پاروکستین

اختلال افسردگی اساسی قرص پاروکستین، USP برای درمان اختلال افسردگی اساسی اندیکاسیون دارد. اثربخشی پاروکستین در درمان یک دوره افسردگی اساسی در کارآزمایی‌های کنترل‌شده 6 هفته‌ای روی بیماران سرپایی مشخص شد که تشخیص‌های آن‌ها بیشتر با دسته DSM-III اختلال افسردگی اساسی مطابقت داشت (به فارماکولوژی بالینی: کارآزمایی‌های بالینی مراجعه کنید). یک دوره افسردگی اساسی حاکی از یک خلق افسرده یا ناخوشایند برجسته و نسبتاً مداوم است که معمولاً با عملکرد روزانه (تقریباً هر روز به مدت حداقل 2 هفته) تداخل دارد. حداقل باید شامل 4 مورد از 8 علامت زیر باشد: تغییر در اشتها، تغییر در خواب، تحریک روانی حرکتی یا عقب ماندگی، از دست دادن علاقه به فعالیت های معمول یا کاهش میل جنسی، افزایش خستگی، احساس گناه یا بی ارزشی، کاهش تفکر یا اختلال در تمرکز، و اقدام به خودکشی یا افکار خودکشی. اثرات پاروکستین در بیماران افسرده بستری در بیمارستان به اندازه کافی مورد مطالعه قرار نگرفته است. اثربخشی پاروکستین در حفظ پاسخ در اختلال افسردگی اساسی تا 1 سال در یک کارآزمایی کنترل‌شده با دارونما نشان داده شد (به داروسازی بالینی: کارآزمایی‌های بالینی مراجعه کنید). با این وجود، پزشکی که استفاده از پاروکستین را برای دوره های طولانی انتخاب می کند، باید به طور دوره ای سودمندی طولانی مدت دارو را برای هر بیمار مورد ارزیابی مجدد قرار دهد. قرص های پاروکستین، USP برای درمان وسواس و اجبار در بیماران مبتلا به اختلال وسواس فکری عملی (OCD) همانطور که در DSM-IV تعریف شده است، نشان داده شده است. وسواس ها یا اجبارها باعث ناراحتی قابل توجهی می شوند، زمان گیر هستند یا به طور قابل توجهی با عملکرد اجتماعی یا شغلی تداخل دارند. اثربخشی پاروکستین در دو کارآزمایی 12 هفته‌ای با بیماران سرپایی وسواسی جبری که تشخیص‌های آنها بیشترین مطابقت را با دسته DSM-IIIR اختلال وسواس فکری جبری داشت (به فارماکولوژی بالینی: کارآزمایی‌های بالینی مراجعه کنید) ثابت شد. اختلال وسواس فکری عملی با ایده‌ها، افکار، تکانه‌ها یا تصاویر (وسواس) تکراری و مداوم مشخص می‌شود که رفتارهای خود دیستونیک و/یا تکراری، هدفمند و عمدی (اجبارها) هستند که توسط فرد به عنوان بیش از حد یا غیرمنطقی تشخیص داده می‌شوند. حفظ اثربخشی طولانی مدت در یک کارآزمایی 6 ماهه پیشگیری از عود نشان داده شد. در این کارآزمایی، بیمارانی که به پاروکستین اختصاص داده شده بودند، در مقایسه با بیمارانی که دارونما مصرف می کردند، میزان عود کمتری نشان دادند (به داروسازی بالینی: کارآزمایی های بالینی مراجعه کنید). با این وجود، پزشکی که استفاده از پاروکستین را برای دوره های طولانی انتخاب می کند، باید به طور دوره ای سودمندی طولانی مدت دارو را برای هر بیمار مورد ارزیابی مجدد قرار دهد (به دوز و نحوه مصرف مراجعه کنید). اختلال پانیک قرص پاروکستین، USP برای درمان اختلال هراس، با یا بدون آگورافوبیا، همانطور که در DSM-IV تعریف شده است، نشان داده شده است. اختلال پانیک با وقوع حملات پانیک غیرمنتظره و نگرانی مرتبط با داشتن حملات اضافی، نگرانی در مورد پیامدها یا پیامدهای حملات و/یا تغییر قابل توجهی در رفتار مرتبط با حملات مشخص می شود. اثربخشی پاروکستین در سه کارآزمایی 10 تا 12 هفته‌ای در بیماران مبتلا به اختلال پانیک که تشخیص‌های آن‌ها با رده اختلال هراس DSM-IIIR مطابقت داشت ثابت شد (به فارماکولوژی بالینی مراجعه کنید: کارآزمایی‌های بالینی). اختلال پانیک (DSM-IV) با حملات پانیک غیرمنتظره مکرر مشخص می شود، به عنوان مثال، یک دوره مجزا از ترس یا ناراحتی شدید که در آن 4 (یا بیشتر) از علائم زیر به طور ناگهانی ایجاد می شود و در عرض 10 دقیقه به اوج خود می رسد: (1) تپش قلب، تپش قلب، یا ضربان قلب تند. (2) عرق کردن؛ (3) لرزیدن یا لرزش. (4) احساس تنگی نفس یا خفگی؛ (5) احساس خفگی؛ (6) درد یا ناراحتی قفسه سینه؛ (7) حالت تهوع یا ناراحتی شکمی. (8) احساس سرگیجه، بی ثباتی، سبکی سر، یا غش. (9) واقع نشدن (احساس غیرواقعی بودن) یا مسخ شخصیت (از خود جدا شدن). (10) ترس از دست دادن کنترل؛ (11) ترس از مردن. (12) پارستزی (بی حسی یا سوزن سوزن شدن)؛ (13) لرز یا گرگرفتگی. حفظ طولانی مدت اثربخشی در یک کارآزمایی 3 ماهه پیشگیری از عود نشان داده شد. در این کارآزمایی، بیماران مبتلا به اختلال پانیک که به پاروکستین اختصاص داده شده بود، میزان عود کمتری در مقایسه با بیمارانی که دارونما مصرف می‌کردند نشان دادند (به داروسازی بالینی: کارآزمایی‌های بالینی مراجعه کنید). با این وجود، پزشکی که پاروکستین را برای دوره های طولانی تجویز می کند، باید به طور دوره ای سودمندی طولانی مدت دارو را برای هر بیمار مورد ارزیابی مجدد قرار دهد (به دوز و نحوه مصرف مراجعه کنید). اختلال اضطراب اجتماعی قرص پاروکستین برای درمان اختلال اضطراب اجتماعی که به عنوان فوبیای اجتماعی نیز شناخته می شود، همانطور که در DSM-IV (300.23) تعریف شده است، نشان داده شده است. اختلال اضطراب اجتماعی با ترس مشخص و مداوم از یک یا چند موقعیت اجتماعی یا عملکردی مشخص می شود که در آن فرد در معرض افراد ناآشنا یا در معرض بررسی احتمالی دیگران قرار می گیرد. قرار گرفتن در معرض موقعیت ترسناک تقریباً همیشه باعث ایجاد اضطراب می شود که ممکن است به شدت حمله پانیک نزدیک شود. از موقعیت های ترسناک اجتناب می شود یا با اضطراب یا پریشانی شدید تحمل می شود. اجتناب، پیش بینی اضطرابی یا پریشانی در موقعیت(های) ترسناک به طور قابل توجهی با روال عادی، عملکرد شغلی یا تحصیلی، یا فعالیت ها یا روابط اجتماعی فرد تداخل می کند، یا ناراحتی مشخصی در مورد داشتن فوبیا وجود دارد. درجات کمتری از اضطراب عملکرد یا کمرویی معمولاً نیازی به درمان روان‌دارویی ندارند. اثربخشی پاروکستین در سه کارآزمایی 12 هفته ای در بیماران بزرگسال مبتلا به اختلال اضطراب اجتماعی (DSM-IV) مشخص شد. پاروکستین در کودکان یا نوجوانان مبتلا به فوبیای اجتماعی مورد مطالعه قرار نگرفته است (به فارماکولوژی بالینی: کارآزمایی های بالینی مراجعه کنید). اثربخشی پاروکستین در درمان طولانی مدت اختلال اضطراب اجتماعی، یعنی برای بیش از 12 هفته، به طور سیستماتیک در کارآزمایی های کافی و به خوبی کنترل شده ارزیابی نشده است. بنابراین، پزشکی که تصمیم می‌گیرد پاروکستین را برای دوره‌های طولانی‌مدت تجویز کند، باید به‌طور دوره‌ای سودمندی طولانی‌مدت دارو را برای هر بیمار مورد ارزیابی مجدد قرار دهد (به دوز و نحوه مصرف مراجعه کنید). اختلال اضطراب فراگیر قرص پاروکستین، USP برای درمان اختلال اضطراب فراگیر (GAD)، همانطور که در DSM-IV تعریف شده است، نشان داده شده است. اضطراب یا تنش مرتبط با استرس زندگی روزمره معمولاً نیازی به درمان با داروهای ضد اضطراب ندارد. اثربخشی پاروکستین در درمان GAD در دو کارآزمایی 8 هفته ای کنترل شده با دارونما در بزرگسالان مبتلا به GAD مشخص شد. پاروکستین در کودکان یا نوجوانان مبتلا به اختلال اضطراب فراگیر مطالعه نشده است (به فارماکولوژی بالینی: کارآزمایی های بالینی مراجعه کنید). اختلال اضطراب فراگیر (DSM-IV) با اضطراب و نگرانی بیش از حد (انتظار دلهره آمیز) مشخص می شود که حداقل به مدت 6 ماه ادامه دارد و کنترل آن برای فرد دشوار است. باید حداقل با 3 مورد از 6 علامت زیر همراه باشد: بیقراری یا احساس بی قراری یا بی قراری، به راحتی خستگی، مشکل در تمرکز یا خالی شدن ذهن، تحریک پذیری، تنش عضلانی، اختلال خواب. اثربخشی پاروکستین در حفظ پاسخ در بیماران مبتلا به اختلال اضطراب فراگیر، که در طول یک مرحله درمان حاد 8 هفته ای در حین مصرف پاروکستین پاسخ دادند و سپس در طی یک دوره 24 هفته ای عود کردند، در یک کارآزمایی کنترل شده با دارونما نشان داده شد (به CLINICAL PHARMACOLOG مراجعه کنید). با این وجود، پزشکی که استفاده از پاروکستین را برای دوره های طولانی انتخاب می کند، باید به طور دوره ای سودمندی طولانی مدت دارو را برای هر بیمار مورد ارزیابی مجدد قرار دهد (به دوز و نحوه مصرف مراجعه کنید). اختلال استرس پس از سانحه قرص پاروکستین برای درمان اختلال استرس پس از سانحه (PTSD) اندیکاسیون دارد. اثربخشی پاروکستین در درمان PTSD در دو کارآزمایی 12 هفته ای کنترل شده با دارونما در بزرگسالان مبتلا به PTSD (DSM-IV) ثابت شد (به فارماکولوژی بالینی: کارآزمایی های بالینی مراجعه کنید). PTSD، همانطور که توسط DSM-IV تعریف شده است، مستلزم قرار گرفتن در معرض یک رویداد آسیب زا است که شامل مرگ واقعی یا تهدید شده یا آسیب جدی، یا تهدیدی برای تمامیت جسمانی خود یا دیگران، و پاسخی است که شامل ترس شدید، درماندگی یا وحشت است. علائمی که در نتیجه قرار گرفتن در معرض رویداد آسیب زا رخ می دهد شامل تجربه مجدد رویداد به شکل افکار مزاحم، بازگشت به گذشته یا رویاها و پریشانی روانی شدید و واکنش فیزیولوژیکی در مواجهه با نشانه های رویداد است. اجتناب از موقعیت‌هایی که یادآور رویداد آسیب‌زا است، ناتوانی در یادآوری جزئیات رویداد، و/یا بی‌حسی در پاسخگویی عمومی که به صورت کاهش علاقه به فعالیت‌های مهم، بیگانگی از دیگران، محدودیت دامنه عاطفه، یا احساس آینده‌ای کوتاه‌شده آشکار می‌شود. و علائم برانگیختگی خودمختار از جمله هوشیاری بیش از حد، واکنش مبالغه آمیز مبهوت کننده، اختلال خواب، اختلال در تمرکز، و تحریک پذیری یا طغیان خشم. تشخیص PTSD مستلزم آن است که علائم حداقل به مدت یک ماه وجود داشته باشد و باعث ناراحتی یا اختلال بالینی قابل توجه در عملکرد اجتماعی، شغلی یا سایر زمینه های مهم شود. اثربخشی پاروکستین در درمان طولانی مدت PTSD، یعنی برای بیش از 12 هفته، به طور سیستماتیک در کارآزمایی های کنترل شده با دارونما ارزیابی نشده است. بنابراین، پزشکی که تصمیم می‌گیرد پاروکستین را برای دوره‌های طولانی‌مدت تجویز کند، باید به‌طور دوره‌ای سودمندی طولانی‌مدت دارو را برای هر بیمار مورد ارزیابی مجدد قرار دهد (به دوز و نحوه مصرف مراجعه کنید).

اختلال افسردگی اساسی دوز اولیه معمول قرص پاروکستین، USP باید به صورت یک دوز روزانه با یا بدون غذا، معمولاً در صبح تجویز شود. دوز اولیه توصیه شده 20 میلی گرم در روز است. بیماران در محدوده 20 تا 50 میلی گرم در روز در کارآزمایی های بالینی که اثربخشی قرص پاروکستین، USP را در درمان اختلال افسردگی اساسی نشان می دهد، دوز دریافت کردند. مانند تمام داروهای مؤثر در درمان اختلال افسردگی اساسی، تأثیر کامل ممکن است به تأخیر بیفتد. برخی از بیمارانی که به دوز 20 میلی گرم پاسخ نمی دهند ممکن است از افزایش دوز 10 میلی گرم در روز تا حداکثر 50 میلی گرم در روز سود ببرند. تغییرات دوز باید در فواصل حداقل 1 هفته رخ دهد. درمان نگهدارنده هیچ مدرکی برای پاسخ به این سوال وجود ندارد که بیمار تحت درمان با قرص پاروکستین، USP چه مدت باید روی آن بماند. به طور کلی توافق بر این است که دوره های حاد اختلال افسردگی اساسی نیازمند چندین ماه یا بیشتر درمان دارویی پایدار است. اینکه آیا دوز مورد نیاز برای القای بهبودی با دوز مورد نیاز برای حفظ و/یا حفظ اتیمیا یکسان است یا خیر، ناشناخته است. ارزیابی سیستماتیک اثربخشی قرص‌های پاروکستین، USP نشان داده است که اثربخشی برای دوره‌های حداکثر 1 سال با دوزهایی که به طور متوسط ​​حدود 30 میلی‌گرم است، حفظ می‌شود. اختلال وسواس جبری دوز اولیه معمول قرص پاروکستین، USP باید به صورت یک دوز روزانه با یا بدون غذا، معمولاً در صبح مصرف شود. دوز توصیه شده از قرص پاروکستین، USP در درمان OCD 40 میلی گرم در روز است. بیماران باید با 20 میلی گرم در روز شروع شوند و دوز را می توان با افزایش 10 میلی گرم در روز افزایش داد. تغییرات دوز باید در فواصل حداقل 1 هفته رخ دهد. بیماران در محدوده 20 تا 60 میلی گرم در روز در کارآزمایی های بالینی که اثربخشی قرص پاروکستین، USP را در درمان OCD نشان می دهد، دوز دریافت کردند. حداکثر دوز نباید از 60 میلی گرم در روز تجاوز کند. درمان نگهدارنده حفظ اثربخشی طولانی مدت در یک کارآزمایی 6 ماهه پیشگیری از عود نشان داده شد. در این کارآزمایی، بیماران مبتلا به OCD که به پاروکستین اختصاص داده شده بود، نرخ عود کمتری نسبت به بیمارانی که دارونما مصرف می کردند، نشان دادند (به داروسازی بالینی: کارآزمایی های بالینی مراجعه کنید). OCD یک بیماری مزمن است، و منطقی است که برای بیمار پاسخ دهنده ادامه یابد. تنظیم دوز باید انجام شود تا بیمار در کمترین دوز موثر نگه داشته شود و بیماران باید به طور دوره‌ای مورد ارزیابی مجدد قرار گیرند تا نیاز به ادامه درمان مشخص شود. اختلال هراس دوز اولیه معمول قرص پاروکستین، USP باید به صورت یک دوز روزانه با یا بدون غذا، معمولاً در صبح تجویز شود. دوز هدف قرص پاروکستین USP در درمان اختلال هراس 40 میلی گرم در روز است. بیماران باید با 10 میلی گرم در روز شروع شوند. تغییرات دوز باید با افزایش 10 میلی گرم در روز و در فواصل حداقل 1 هفته رخ دهد. بیماران در محدوده 10 تا 60 میلی گرم در روز در کارآزمایی های بالینی که اثربخشی قرص پاروکستین، USP را نشان می دهد، دوز دریافت کردند. حداکثر دوز نباید از 60 میلی گرم در روز تجاوز کند. درمان نگهدارنده حفظ اثربخشی طولانی مدت در یک کارآزمایی 3 ماهه پیشگیری از عود نشان داده شد. در این کارآزمایی، بیماران مبتلا به اختلال پانیک که به پاروکستین اختصاص داده شده بود، میزان عود کمتری در مقایسه با بیمارانی که دارونما مصرف می‌کردند نشان دادند (به داروسازی بالینی: کارآزمایی‌های بالینی مراجعه کنید). اختلال پانیک یک وضعیت مزمن است و منطقی است که برای بیمار پاسخگو ادامه یابد. تنظیم دوز باید انجام شود تا بیمار در کمترین دوز موثر نگه داشته شود و بیماران باید به طور دوره‌ای مورد ارزیابی مجدد قرار گیرند تا نیاز به ادامه درمان مشخص شود. اختلال اضطراب اجتماعی دوز اولیه معمول قرص پاروکستین، USP باید به صورت یک دوز روزانه با یا بدون غذا، معمولاً در صبح تجویز شود. دوز توصیه شده و اولیه 20 میلی گرم در روز است. در کارآزمایی‌های بالینی، اثربخشی قرص پاروکستین، USP در بیمارانی که در محدوده 20 تا 60 میلی‌گرم در روز مصرف می‌شد، نشان داده شد. در حالی که ایمنی قرص پاروکستین، USP در بیماران مبتلا به اختلال اضطراب اجتماعی در دوزهای تا 60 میلی گرم در روز ارزیابی شده است، اطلاعات موجود هیچ مزیت اضافی را برای دوزهای بالای 20 میلی گرم در روز نشان نمی دهد (به فارماکولوژی بالینی مراجعه کنید: کارآزمایی های بالینی). درمان نگهدارنده هیچ مدرکی برای پاسخ به این سوال وجود ندارد که بیمار تحت درمان با قرص پاروکستین، USP چه مدت باید روی آن بماند. اگرچه اثربخشی قرص پاروکستین، USP بیش از 12 هفته از دوز در کارآزمایی های بالینی کنترل شده نشان داده نشده است، اختلال اضطراب اجتماعی به عنوان یک وضعیت مزمن شناخته شده است، و منطقی است که ادامه درمان را برای بیمار پاسخ دهنده در نظر بگیریم. تنظیم دوز باید انجام شود تا بیمار در کمترین دوز موثر نگه داشته شود و بیماران باید به طور دوره‌ای مورد ارزیابی مجدد قرار گیرند تا نیاز به ادامه درمان مشخص شود. اختلال اضطراب فراگیر دوز اولیه معمول قرص پاروکستین، USP باید به صورت تک دوز روزانه با یا بدون غذا، معمولاً در صبح تجویز شود. در کارآزمایی‌های بالینی، اثربخشی قرص پاروکستین، USP در بیمارانی که در محدوده 20 تا 50 میلی‌گرم در روز مصرف می‌شدند، نشان داده شد. دوز شروع توصیه شده و دوز موثر تعیین شده 20 میلی گرم در روز است. شواهد کافی برای نشان دادن سود بیشتر برای دوزهای بالاتر از 20 میلی گرم در روز وجود ندارد. تغییرات دوز باید با افزایش 10 میلی گرم در روز و در فواصل حداقل 1 هفته رخ دهد. درمان نگهدارنده ارزیابی سیستماتیک تداوم قرص پاروکستین، USP برای دوره های حداکثر 24 هفته در بیماران مبتلا به اختلال اضطراب فراگیر که در حین مصرف قرص پاروکستین، USP در طول یک مرحله درمان حاد 8 هفته ای پاسخ داده بودند، مزایای چنین نگهداری را نشان داده است (به Tribune: Clinical PHARMACOLOGY مراجعه کنید). با این وجود، بیماران باید به طور دوره ای مجدداً ارزیابی شوند تا نیاز به درمان نگهدارنده مشخص شود. اختلال استرس پس از سانحه دوز اولیه معمول قرص پاروکستین، USP باید به صورت یک دوز روزانه با یا بدون غذا، معمولاً در صبح تجویز شود. دوز شروع توصیه شده و دوز موثر تعیین شده 20 میلی گرم در روز است. در 1 کارآزمایی بالینی، اثربخشی قرص پاروکستین، USP در بیمارانی که در محدوده 20 تا 50 میلی گرم در روز دوز مصرف شده بودند، نشان داده شد. با این حال، در یک مطالعه با دوز ثابت، شواهد کافی برای نشان دادن سود بیشتر برای دوز 40 میلی گرم در روز در مقایسه با 20 میلی گرم در روز وجود نداشت. تغییرات دوز، در صورت لزوم، باید با افزایش 10 میلی گرم در روز و در فواصل حداقل 1 هفته رخ دهد. درمان نگهدارنده هیچ مدرکی برای پاسخ به این سوال وجود ندارد که بیمار تحت درمان با قرص پاروکستین، USP چه مدت باید روی آن بماند. اگرچه اثربخشی قرص پاروکستین، USP بیش از 12 هفته از دوز در کارآزمایی‌های بالینی کنترل‌شده نشان داده نشده است، PTSD به عنوان یک بیماری مزمن شناخته شده است، و منطقی است که ادامه درمان را برای بیمار پاسخ‌دهنده در نظر بگیریم. تنظیم دوز باید انجام شود تا بیمار در کمترین دوز موثر نگه داشته شود و بیماران باید به طور دوره‌ای مورد ارزیابی مجدد قرار گیرند تا نیاز به ادامه درمان مشخص شود. درمان جمعیت ویژه زنان باردار در طول سه ماهه سوم نوزادانی که در اواخر سه ماهه سوم در معرض قرص های پاروکستین، USP و سایر SSRI ها یا SNRI ها قرار گرفته اند، عوارضی ایجاد کرده اند که نیاز به بستری طولانی مدت، حمایت تنفسی و تغذیه لوله ای دارند (به هشدارها: مصرف در قبل مراجعه کنید). هنگام درمان زنان باردار با پاروکستین در طول سه ماهه سوم، پزشک باید به دقت خطرات و مزایای درمان را در نظر بگیرد. دوز برای بیماران مسن یا ناتوان و بیماران با نارسایی شدید کلیوی یا کبدی دوز اولیه توصیه شده 10 میلی گرم در روز برای بیماران مسن، بیماران ناتوان و/یا بیماران با نارسایی شدید کلیوی یا کبدی است. در صورت لزوم، افزایش ممکن است انجام شود. مقدار مصرف نباید بیش از 40 میلی گرم در روز باشد. تعویض بیمار به یا از یک مهارکننده مونوآمین اکسیداز (MAOI) که برای درمان اختلالات روانپزشکی در نظر گرفته شده است، حداقل 14 روز بین قطع MAOI که برای درمان اختلالات روانپزشکی و شروع درمان با قرص پاروکستین، USP است، فاصله خواهد داشت. برعکس، حداقل 14 روز پس از قطع قرص پاروکستین، USP قبل از شروع MAOI که برای درمان اختلالات روانپزشکی است، باید اجازه داده شود (به موارد منع مصرف مراجعه کنید). استفاده از قرص های پاروکستین، USP با سایر MAOI ها، مانند لینزولید یا متیلن بلو، قرص پاروکستین، USP را در بیمارانی که تحت درمان با لینزولید یا متیلن بلو داخل وریدی هستند، شروع نکنید زیرا خطر ابتلا به سندرم سروتونین افزایش می یابد. در بیماری که نیاز به درمان فوری تری برای یک بیماری روانپزشکی دارد، مداخلات دیگر، از جمله بستری شدن در بیمارستان، باید در نظر گرفته شود (به موارد منع مصرف مراجعه کنید). در برخی موارد، بیمار در حال حاضر تحت درمان با قرص پاروکستین، USP ممکن است نیاز به درمان فوری با لینزولید یا متیلن بلو داخل وریدی داشته باشد. اگر جایگزین های قابل قبولی برای لینزولید یا درمان وریدی متیلن بلو در دسترس نباشد و مزایای بالقوه درمان لینزولید یا متیلن بلو داخل وریدی بیشتر از خطرات سندرم سروتونین در یک بیمار خاص ارزیابی شود، قرص پاروکستین، USP باید فوراً قطع شود، و می توان لینزولید یا ادمینیستر بلو را می توان ادمینیستر بلو وریدی کرد. بیمار باید به مدت 2 هفته یا تا 24 ساعت پس از آخرین دوز لینزولید یا متیلن بلو وریدی از نظر علائم سندرم سروتونین تحت نظر باشد. درمان با قرص پاروکستین، USP ممکن است 24 ساعت پس از آخرین دوز لینزولید یا متیلن بلو وریدی از سر گرفته شود (به هشدارها مراجعه کنید). خطر تجویز متیلن بلو از راه های غیر وریدی (مانند قرص های خوراکی یا تزریق موضعی) یا در دوزهای داخل وریدی بسیار کمتر از mg/kg 1 همراه با قرص پاروکستین مشخص نیست. با این وجود، پزشک باید از احتمال بروز علائم سندرم سروتونین با چنین استفاده ای آگاه باشد (به هشدارها مراجعه کنید). قطع درمان با قرص پاروکستین، USP علائم مرتبط با قطع قرص پاروکستین، USP گزارش شده است (به موارد احتیاطی مراجعه کنید: قطع درمان با قرص پاروکستین). بدون توجه به نشانه ای که برای کدام قرص پاروکستین، USP تجویز می شود، بیماران باید از نظر این علائم در هنگام قطع درمان تحت نظر باشند. کاهش تدریجی دوز به جای قطع ناگهانی در صورت امکان توصیه می شود. اگر علائم غیرقابل تحمل به دنبال کاهش دوز یا پس از قطع درمان رخ دهد، ممکن است از سرگیری دوز قبلی استفاده شود. پس از آن، پزشک ممکن است به کاهش دوز ادامه دهد اما با سرعت تدریجی تر.

بدتر شدن بالینی و خطر خودکشی بیماران مبتلا به اختلال افسردگی اساسی (MDD)، اعم از بزرگسالان و کودکان، ممکن است بدتر شدن افسردگی خود و/یا ظهور افکار و رفتار خودکشی (خودکشی) یا تغییرات غیرعادی در رفتار را تجربه کنند، خواه از داروهای ضد افسردگی استفاده کنند یا نه، و این خطر ممکن است تا زمانی که بهبودی قابل توجهی رخ ندهد، ادامه یابد. خودکشی یک خطر شناخته شده افسردگی و برخی دیگر از اختلالات روانپزشکی است و این اختلالات خود قوی ترین پیش بینی کننده خودکشی هستند. با این حال، نگرانی طولانی مدتی وجود داشته است که داروهای ضد افسردگی ممکن است در القای بدتر شدن افسردگی و ظهور خودکشی در برخی از بیماران در مراحل اولیه درمان نقش داشته باشند. تجزیه و تحلیل‌های تلفیقی از کارآزمایی‌های کوتاه‌مدت کنترل‌شده با دارونما داروهای ضد افسردگی (SSRIs و سایرین) نشان داد که این داروها خطر تفکر و رفتار خودکشی (خودکشی) را در کودکان، نوجوانان و بزرگسالان جوان (18 تا 24 سال) مبتلا به اختلال افسردگی اساسی (MDD) و سایر اختلالات روان‌پزشکی افزایش می‌دهند. مطالعات کوتاه مدت افزایش خطر خودکشی با داروهای ضد افسردگی را در مقایسه با دارونما در بزرگسالان بالای 24 سال نشان نداد. کاهش مصرف داروهای ضد افسردگی در مقایسه با دارونما در بزرگسالان 65 سال و بالاتر مشاهده شد. تجزیه و تحلیل های تلفیقی از کارآزمایی های کنترل شده با دارونما در کودکان و نوجوانان مبتلا به MDD، اختلال وسواس فکری اجباری (OCD) یا سایر اختلالات روانپزشکی شامل 24 کارآزمایی کوتاه مدت از 9 داروی ضد افسردگی در بیش از 4400 بیمار بود. تجزیه و تحلیل های تلفیقی از کارآزمایی های کنترل شده با دارونما در بزرگسالان مبتلا به MDD یا سایر اختلالات روانپزشکی شامل 295 کارآزمایی کوتاه مدت (مدت زمان متوسط ​​2 ماه) از 11 داروی ضد افسردگی در بیش از 77000 بیمار بود. تنوع قابل توجهی در خطر خودکشی در بین داروها وجود داشت، اما تقریباً برای همه داروهای مورد مطالعه تمایل به افزایش در بیماران جوان‌تر وجود داشت. تفاوت در خطر مطلق خودکشی در نشانه های مختلف وجود داشت که بیشترین میزان بروز در MDD بود. تفاوت خطر (دارو در مقابل دارونما)، با این حال، در طبقات سنی و در بین نشانه ها نسبتاً پایدار بود. این تفاوت های خطر (تفاوت دارو و دارونما در تعداد موارد خودکشی به ازای هر 1000 بیمار درمان شده) در جدول 1 ارائه شده است. جدول 1 تفاوت محدوده سنی دارو و دارونما در تعداد موارد خودکشی به ازای هر 1000 بیمار درمان شده در مقایسه با دارونما افزایش می یابد <18 14 مورد اضافی 18 تا 24 5 مورد اضافی کاهش در مقایسه با دارونما 25 تا 64 مورد، 165 مورد کمتر در موارد معدودی رخ داده است. آزمایشات کودکان در کارآزمایی‌های بزرگسالان، خودکشی‌هایی وجود داشت، اما این تعداد برای رسیدن به نتیجه‌ای در مورد تأثیر دارو بر خودکشی کافی نبود. ناشناخته است که آیا خطر خودکشی به مصرف طولانی‌مدت، یعنی بیش از چندین ماه گسترش می‌یابد یا خیر. با این حال، شواهد قابل توجهی از کارآزمایی های نگهدارنده کنترل شده با دارونما در بزرگسالان مبتلا به افسردگی وجود دارد که نشان می دهد استفاده از داروهای ضد افسردگی می تواند عود افسردگی را به تاخیر بیندازد. همه بیماران تحت درمان با داروهای ضد افسردگی برای هر نشانه ای باید به طور مناسب تحت نظر قرار گیرند و از نظر بدتر شدن بالینی، خودکشی، و تغییرات غیرعادی در رفتار، به ویژه در طول چند ماه اولیه دوره درمان دارویی، یا در زمان هایی که تغییر دوز، افزایش یا کاهش می یابد، از نزدیک تحت نظر قرار گیرند. علائم زیر، اضطراب، بی قراری، حملات پانیک، بی خوابی، تحریک پذیری، خصومت، پرخاشگری، تکانشگری، آکاتیزیا (بی قراری روانی حرکتی)، هیپومانیا و شیدایی در بیماران بزرگسال و کودکی که با داروهای ضد افسردگی برای اختلال افسردگی اساسی و همچنین برای سایر نشانه های روانپزشکی درمان می شوند گزارش شده است. اگرچه ارتباط علی بین ظهور چنین علائمی و یا بدتر شدن افسردگی و/یا ظهور تکانه های خودکشی ثابت نشده است، نگرانی وجود دارد که چنین علائمی ممکن است پیش سازهای خودکشی در حال ظهور باشد. تغییر رژیم درمانی، از جمله قطع احتمالی دارو، در بیمارانی که افسردگی آنها به طور مداوم بدتر است، یا افرادی که خودکشی اضطراری یا علائمی را تجربه می کنند که ممکن است مقدماتی برای بدتر شدن افسردگی یا خودکشی باشد، باید مد نظر قرار گیرد، به خصوص اگر این علائم شدید، در شروع ناگهانی باشند، یا بخشی از بیمار نباشند. علائم اگر تصمیم به قطع درمان گرفته شده باشد، باید دارو را با سرعتی که امکان پذیر است کاهش داد، اما با توجه به اینکه قطع ناگهانی دارو می تواند با علائم خاصی همراه باشد (به احتیاط ها و دوز و نحوه مصرف مراجعه کنید: قطع درمان با قرص پاروکستین، خطر دیسکونوکس را ببینید). خانواده‌ها و مراقبان بیمارانی که برای اختلال افسردگی اساسی یا سایر نشانه‌ها، اعم از روانپزشکی و غیرروانی، تحت درمان با داروهای ضدافسردگی قرار می‌گیرند، باید در مورد نیاز به نظارت بر بیماران از نظر بروز آشفتگی، تحریک‌پذیری، تغییرات غیرعادی در رفتار و سایر علائمی که در بالا توضیح داده شد و همچنین بروز چنین علائمی و گزارش خودکشی آگاه شوند. بلافاصله به ارائه دهندگان مراقبت های بهداشتی. چنین نظارتی باید شامل مشاهده روزانه توسط خانواده ها و مراقبان باشد. نسخه های پاروکستین باید برای کمترین مقدار قرص نوشته شود که با مدیریت خوب بیمار سازگار باشد، تا خطر مصرف بیش از حد را کاهش دهد. غربالگری بیماران برای اختلال دوقطبی یک دوره افسردگی اساسی ممکن است تظاهر اولیه اختلال دوقطبی باشد. عموماً اعتقاد بر این است (اگرچه در کارآزمایی‌های کنترل‌شده ثابت نشده است) که درمان چنین دوره‌ای با یک داروی ضد افسردگی به تنهایی ممکن است احتمال وقوع یک دوره مختلط/مانیک را در بیماران در معرض خطر اختلال دوقطبی افزایش دهد. اینکه آیا هر یک از علائم شرح داده شده در بالا نشان دهنده چنین تبدیلی است یا نه ناشناخته است. با این حال، قبل از شروع درمان با داروهای ضد افسردگی، بیماران مبتلا به علائم افسردگی باید به اندازه کافی غربالگری شوند تا مشخص شود که آیا در معرض خطر اختلال دوقطبی هستند یا خیر. چنین غربالگری باید شامل یک تاریخچه دقیق روانپزشکی، از جمله سابقه خانوادگی خودکشی، اختلال دوقطبی و افسردگی باشد. لازم به ذکر است که پاروکستین برای استفاده در درمان افسردگی دوقطبی تایید نشده است. سندرم سروتونین ایجاد یک سندرم سروتونین بالقوه تهدید کننده زندگی با SNRI ها و SSRI ها، از جمله پاروکستین، به تنهایی گزارش شده است، اما به ویژه با استفاده همزمان با سایر داروهای سروتونرژیک (از جمله تریپتان ها، ضد افسردگی های سه حلقه ای، فنتانیل، لیتیوم، ترامادول، تریپتومپینس آمپون، و...). John's Wort) و با داروهایی که متابولیسم سروتونین را مختل می کنند (به ویژه، MAOIها، هم آنهایی که برای درمان اختلالات روانپزشکی و هم داروهای دیگر، مانند لینزولید و متیلن بلو وریدی). علائم سندرم سروتونین ممکن است شامل تغییرات وضعیت روانی (مانند بی قراری، توهم، هذیان، و کما)، بی ثباتی اتونومیک (مانند تاکی کاردی، فشار خون ناپایدار، سرگیجه، دیافورز، گرگرفتگی، گرمازایی)، علائم عصبی-عضلانی (مانند لرزش، نارسایی ریژیکولینوس) تشنج و/یا علائم گوارشی (به عنوان مثال، تهوع، استفراغ، اسهال). بیماران باید از نظر بروز سندرم سروتونین تحت نظر باشند. مصرف همزمان پاروکستین با MAOIهایی که برای درمان اختلالات روانپزشکی طراحی شده اند منع مصرف دارد. همچنین در بیمارانی که تحت درمان با MAOI مانند لینزولید یا متیلن بلو داخل وریدی هستند، نباید پاروکستین را شروع کرد. تمام گزارش‌های مربوط به متیلن بلو که اطلاعاتی در مورد مسیر تجویز ارائه می‌کردند شامل تجویز داخل وریدی در محدوده دوز 1 میلی‌گرم بر کیلوگرم تا 8 میلی‌گرم بر کیلوگرم بود. هیچ گزارشی مبنی بر تجویز متیلن بلو از راه‌های دیگر (مانند قرص‌های خوراکی یا تزریق موضعی بافت) یا در دوزهای پایین‌تر وجود نداشت. ممکن است شرایطی وجود داشته باشد که شروع درمان با یک MAOI مانند لینزولید یا متیلن بلو داخل وریدی در بیمار مصرف کننده پاروکستین ضروری باشد. قبل از شروع درمان با MAOI باید پاروکستین را قطع کرد (به موارد منع مصرف و دوز و نحوه مصرف مراجعه کنید). اگر مصرف همزمان پاروکستین با برخی از داروهای سروتونرژیک دیگر، مانند تریپتان ها، داروهای ضد افسردگی سه حلقه ای، فنتانیل، لیتیوم، ترامادول، بوسپیرون، تریپتوفان، آمفتامین ها و خارمریم از نظر بالینی ضروری است، از افزایش خطر بالقوه افزایش خاص درمان در طول سندرم سروتونین آگاه باشید. در صورت بروز حوادث فوق، درمان با پاروکستین و هر داروی سروتونرژیک همزمان باید فوراً قطع شود و درمان علامتی حمایتی باید آغاز شود. گلوکوم زاویه بسته اتساع مردمک چشم که به دنبال استفاده از بسیاری از داروهای ضد افسردگی از جمله پاروکستین رخ می دهد، ممکن است باعث حمله بسته شدن زاویه در یک بیمار با زوایای آناتومیک باریک شود که ایریدکتومی ثبت شده انجام نمی دهد. تداخل بالقوه با تیوریدازین تجویز تیوریدازین به تنهایی باعث طولانی شدن فاصله QTc می شود که با آریتمی های بطنی جدی مانند آریتمی های نوع تورساد د پوینت و مرگ ناگهانی همراه است. به نظر می رسد این اثر مربوط به دوز باشد. یک مطالعه in vivo نشان می‌دهد که داروهایی که CYP2D6 را مهار می‌کنند، مانند پاروکستین، سطح تیوریدازین را در پلاسما افزایش می‌دهند. بنابراین، توصیه می شود که پاروکستین همراه با تیوریدازین استفاده نشود (به موارد منع مصرف و اقدامات احتیاطی مراجعه کنید). مصرف در بارداری اثرات تراتوژنیک مطالعات اپیدمیولوژیک نشان داده است که نوزادانی که در سه ماهه اول بارداری در معرض پاروکستین قرار می گیرند، خطر ناهنجاری های مادرزادی، به ویژه ناهنجاری های قلبی عروقی را افزایش می دهند. یافته‌های حاصل از این مطالعات در زیر خلاصه می‌شود: مطالعه‌ای بر اساس داده‌های ثبت ملی سوئد نشان داد که نوزادانی که در دوران بارداری در معرض پاروکستین قرار گرفته‌اند (تعداد = 815) خطر ناهنجاری‌های قلبی عروقی (2٪ خطر در نوزادان در معرض پاروکستین) در مقایسه با کل جمعیت ثبت شده (1٪)، برای یک شانس بینابینی 1٪ (8.1٪) برای اطمینان . به 2.8). هیچ افزایشی در خطر ناهنجاری های مادرزادی کلی در نوزادانی که در معرض پاروکستین قرار داشتند مشاهده نشد. ناهنجاری های قلبی در نوزادانی که در معرض پاروکستین قرار گرفته بودند، عمدتاً نقص دیواره بین بطنی (VSDs) و نقایص سپتوم دهلیزی (ASDs) بودند. نقایص سپتوم از نظر شدت، از مواردی که خود به خود برطرف می شوند تا مواردی که نیاز به جراحی دارند، متغیر است. یک مطالعه کوهورت گذشته‌نگر جداگانه از ایالات متحده (داده‌های مراقبت‌های بهداشتی ایالات متحده) 5956 نوزاد از مادرانی که داروهای ضدافسردگی را در طول سه ماهه اول تجویز کردند (تعداد = 815 برای پاروکستین) ارزیابی کرد. این مطالعه روندی را به سمت افزایش خطر ناهنجاری های قلبی عروقی برای پاروکستین (خطر 1.5٪) در مقایسه با سایر داروهای ضد افسردگی (خطر 1٪) برای OR 1.5 (فاصله اطمینان 95٪ 0.8 تا 2.9) نشان داد. از 12 نوزاد مبتلا به ناهنجاری های قلبی عروقی در معرض پاروکستین، 9 نفر مبتلا به VSD بودند. این مطالعه همچنین افزایش خطر کلی ناهنجاری های مادرزادی عمده از جمله نقایص قلبی عروقی برای پاروکستین (خطر 4٪) را در مقایسه با سایر داروهای ضد افسردگی (2٪ خطر) (OR 1.8؛ 95٪ فاصله اطمینان 1.2 تا 2.8) پیشنهاد کرد. دو مطالعه مورد-شاهدی بزرگ با استفاده از پایگاه‌های داده جداگانه، هر کدام با بیش از 9000 مورد نقص مادرزادی و بیش از 4000 مورد کنترل، نشان دادند که استفاده مادر از پاروکستین در سه ماهه اول بارداری با افزایش 2 تا 3 برابری خطر انسداد مجرای خروجی بطن راست همراه بود. در یک مطالعه نسبت شانس 2.5 (فاصله اطمینان 95٪، 1 تا 6، 7 نوزاد در معرض تماس) و در مطالعه دیگر نسبت شانس 3.3 (فاصله اطمینان 95٪، 1.3 تا 8.8، 6 نوزاد در معرض تماس) بود. مطالعات دیگر نتایج متفاوتی در مورد افزایش خطر ناهنجاری های کلی، قلبی عروقی یا مادرزادی خاص یافته اند. متاآنالیز داده‌های اپیدمیولوژیک در یک دوره 16 ساله (1992 تا 2008) در مورد استفاده از پاروکستین در سه ماهه اول بارداری و ناهنجاری‌های مادرزادی شامل مطالعات ذکر شده در بالا علاوه بر مطالعات دیگر بود (17 مطالعه شامل ناهنجاری‌های کلی و 14 مطالعه شامل ناهنجاری‌های قلبی عروقی = 0). با وجود محدودیت‌ها، این متاآنالیز افزایش بروز ناهنجاری‌های قلبی عروقی (نسبت شانس شیوع [POR] 1.5؛ فاصله اطمینان 95% از 1.2 تا 1.9) و ناهنجاری‌های کلی (POR 1.2؛ 95% فاصله اطمینان 1.1 تا 1.4) را در اولین استفاده از paroxinester پیشنهاد کرد. در این متاآنالیز تعیین میزانی که شیوع ناهنجاری‌های قلبی عروقی ممکن است در ناهنجاری‌های کلی نقش داشته باشد، امکان‌پذیر نبود، همچنین تعیین اینکه آیا هر نوع خاصی از ناهنجاری‌های قلبی عروقی ممکن است در شیوع مشاهده‌شده همه ناهنجاری‌های قلبی عروقی نقش داشته باشد، ممکن نبود. اگر بیمار در حین مصرف پاروکستین باردار شود، باید از آسیب احتمالی جنین مطلع شود. مگر اینکه فواید پاروکستین برای مادر ادامه درمان را توجیه کند، باید به قطع درمان با پاروکستین یا جایگزینی به یک داروی ضد افسردگی دیگر توجه شود (به موارد احتیاطی مراجعه کنید: قطع درمان با قرص پاروکستین). برای زنانی که قصد باردار شدن دارند یا در سه ماهه اول بارداری خود هستند، پاروکستین تنها باید پس از بررسی سایر گزینه های درمانی موجود شروع شود. یافته‌های حیوانی مطالعات تولید مثل در دوزهای 50 میلی‌گرم بر کیلوگرم در روز در موش‌ها و 6 میلی‌گرم بر کیلوگرم در روز در خرگوش‌هایی که در طول اندام‌زایی تجویز شده بودند، انجام شد. این دوزها تقریباً 8 (موش) و 2 (خرگوش) برابر حداکثر دوز توصیه شده برای انسان (MRHD) بر اساس mg/m 2 است. این مطالعات هیچ شواهدی از اثرات تراتوژنیک نشان نداده اند. با این حال، در موش ها، افزایش مرگ و میر توله ها در طول 4 روز اول شیردهی وجود داشت، زمانی که دوز در سه ماهه آخر بارداری رخ داد و در طول دوره شیردهی ادامه یافت. این اثر در دوز mg/kg/day 1 یا تقریباً یک ششم MRHD بر اساس mg/m2 رخ داد. دوز بدون اثر برای مرگ و میر توله سگ موش تعیین نشد. علت این مرگ و میرها مشخص نیست. اثرات غیرتراتوژنیک نوزادانی که در اواخر سه ماهه سوم در معرض پاروکستین و سایر SSRI ها یا مهارکننده های بازجذب سروتونین و نوراپی نفرین (SNRIs) قرار می گیرند، عوارضی ایجاد کرده اند که نیاز به بستری طولانی مدت، حمایت تنفسی و تغذیه لوله ای دارند. چنین عوارضی می تواند بلافاصله پس از زایمان ایجاد شود. یافته های بالینی گزارش شده شامل دیسترس تنفسی، سیانوز، آپنه، تشنج، بی ثباتی دما، مشکل در تغذیه، استفراغ، هیپوگلیسمی، هیپوتونی، هیپرتونی، هیپررفلکسی، لرزش، بی قراری، تحریک پذیری و گریه مداوم است. این ویژگی ها با اثر سمی مستقیم SSRI ها و SNRI ها یا احتمالاً با سندرم قطع دارو سازگار است. لازم به ذکر است که در برخی موارد، تصویر بالینی با سندرم سروتونین مطابقت دارد (به هشدارها مراجعه کنید: سندرم سروتونین). نوزادانی که در حاملگی در معرض SSRI ها قرار می گیرند ممکن است خطر افزایش فشار خون ریوی مداوم نوزاد (PPHN) را داشته باشند. PPHN در 1 تا 2 تولد در هر 1000 تولد زنده در جمعیت عمومی رخ می دهد و با عوارض و مرگ و میر نوزادان قابل توجهی همراه است. چندین مطالعه اپیدمیولوژیک اخیر ارتباط آماری مثبتی را بین مصرف SSRI (از جمله پاروکستین) در بارداری و PPHN نشان می دهد. سایر مطالعات ارتباط آماری معنی داری را نشان نمی دهند. پزشکان همچنین باید به نتایج یک مطالعه طولی آینده‌نگر روی 201 زن باردار با سابقه افسردگی اساسی که یا داروهای ضدافسردگی مصرف می‌کردند یا کمتر از 12 هفته قبل از آخرین قاعدگی خود داروهای ضدافسردگی دریافت کرده بودند و در حال بهبودی بودند، یادداشت کنند. زنانی که داروهای ضد افسردگی را در دوران بارداری قطع کردند، در مقایسه با زنانی که در طول بارداری از داروهای ضد افسردگی استفاده کردند، افزایش قابل توجهی در عود افسردگی اساسی خود نشان دادند. هنگام درمان یک زن باردار با پاروکستین، پزشک باید خطرات بالقوه مصرف SSRI و فواید ثابت شده درمان افسردگی با داروهای ضد افسردگی را به دقت در نظر بگیرد. این تصمیم را می‌توان تنها بر اساس مورد به مورد اتخاذ کرد (به دوز و تجویز و واکنش‌های نامطلوب مراجعه کنید: گزارش‌های پس از بازاریابی).

General Activation of Mania/Hypomania During premarketing testing, hypomania or mania occurred in approximately 1% of unipolar patients treated with paroxetine compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine should be used cautiously in patients with a history of mania. Seizures During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Discontinuation of Treatment With Paroxetine Tablets Recent clinical trials supporting the various approved indications for paroxetine employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention. During marketing of paroxetine and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with paroxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION ). See also PRECAUTIONS: Pediatric Use , for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients. Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions ). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. Akathisia The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including paroxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use ). Discontinuation of paroxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation. Bone Fracture Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising. Use in Patients With Concomitant Illness Clinical experience with paroxetine in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine is prescribed for patients with narrow angle glaucoma. Paroxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Similarly, paroxetine does not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION ). Information for Patients Paroxetine should not be chewed or crushed, and should be swallowed whole. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine and triptans, tramadol, or other serotonergic agents. Patients should be advised that taking paroxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine. Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Interference With Cognitive and Motor Performance Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine does not affect their ability to engage in such activities. Completing Course of Therapy While patients may notice improvement with treatment with paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol Although paroxetine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects ). Nursing Patients should be advised to notify their physician if they are breastfeeding an infant (see PRECAUTIONS: Nursing Mothers ). Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions Tryptophan As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome ). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. Pimozide In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C max of 62%, compared to pimozide administered alone. The increase in pimozide AUC and C max is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see CONTRAINDICATIONS ). Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John’s Wort (see WARNINGS: Serotonin Syndrome ). The concomitant use of paroxetine with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS ). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan ). Thioridazine See CONTRAINDICATIONS and WARNINGS . Warfarin Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere With Hemostasis ). Triptans There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome ). Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes. Cimetidine Cimetidine inhibits many cytochrome P 450 (oxidative) enzymes. In a study where paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied. Phenobarbital Phenobarbital induces many cytochrome P 450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T ½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect. Phenytoin When a single oral 30 mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T ½ were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports ). Drugs Metabolized by CYP2D6 Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P 450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine. In 1 study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C max , AUC, and T ½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine C max values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug. Therefore, coadministration of paroxetine with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS ). Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS ). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P 450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Tricyclic Antidepressants (TCAs)). Drugs Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro K i and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Tricyclic Antidepressants (TCAs) Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6 ). Drugs Highly Bound to Plasma Protein Because paroxetine is highly bound to plasma protein, administration of paroxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs. Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued. Alcohol Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine. Lithium A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with lithium. Digoxin The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution. Diazepam Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated. Procyclidine Daily oral dosing of paroxetine (30 mg once daily) increased steady-state AUC 0-24 , C max , and C min values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing Reports ). Theophylline Reports of elevated theophylline levels associated with treatment with paroxetine have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Fosamprenavir/Ritonavir Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy). Electroconvulsive Therapy (ECT) There are no clinical studies of the combined use of ECT and paroxetine. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD on a mg/m 2 basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Impairment of Fertility Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m 2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m 2 basis). Pregnancy Pregnancy Category D. See WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects . Labor and Delivery The effect of paroxetine on labor and delivery in humans is unknown. Nursing Mothers Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine is administered to a nursing woman. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk ). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with paroxetine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine in a child or adolescent must balance the potential risks with the clinical need. Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as paroxetine. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Events reported upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION: Discontinuation of Treatment With Paroxetine Tablets ). Geriatric Use SSRIs and SNRIs, including paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS: Hyponatremia ). In worldwide premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

General Activation of Mania/Hypomania During premarketing testing, hypomania or mania occurred in approximately 1% of unipolar patients treated with paroxetine compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine should be used cautiously in patients with a history of mania. Seizures During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Discontinuation of Treatment With Paroxetine Tablets Recent clinical trials supporting the various approved indications for paroxetine employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention. During marketing of paroxetine and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with paroxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION ). See also PRECAUTIONS: Pediatric Use , for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients. Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions ). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. Akathisia The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including paroxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use ). Discontinuation of paroxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation. Bone Fracture Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising. Use in Patients With Concomitant Illness Clinical experience with paroxetine in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine is prescribed for patients with narrow angle glaucoma. Paroxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Similarly, paroxetine does not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION ).

Tryptophan As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome ). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS. Pimozide In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C max of 62%, compared to pimozide administered alone. The increase in pimozide AUC and C max is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see CONTRAINDICATIONS ). Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John’s Wort (see WARNINGS: Serotonin Syndrome ). The concomitant use of paroxetine with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS ). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan ). Thioridazine See CONTRAINDICATIONS and WARNINGS . Warfarin Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere With Hemostasis ). Triptans There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome ). Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes. Cimetidine Cimetidine inhibits many cytochrome P 450 (oxidative) enzymes. In a study where paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied. Phenobarbital Phenobarbital induces many cytochrome P 450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T ½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect. Phenytoin When a single oral 30 mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T ½ were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports ). Drugs Metabolized by CYP2D6 Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P 450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine. In 1 study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C max , AUC, and T ½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine C max values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug. Therefore, coadministration of paroxetine with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS ). Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS ). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P 450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Tricyclic Antidepressants (TCAs)). Drugs Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro K i and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Tricyclic Antidepressants (TCAs) Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6 ). Drugs Highly Bound to Plasma Protein Because paroxetine is highly bound to plasma protein, administration of paroxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs. Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued. Alcohol Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine. Lithium A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with lithium. Digoxin The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution. Diazepam Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated. Procyclidine Daily oral dosing of paroxetine (30 mg once daily) increased steady-state AUC 0-24 , C max , and C min values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing Reports ). Theophylline Reports of elevated theophylline levels associated with treatment with paroxetine have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Fosamprenavir/Ritonavir Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy). Electroconvulsive Therapy (ECT) There are no clinical studies of the combined use of ECT and paroxetine.

Associated With Discontinuation of Treatment Twenty percent (1,199/6,145) of patients treated with paroxetine in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with paroxetine in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD, and PTSD, respectively, discontinued treatment due to an adverse event. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) included the following: Major Depressive Disorder OCD Panic Disorder Social Anxiety Disorder Generalized Anxiety Disorder PTSD Paroxetine Placebo Paro xetine Placebo Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo CNS Somnolence 2.3% 0.7% — 1.9% 0.3% 3.4% 0.3% 2% 0.2% 2.8% 0.6% Insomnia — — 1.7% 0% 1.3% 0.3% 3.1% 0% - - Agitation 1.1% 0.5% — - - Tremor 1.1% 0.3% — 1.7% 0% 1% 0.2% Anxiety — — — 1.1% 0% - - Dizziness — — 1.5% 0% 1.9% 0% 1% 0.2% - - Gastrointestinal Constipation — 1.1% 0% - - Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 4% 0.3% 2% 0.2% 2.2% 0.6% Diarrhea 1% 0.3% — Dry mouth 1% 0.3% — - - Vomiting 1% 0.3% — 1% 0% - - Flatulence 1% 0.3% - - Other Asthenia 1.6% 0.4% 1.9% 0.4% 2.5% 0.6% 1.8% 0.2% 1.6% 0.2% Abnormal Ejaculation 1 1.6% 0% 2.1% 0% 4.9% 0.6% 2.5% 0.5% - - Sweating 1% 0.3% — 1.1% 0% 1.1% 0.2% - - Impotence 1 — 1.5% 0% - - Libido Decreased 1% 0% - - Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not >1% or was not greater than or equal to 2 times the incidence of placebo. 1. Incidence corrected for gender. Commonly Observed Adverse Events Major Depressive Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 2) were: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. Obsessive Compulsive Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. Panic Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. Social Anxiety Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. Generalized Anxiety Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. Posttraumatic Stress Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Incidence in Controlled Clinical Trials The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied. Major Depressive Disorder Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder 1 Body System Preferred Term Paroxetine (n=421) Placebo (n=421) Body as a Whole Headache 18% 17% Asthenia 15% 6% Cardiovascular Palpitation 3% 1% Vasodilation 3% 1% Dermatologic Sweating 11% 2% Rash 2% 1% Gastrointestinal Nausea 26% 9% Dry Mouth 18% 12% Constipation 14% 9% Diarrhea 12% 8% Decreased Appetite 6% 2% Flatulence 4% 2% Oropharynx Disorder 2 2% 0% Dyspepsia 2% 1% Musculoskeletal Myopathy 2% 1% Myalgia 2% 1% Myasthenia 1% 0% Nervous System Somnolence 23% 9% Dizziness 13% 6% Insomnia 13% 6% Tremor 8% 2% Nervousness 5% 3% Anxiety 5% 3% Paresthesia 4% 2% Libido Decreased 3% 0% Drugged Feeling 2% 1% Confusion 1% 0% Respiration Yawn 4% 0% Special Senses Blurred Vision 4% 1% Taste Perversion 2% 0% Urogenital System Ejaculatory Disturbance 3,4 13% 0% Other Male Genital Disorders 3,5 10% 0% Urinary Frequency 3% 1% Urination Disorder 6 3% 0% Female Genital Disorders 3,7 2% 0% Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: Abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly "cold symptoms" or "URI"), trauma, and vomiting. Includes mostly "lump in throat" and "tightness in throat." Percentage corrected for gender. Mostly "ejaculatory delay." Includes "anorgasmia," "erectile difficulties," "delayed ejaculation/orgasm, and "sexual dysfunction," and "impotence." Includes mostly "difficulty with micturition" and "urinary hesitancy." Includes mostly "anorgasmia" and "difficulty reaching climax/orgasm." Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder 1 Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Body System Preferred Term Paroxetine (n=542) Placebo (n=265) Paroxetine (n=469) Placebo (n=324) Paroxetine (n=425) Placebo (n=339) Body as a Whole Asthenia 22% 14% 14% 5% 22% 14% Abdominal Pain — — 4% 3% — — Chest Pain 3% 2% — — — — Back Pain — — 3% 2% — — Chills 2% 1% 2% 1% — — Trauma — — — — 3% 1% Cardiovascular Vasodilation 4% 1% — — — — Palpitation 2% 0% — — — — Dermatologic Sweating 9% 3% 14% 6% 9% 2% Rash 3% 2% — — — — Gastrointestinal Nausea 23% 10% 23% 17% 25% 7% Dry Mouth 18% 9% 18% 11% 9% 3% Constipation 16% 6% 8% 5% 5% 2% Diarrhea 10% 10% 12% 7% 9% 6% Decreased Appetite 9% 3% 7% 3% 8% 2% Dyspepsia — — — — 4% 2% Flatulence — — — — 4% 2% Increased Appetite 4% 3% 2% 1% — — Vomiting — — — — 2% 1% Musculoskeletal Myalgia — — — — 4% 3% Nervous System Insomnia 24% 13% 18% 10% 21% 16% Somnolence 24% 7% 19% 11% 22% 5% Dizziness 12% 6% 14% 10% 11% 7% Tremor 11% 1% 9% 1% 9% 1% Nervousness 9% 8% — — 8% 7% Libido Decreased 7% 4% 9% 1% 12% 1% Agitation — — 5% 4% 3% 1% Anxiety — — 5% 4% 5% 4% Abnormal Dreams 4% 1% — — — — Concentration Impaired 3% 2% — — 4% 1% Depersonalization 3% 0% — — — — Myoclonus 3% 0% 3% 2% 2% 1% Amnesia 2% 1% — — — — Respiratory System Rhinitis — — 3% 0% — — Pharyngitis — — — — 4% 2% Yawn — — — — 5% 1% Special Senses Abnormal Vision 4% 2% — — 4% 1% Taste Perversion 2% 0% — — — — Urogenital System Abnormal Ejaculation 2 23% 1% 21% 1% 28% 1% Dysmenorrhea — — — — 5% 4% Female Genital Disorder 2 3% 0% 9% 1% 9% 1% Impotence 2 8% 1% 5% 0% 5% 1% Urinary Frequency 3% 1% 2% 0% — — Urination Impaired 3% 0% — — — — Urinary Tract Infection 2% 1% 2% 1% — — Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and sinusitis. Percentage corrected for gender. Generalized Anxiety Disorder and Posttraumatic Stress Disorder Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg/day to 50 mg/day. Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disorder 1 Body System Preferred Term Generalized Anxiety Disorder Posttraumatic Stress Disorder Paroxetine (n = 735) Placebo (n = 529) Paroxetine (n = 676) Placebo (n = 504) Body as a Whole Asthenia 14% 6% 12% 4% Headache 17% 14% — — Infection 6% 3% 5% 4% Abdominal Pain 4% 3% Trauma 6% 5% Cardiovascular Vasodilation 3% 1% 2% 1% Dermatologic Sweating 6% 2% 5% 1% Gastrointestinal Nausea 20% 5% 19% 8% Dry Mouth 11% 5% 10% 5% Constipation 10% 2% 5% 3% Diarrhea 9% 7% 11% 5% Decreased Appetite 5% 1% 6% 3% Vomiting 3% 2% 3% 2% Dyspepsia — — 5% 3% Nervous System Insomnia 11% 8% 12% 11% Somnolence 15% 5% 16% 5% Dizziness 6% 5% 6% 5% Tremor 5% 1% 4% 1% Nervousness 4% 3% — — Libido Decreased 9% 2% 5% 2% Abnormal Dreams 3% 2% Respiratory System Respiratory Disorder 7% 5% — — Sinusitis 4% 3% — — Yawn 4% — 2% <1% Special Senses Abnormal Vision 2% 1% 3% 1% Urogenital System Abnormal Ejaculation 2 25% 2% 13% 2% Female Genital Disorder 2 4% 1% 5% 1% Impotence 2 4% 3% 9% 1% Events reported by at least 2% of GAD and PTSD in patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain, headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis Percentage corrected for gender. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine, as shown in Table 5: Table 5. Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder* Body System/Preferred Term Placebo Paroxetine n=51 10mg n=102 20 mg n=104 30 mg n=101 40 mg n=102 Body as a Whole Asthenia 0% 2.9% 10.6% 13.9% 12.7% Dermatology Sweating 2% 1% 6.7% 8.9% 11.8% Gastrointestinal Constipation Decreased Appetite Diarrhea Dry Mouth Nausea 5.9% 2% 7.8% 2% 13.7% 4.9% 2% 9.8% 10.8% 14.7% 7.7% 5.8% 19.2% 18.3% 26.9% 9.9% 4% 7.9% 15.8% 34.7% 12.7% 4.9% 14.7% 20.6% 36.3% Nervous System Anxiety Dizziness Nervousness Paresthesia Somnolence Tremor 0% 3.9% 0% 0% 7.8% 0% 2% 6.9% 5.9% 2.9% 12.7% 0% 5.8% 6.7% 5.8% 1% 18.3% 7.7% 5.9% 8.9% 4% 5% 20.8% 7.9% 5.9% 12.7% 2.9% 5.9% 21.6% 14.7% Special Senses Blurred Vision 2% 2.9% 2.9% 2% 7.8% Urogenital System Abnormal Ejaculation Impotence Male Genital Disorders 0% 0% 0% 5.8% 1.9% 3.8% 6.5% 4.3% 8.7% 10.6% 6.4% 6.4% 13% 1.9% 3.7% * Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups and ≥ twice the placebo incidence for at least 1 paroxetine group. In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned. In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation. In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine in the treatment of posttraumatic stress disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for impotence and abnormal ejaculation. Adaptation to Certain Adverse Events Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia). Male and Female Sexual Dysfunction With SSRIs Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence. In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6. Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials Paroxetine Placebo n (males) 1446 1042 Decreased Libido 6 to 15% 0 to 5% Ejaculatory Disturbance 13 to 28% 0 to 2% Impotence 2 to 9% 0 to 3% n (females) 1822 1340 Decreased Libido 0 to 9% 0 to 2% Orgasmic Disturbance 2 to 9% 0 to 1% There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment. Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Weight and Vital Sign Changes Significant weight loss may be an undesirable result of treatment with paroxetine for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine in controlled clinical trials. ECG Changes In an analysis of ECGs obtained in 682 patients treated with paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. Liver Function Tests In placebo-controlled clinical trials, patients treated with paroxetine exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities. Hallucinations In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo. Other Events Observed During the Premarketing Evaluation of Paroxetine During its premarketing assessment in major depressive disorder, multiple doses of paroxetine were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676 patients, respectively, received multiple doses of paroxetine. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine who experienced an event of the type cited on at least 1 occasion while receiving paroxetine. All reported events are included except those already listed in Tables 2 to 5, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also described in the PRECAUTIONS section. Body as a Whole Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare : Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System Frequent: Hypertension, tachycardia; infrequent : Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare : Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles. Digestive System Infrequent : Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; rare : Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems Infrequent : Anemia, leukopenia, lymphadenopathy, purpura; rare : Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased. Musculoskeletal System Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare : Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome. Respiratory System Infrequent : Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages Frequent: Pruritus; infrequent : Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses Frequent: Tinnitus; infrequent : Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect. Urogenital System Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare : Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis. Postmarketing Reports Voluntary reports of adverse events in patients taking paroxetine that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

Pharmacodynamics The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha 1 -, alpha 2 -, beta-adrenergic-, dopamine (D 2 )-, 5-HT 1 -, 5-HT 2 -, and histamine (H 1 )-receptors; antagonism of muscarinic, histaminergic, and alpha 1 -adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent compound, they are essentially inactive. Pharmacokinetics Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower C max or AUC than females. Absorption and Distribution Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C max , T max , C min , and T ½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21 hours (CV 32%), respectively. The steady-state C max and C min values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC 0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable. The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the C max was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Metabolism and Excretion The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to C min values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6 ). Other Clinical Pharmacology Information Specific Populations Renal and Liver Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, C max ). The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION ). Elderly Patients : In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30, and 40 mg, C min concentrations were about 70% to 80% greater than the respective C min concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION ). Drug-Drug Interactions In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions ). Clinical Trials Major Depressive Disorder The efficacy of paroxetine as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine was shown to be significantly more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. A study of outpatients with major depressive disorder who had responded to paroxetine (HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. Obsessive Compulsive Disorder The effectiveness of paroxetine in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1 Outcome Classification Placebo (n = 74) Paroxetine 20 mg (n = 75) Paroxetine 40 mg (n = 66) Paroxetine 60 mg (n = 66) Worse 14% 7% 7% 3% No Change 44% 35% 22% 19% Minimally Improved 24% 33% 29% 34% Much Improved 11% 18% 22% 24% Very Much Improved 7% 7% 20% 20% Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term maintenance effects of paroxetine in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Panic Disorder The effectiveness of paroxetine in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1 to 3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients. In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. Long-term maintenance effects of paroxetine in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. Social Anxiety Disorder The effectiveness of paroxetine in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively. Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender. Generalized Anxiety Disorder The effectiveness of paroxetine in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV). Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine, were randomized to continuation of paroxetine at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. Posttraumatic Stress Disorder The effectiveness of paroxetine in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to placebo. Doses of 20 mg and 40 mg of paroxetine were demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo. Paroxetine was demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo, demonstrated paroxetine to be significantly superior to placebo on change from baseline for CAPS¬2 total score, but not on proportion of responders on the CGI-I. The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively.