayed-release tablets, a combination of naproxen and esomeprazole. Naproxen Reproduction studies with naproxen administered during the period of organogenesis have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.56 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of harm to the fetus due to the drug. Esomeprazole No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis and have revealed no evidence of harm to the fetus due to esomeprazole magnesium. A pre-and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times a daily human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times a daily human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times the daily human dose of 40 mg on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in the pre-and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre-and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

8.2 Lactation Risk Summary Limited data from published literature report that naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Esomeprazole is the S-isomer of omeprazole and limited data from published literature suggest omeprazole may be present in human milk. There is no information on the effects of naproxen or omeprazole on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for naproxen and esomeprazole magnesium delayed-release tablets and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, may delay or prevent rupture of ovarian follicles that may lead to reversible infertility in some women. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Published animal studies have shown that administration of prostaglandin synthesis inhibitors have the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Consider withdrawal of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use The safety and effectiveness of naproxen and esomeprazole magnesium delayed-release tablets have been established in adolescent patients 12 years of age and older weighing at least 38 kg for the symptomatic relief of JIA and to decrease the risk of developing naproxen-associated gastric ulcers. Use of naproxen and esomeprazole magnesium delayed-release tablets in this age group is based on extrapolation of adequate and well-controlled studies in adults and supported by a 6 month safety study including pharmacokinetic assessment of naproxen and esomeprazole magnesium in 36 adolescent patients with JIA. Based on the limited data, the plasma naproxen and plasma esomeprazole concentrations were found to be within the range to that observed to those found in healthy adults. The safety profile of naproxen and esomeprazole magnesium delayed-release tablets in adolescent patients with JIA was similar to adults with RA. The safety and effectiveness of naproxen and esomeprazole magnesium delayed-release tablets in pediatric patients less than 12 years of age or less than 38 kg with JIA have not been established. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology ( 13.2 )].

8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.14 )] . Of the total number of patients who received naproxen and esomeprazole magnesium delayed-release tablets (n=1,157) in clinical trials, 387 were greater than or equal to 65 years of age, of which 85 patients were 75 years and over. No meaningful differences in efficacy or safety were observed between these subjects and younger subjects [see Adverse Reactions ( 6 )]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose [see Dosage and Administration ( 2 ), Clinical Pharmacology ( 12.3 )]. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of NSAIDs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions ( 5.2 )]. Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of NSAIDs [see Warnings and Precautions ( 5.6 )].

8.6 Hepatic Impairment Naproxen and esomeprazole magnesium delayed-release tablets should be avoided in patients with severe hepatic impairment because naproxen may increase the risk of renal failure or bleeding and esomeprazole doses should not exceed 20 mg daily in these patients [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.3 ), Clinical Pharmacology ( 12.3 )].

8.7 Renal Impairment Naproxen-containing products, including naproxen and esomeprazole magnesium delayed-release tablets, are not recommended for use in patients with advanced renal disease [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.6 )].

Risk Summary Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal and renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of naproxen and esomeprazole magnesium delayed-release tablets use between about 20 weeks and 30 weeks of gestation and avoid naproxen and esomeprazole magnesium delayed-release tablets use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data) . Premature Closure of the Fetal Ductus Arteriosus Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Naproxen and esomeprazole magnesium delayed-release tablets contain naproxen and esomeprazole magnesium. Esomeprazole is the S-isomer of omeprazole. Naproxen Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, naproxen administered during organogenesis to rats and rabbits at doses less than the maximum recommended human daily dose of 1500 mg/day showed no evidence of harm to the fetus (see Data) . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen resulted in increased pre-and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Esomeprazole There are no human data for esomeprazole. However, available epidemiologic data for omeprazole (esomeprazole is the S-isomer of omeprazole) fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use (see Data) . In animal studies with administration of oral esomeprazole magnesium in rats, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data] . The estimated background risks of major birth defects and miscarriage for the indicated population 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 Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If naproxen and esomeprazole magnesium delayed-release tablets treatment is needed in pregnant women, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue naproxen and esomeprazole magnesium delayed-release tablets and follow up according to clinical practice (see Data) . Labor or Delivery There are no studies on the effects of naproxen and esomeprazole magnesium delayed-release tablets during labor or delivery. In animal studies, NSAIDs, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Naproxen When used to delay preterm labor, inhibitors of prostaglandin synthesis, including NSAIDs such naproxen, may increase the risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Esomeprazole Esomeprazole is the S-isomer of omeprazole. Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H 2 -receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H 2 -blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H 2 -blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data There are no reproduction studies in animals with naproxen and esomeprazole magnesium delayed-release tablets, a combination of naproxen and esomeprazole. Naproxen Reproduction studies with naproxen administered during the period of organogenesis have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.56 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of harm to the fetus due to the drug. Esomeprazole No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis and have revealed no evidence of harm to the fetus due to esomeprazole magnesium. A pre-and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times a daily human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times a daily human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times the daily human dose of 40 mg on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in the pre-and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre-and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

12.1 Mechanism of Action Naproxen and esomeprazole magnesium delayed-release tablets consist of an immediate-release esomeprazole magnesium layer and an enteric-coated naproxen core. As a result, esomeprazole is released first in the stomach, prior to the dissolution of naproxen in the small intestine. The enteric coating prevents naproxen release at pH levels below 5.5. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen and esomeprazole magnesium delayed-release tablets have analgesic, anti-inflammatory, and antipyretic properties contributed by the naproxen component. Naproxen is a potent inhibitor of prostaglandin synthesis in vitro . Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to an increase of prostaglandins in peripheral tissues. Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H + /K + -ATPase in the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 mg to 40 mg and leads to inhibition of gastric acid secretion.

12.2 Pharmacodynamics Interaction with Aspirin In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B 2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%] [see Drug Interactions ( 7 )]. Antisecretory Activity The effect of naproxen and esomeprazole magnesium delayed-release tablets on intragastric pH was determined in 25 healthy volunteers in one study. Three naproxen and esomeprazole magnesium delayed-release tablets combinations (naproxen 500 mg combined with either esomeprazole 10 mg, 20 mg, or 30 mg) were administered twice daily over 9 days. The results are shown in the following table: Table 5: Effect on Intragastric pH on Day 9 (N=25) † Gastric pH was measured over a 24-hour period LS Mean (SE) Naproxen 500 mg combined with esomeprazole 10 mg 20 mg 30 mg % Time Gastric pH >4 † 41.1 (3.0) 71.5 (3.0) 76.8 (3.0) Coefficient of variation 55% 18% 16% Serum Gastrin Effects The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6 to12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. Enterochromaffin-like (ECL) Cell Effects In over 1,000 patients treated with esomeprazole (10, 20 or 40 mg/day) up to 6 to12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa. Endocrine Effects Esomeprazole had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. Effects on Gastrointestinal Microbial Ecology Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile .

12.3 Pharmacokinetics Absorption Naproxen At steady state following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose. Bioequivalence between naproxen and esomeprazole magnesium delayed-release tablets and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses. Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. Steady-state levels of naproxen are reached in 4 to 5 days. Esomeprazole Following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of naproxen and esomeprazole magnesium delayed-release tablets. Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of naproxen and esomeprazole magnesium delayed-release tablets 500 mg/20 mg. Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of naproxen and esomeprazole magnesium delayed-release tablets (500mg/20 mg) Food Effect Administration of naproxen and esomeprazole magnesium delayed-release tablets together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs t max by 10 hours and decreases peak plasma concentration (C max ) by about 12%. Administration of naproxen and esomeprazole magnesium delayed-release tablets together with high-fat food in healthy volunteers delays t max of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C max ), respectively. Administration of naproxen and esomeprazole magnesium delayed-release tablets 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C max ) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions [see Dosage and Administration ( 2 )]. Administration of naproxen and esomeprazole magnesium delayed-release tablets 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C max by 50% compared to administration under fasted conditions. This increase in esomeprazole C max does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C max [see Dosage and Administration ( 2 )]. Therefore, naproxen and esomeprazole magnesium delayed-release tablets should be taken at least 30 minutes before the meal. Distribution Naproxen Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C ss 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [see Use in Specific Populations ( 8.2 )]. Esomeprazole The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound. Elimination Metabolism Naproxen Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half-life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of naproxen and esomeprazole magnesium delayed-release tablets twice daily. Esomeprazole Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl-and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion. The area under the plasma esomeprazole concentration-time curve increases with repeated administration of naproxen and esomeprazole magnesium delayed-release tablets. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of naproxen and esomeprazole magnesium delayed-release tablets probably also contributes to the time-and dose-dependency. Excretion Naproxen Following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing. The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate [see Warnings and Precautions ( 5.6 )]. Esomeprazole Following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2 hours to 1.5 hours). Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine. Specific Populations Geriatric Patients There is no specific data on the pharmacokinetics of naproxen and esomeprazole magnesium delayed-release tablets in patients over age 65. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is less than 1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients [see Adverse Reactions ( 6 ) and Use in Specific Populations ( 8.5 )]. The AUC and C max values of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary. Male and Female Patients The AUC and C max values of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary. Racial or Ethnic Groups Pharmacokinetic differences due to race have not been studied for naproxen. Approximately 3% of Caucasians and 15 % to 20 % of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Patients with Renal Impairment The pharmacokinetics of naproxen and esomeprazole magnesium delayed-release tablets or naproxen have not been determined in subjects with renal impairment. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products, including naproxen and esomeprazole magnesium delayed-release tablets, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance less than 30 ml/min) [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.7 )]. No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function. Patients with Hepatic Impairment The pharmacokinetics of naproxen and esomeprazole magnesium delayed-release tablets or naproxen have not been determined in subjects with hepatic impairment. In patients with severe hepatic impairment, naproxen and esomeprazole magnesium delayed-release tablets should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen. Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of naproxen and esomeprazole magnesium delayed-release tablets dosing is unknown but it is prudent to use the lowest effective dose. The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2 times to 3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of naproxen and esomeprazole magnesium delayed-release tablets. There is no naproxen and esomeprazole magnesium delayed-release tablets dosage form that contains less than 20 mg esomeprazole for twice daily dosing [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.3 )]. Drug Interaction Studies Effect of Naproxen on Other Drugs Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions ( 7 )]. Effect of Esomeprazole on Other Drugs Cytochrome P 450 Interactions Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Clopidogrel : Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite [see Warnings and Precautions ( 5.22 ), Drug Interactions ( 7 )]. Mycophenolate Mofetil : Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C max and 23% reduction in the AUC of MPA [see Drug Interactions ( 7 )]. Cilostazol: Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max and AUC of cilostazol by 18% and 26% respectively. C max and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69% respectively [see Drug Interactions ( 7 )]. Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy- t -butylamide (M8) [see Drug Interactions ( 7 )]. Atazanavir: Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C max by 96%, and C min by 95% [see Drug Interactions ( 7 )]. Saquinavir: Elevated serum levels have been reported with an increase in AUC by 82% in C max by 75% and in C min by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15 [see Drug Interactions ( 7 )]. Diazepam: Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam [see Drug Interactions ( 7 )]. Digoxin: Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions ( 7 )]. Effect of Other Drugs on Esomeprazole Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole. St. John’s Wort: In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C max and AUC decreased by 49.6% and 43.9%, respectively) [see Warnings and Precautions ( 5.25 ), Drug Interactions ( 7 )]. Voriconazole: Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C max and AUC 0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [see Drug Interactions ( 7 )]. figure1

Absorption Naproxen At steady state following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose. Bioequivalence between naproxen and esomeprazole magnesium delayed-release tablets and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses. Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. Steady-state levels of naproxen are reached in 4 to 5 days. Esomeprazole Following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of naproxen and esomeprazole magnesium delayed-release tablets. Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of naproxen and esomeprazole magnesium delayed-release tablets 500 mg/20 mg. Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of naproxen and esomeprazole magnesium delayed-release tablets (500mg/20 mg) Food Effect Administration of naproxen and esomeprazole magnesium delayed-release tablets together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs t max by 10 hours and decreases peak plasma concentration (C max ) by about 12%. Administration of naproxen and esomeprazole magnesium delayed-release tablets together with high-fat food in healthy volunteers delays t max of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C max ), respectively. Administration of naproxen and esomeprazole magnesium delayed-release tablets 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C max ) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions [see Dosage and Administration ( 2 )]. Administration of naproxen and esomeprazole magnesium delayed-release tablets 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C max by 50% compared to administration under fasted conditions. This increase in esomeprazole C max does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C max [see Dosage and Administration ( 2 )]. Therefore, naproxen and esomeprazole magnesium delayed-release tablets should be taken at least 30 minutes before the meal. Distribution Naproxen Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C ss 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [see Use in Specific Populations ( 8.2 )]. Esomeprazole The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound. Elimination Metabolism Naproxen Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half-life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of naproxen and esomeprazole magnesium delayed-release tablets twice daily. Esomeprazole Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl-and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion. The area under the plasma esomeprazole concentration-time curve increases with repeated administration of naproxen and esomeprazole magnesium delayed-release tablets. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of naproxen and esomeprazole magnesium delayed-release tablets probably also contributes to the time-and dose-dependency. Excretion Naproxen Following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing. The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate [see Warnings and Precautions ( 5.6 )]. Esomeprazole Following administration of naproxen and esomeprazole magnesium delayed-release tablets twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2 hours to 1.5 hours). Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine. Specific Populations Geriatric Patients There is no specific data on the pharmacokinetics of naproxen and esomeprazole magnesium delayed-release tablets in patients over age 65. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is less than 1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients [see Adverse Reactions ( 6 ) and Use in Specific Populations ( 8.5 )]. The AUC and C max values of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary. Male and Female Patients The AUC and C max values of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary. Racial or Ethnic Groups Pharmacokinetic differences due to race have not been studied for naproxen. Approximately 3% of Caucasians and 15 % to 20 % of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Patients with Renal Impairment The pharmacokinetics of naproxen and esomeprazole magnesium delayed-release tablets or naproxen have not been determined in subjects with renal impairment. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products, including naproxen and esomeprazole magnesium delayed-release tablets, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance less than 30 ml/min) [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.7 )]. No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function. Patients with Hepatic Impairment The pharmacokinetics of naproxen and esomeprazole magnesium delayed-release tablets or naproxen have not been determined in subjects with hepatic impairment. In patients with severe hepatic impairment, naproxen and esomeprazole magnesium delayed-release tablets should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen. Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of naproxen and esomeprazole magnesium delayed-release tablets dosing is unknown but it is prudent to use the lowest effective dose. The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2 times to 3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of naproxen and esomeprazole magnesium delayed-release tablets. There is no naproxen and esomeprazole magnesium delayed-release tablets dosage form that contains less than 20 mg esomeprazole for twice daily dosing [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.3 )]. Drug Interaction Studies Effect of Naproxen on Other Drugs Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions ( 7 )]. Effect of Esomeprazole on Other Drugs Cytochrome P 450 Interactions Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Clopidogrel : Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite [see Warnings and Precautions ( 5.22 ), Drug Interactions ( 7 )]. Mycophenolate Mofetil : Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C max and 23% reduction in the AUC of MPA [see Drug Interactions ( 7 )]. Cilostazol: Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max and AUC of cilostazol by 18% and 26% respectively. C max and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69% respectively [see Drug Interactions ( 7 )]. Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy- t -butylamide (M8) [see Drug Interactions ( 7 )]. Atazanavir: Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C max by 96%, and C min by 95% [see Drug Interactions ( 7 )]. Saquinavir: Elevated serum levels have been reported with an increase in AUC by 82% in C max by 75% and in C min by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15 [see Drug Interactions ( 7 )]. Diazepam: Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam [see Drug Interactions ( 7 )]. Digoxin: Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions ( 7 )]. Effect of Other Drugs on Esomeprazole Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole. St. John’s Wort: In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C max and AUC decreased by 49.6% and 43.9%, respectively) [see Warnings and Precautions ( 5.25 ), Drug Interactions ( 7 )]. Voriconazole: Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C max and AUC 0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [see Drug Interactions ( 7 )]. figure1

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or caregivers of the following before initiating therapy with naproxen and esomeprazole magnesium delayed-release tablets and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions ( 5.1 )]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions ( 5.2 )]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop naproxen and esomeprazole magnesium delayed-release tablets and seek immediate medical therapy [see Warnings and Precautions ( 5.3 )]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their health care provider if such symptoms occur [see Warnings and Precautions ( 5.5 )]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 )]. Serious or Severe Skin Reactions, Including DRESS Advise patients to stop taking naproxen and esomeprazole magnesium delayed-release tablets immediately if they develop any type of rash or fever and contact their health care provider as soon as possible [see Warnings and Precautions ( 5.9 , 5.10 )]. Fetal Toxicity Inform pregnant women to avoid use of naproxen and esomeprazole magnesium delayed-release tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with naproxen and esomeprazole magnesium delayed-release tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios [see Warnings and Precautions ( 5.11 ) Use in Specific Populations ( 8.1 )]. Infertility Advise females of reproductive potential that NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, may be associated with reversible infertility [see Use in Specific Populations ( 8.3 )]. Gastric Malignancy To return to their healthcare provider if they have gastric symptoms while taking naproxen and esomeprazole magnesium delayed-release tablets or after completing treatment [see Warnings and Precautions ( 5.17 )]. Acute Tubulointerstitial Nephritis Advise patients to report to their health care provider immediately if they experience a decrease in the amount they urinate or have blood in their urine [see Warnings and Precautions ( 5.18 )]. Clostridium difficile -Associated Diarrhea Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions ( 5.19 )]. Bone Fracture Advise patients to report any sign or symptom of osteoporosis (e.g., recent bone fracture, low bone density) to their health care provider [see Warnings and Precautions ( 5.20 )]. Cutaneous and Systemic Lupus Erythematosus Advise patients to immediately call their healthcare provider any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions ( 5.21 )]. Cyanocobalamin (Vitamin B-12) Deficiency Advise patients taking naproxen and esomeprazole magnesium delayed-release tablets for long periods of time, to report to their healthcare provider if they experience weakness, tiredness, or light-headedness or rapid heartbeat and breathing or pale skin [see Warnings and Precautions ( 5.23 )]. Hypomagnesemia and Mineral Metabolism Advise patients to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to their healthcare provider, if they have been receiving naproxen and esomeprazole magnesium delayed-release tablets for at least 3 months. [see Warnings and Precautions ( 5.24 )]. Drug Interactions

• Inform patients that the concomitant use of naproxen and esomeprazole magnesium delayed-release tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) it is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions ( 5.16 ), Drug Interactions ( 7 )] . Alert patients that NSAIDs may be present in the “over the counter” medications for treatment of colds, fever or insomnia.
• Advise patients to report to their healthcare provider if they start treatment with clopidogrel, St. John’s Wort or rifampin; or, if they take high-dose methotrexate [see Warnings and Precautions ( 5.22 , 5.25 , 5.27 )].
• Inform patients not to use low-dose aspirin concomitantly with naproxen and esomeprazole magnesium delayed-release tablets until they talk to their health care provider [see Drug Interactions ( 7 )]. Administration
• Inform patients that naproxen and esomeprazole magnesium delayed-release tablets should be swallowed whole with liquid. Tablets should not be split, chewed, crushed or dissolved. Naproxen and esomeprazole magnesium delayed-release tablets should be taken at least 30 minutes before meals [see Dosage and Administration ( 2 )].
• Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose.
• Inform patients that antacids may be used while taking naproxen and esomeprazole magnesium delayed-release tablets. Product of India Manufactured by: Ajanta Pharma Limited, India Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Repackaged By: Preferred Pharmaceuticals Inc. #All trademarks are the properties of their respective owners Revised: 12/2025