بوپرنورفین هیدروکلراید

اعتیاد، سوء استفاده و استفاده نادرست تزریق بوپرنورفین هیدروکلراید حاوی بوپرنورفین، یک ماده کنترل شده در جدول III است. بوپرنورفین به عنوان یک ماده افیونی، مصرف کنندگان را در معرض خطرات اعتیاد، سوء استفاده و سوء استفاده قرار می دهد. اگرچه خطر اعتیاد در هر فردی ناشناخته است، اما می تواند در بیمارانی که بوپرنورفین به طور مناسب تجویز می کنند رخ دهد. اعتیاد می تواند در دوزهای توصیه شده و در صورت سوء استفاده یا سوء استفاده از دارو رخ دهد. خطر مصرف بیش از حد مواد افیونی یا مرگ ناشی از مصرف بیش از حد با دوزهای بالاتر مواد افیونی افزایش می یابد و این خطر در طول دوره درمان ادامه می یابد. در مطالعات پس از بازاریابی، اعتیاد، سوء استفاده، استفاده نادرست، و مصرف بیش از حد مواد مخدر کشنده و غیرکشنده در بیماران با مصرف طولانی مدت مواد افیونی مشاهده شد [به واکنش های نامطلوب مراجعه کنید]. قبل از تجویز بوپرنورفین، خطر اعتیاد، سوء مصرف یا سوء مصرف هر بیمار را برای اعتیاد به مواد افیونی ارزیابی کنید و همه بیماران دریافت کننده بوپرنورفین را برای ایجاد این رفتارها و شرایط مورد ارزیابی مجدد قرار دهید. خطرات در بیماران با سابقه شخصی یا خانوادگی سوء مصرف مواد (از جمله اعتیاد به مواد مخدر یا الکل یا سوء مصرف) یا بیماری روانی (مانند افسردگی اساسی) افزایش می یابد. با این حال، پتانسیل این خطرات نباید مانع از تجویز بوپرنورفین برای مدیریت مناسب درد در هر بیمار خاص شود. برای بیماران در معرض خطر ممکن است مواد افیونی مانند بوپرنورفین تجویز شود، اما استفاده در چنین بیمارانی مستلزم مشاوره شدید در مورد خطرات و استفاده صحیح بوپرنورفین همراه با ارزیابی مجدد مکرر برای علائم اعتیاد، سوء استفاده و سوء استفاده است. مواد افیونی برای استفاده غیرپزشکی جستجو می شوند و در معرض انحراف از استفاده قانونی تجویز شده هستند. این خطرات را هنگام تجویز یا توزیع بوپرنورفین در نظر بگیرید. استراتژی های کاهش این خطرات شامل ذخیره سازی مناسب محصول و شیوه های کنترل برای یک داروی C-III است. برای اطلاع از نحوه جلوگیری و تشخیص سوء استفاده یا انحراف از این محصول، با هیئت صدور مجوز حرفه ای ایالتی یا مرجع مواد کنترل شده دولتی تماس بگیرید. افسردگي تنفسي تهديد كننده حيات، افسردگي تنفسي شديد، تهديد كننده يا كشنده حتي در صورت استفاده از مواد افيوني گزارش شده است. افسردگی تنفسی، اگر فورا تشخیص داده نشود و درمان نشود، ممکن است منجر به افسردگی تنفسی و مرگ شود. مدیریت افسردگی تنفسی ممکن است شامل مشاهده دقیق، اقدامات حمایتی و استفاده از داروهای معکوس کننده مصرف بیش از حد مواد افیونی (مانند نالوکسان، نالمفن)، بسته به وضعیت بالینی بیمار باشد. احتباس دی اکسید کربن (CO 2) ناشی از دپرسیون تنفسی ناشی از مواد افیونی می تواند اثرات آرام بخش مواد افیونی را تشدید کند. در حالی که افسردگی جدی، تهدید کننده زندگی یا کشنده تنفسی می تواند در هر زمانی در طول استفاده از بوپرنورفین رخ دهد، این خطر در طول شروع درمان یا پس از افزایش دوز بیشتر است. برای کاهش خطر افسردگی تنفسی، دوز مناسب و تیتراسیون بوپرنورفین ضروری است. تخمین بیش از حد دوز بوپرنورفین هنگام تبدیل بیماران از یک فرآورده مخدر دیگر می تواند منجر به مصرف بیش از حد دوز کشنده با اولین دوز شود. مواد افیونی می توانند باعث اختلالات تنفسی مرتبط با خواب از جمله آپنه مرکزی خواب (CSA) و هیپوکسمی مرتبط با خواب شوند. مصرف مواد افیونی خطر ابتلا به CSA را به صورت وابسته به دوز افزایش می دهد. در بیمارانی که با CSA مراجعه می‌کنند، کاهش دوز مواد افیونی را با استفاده از بهترین روش‌ها برای کاهش اپیوئیدها در نظر بگیرید [به دوز و تجویز مراجعه کنید]. خطرات ناشی از مصرف همزمان با بنزودیازپین ها یا سایر داروهای مضعف CNS آرامبخشی عمیق، افسردگی تنفسی، کما و مرگ ممکن است ناشی از مصرف همزمان بوپرنورفین هیدروکلراید با بنزودیازپین ها و/یا سایر داروهای مضعف CNS، از جمله الکل (به عنوان مثال، داروهای غیر بنزودیازپین، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشنج، ضداکسیلینوز، داروهای ضد تشنج، داروهای ضد تشنج، داروهای ضد تشعشعات عصبی)، خطرات ناشی از مصرف همزمان بوپرنورفین هیدروکلراید و مرگ باشد. شل کننده های عضلانی، داروهای بیهوشی عمومی، داروهای ضد روان پریشی، گاباپنتینوئیدها [گاباپنتین یا پره گابالین] و سایر مواد افیونی). به دلیل این خطرات، تجویز همزمان این داروها را برای استفاده در بیمارانی که گزینه های درمانی جایگزین برای آنها ناکافی است، رزرو کنید. مطالعات مشاهده‌ای نشان داده‌اند که مصرف همزمان مسکن‌های اپیوئیدی و بنزودیازپین‌ها خطر مرگ و میر ناشی از مصرف دارو را در مقایسه با استفاده از مسکن‌های مخدر به تنهایی افزایش می‌دهد. به دلیل خواص دارویی مشابه، منطقی است که خطر مشابهی را با مصرف همزمان سایر داروهای مضعف CNS با مسکن‌های اپیوئیدی انتظار داشته باشیم [به تداخلات دارویی مراجعه کنید]. اگر تصمیم به تجویز بنزودیازپین یا سایر داروهای مضعف CNS به همراه مسکن مخدر گرفته شده است، کمترین دوز موثر و حداقل مدت زمان مصرف همزمان را تجویز کنید. در بیمارانی که قبلاً مسکن اپیوئیدی دریافت می‌کنند، دوز اولیه بنزودیازپین یا سایر داروهای مضعف CNS را کمتر از آنچه در غیاب یک اپیوئید نشان داده شده است تجویز کنید و بر اساس پاسخ بالینی آن را تیتر کنید. اگر در بيماري كه قبلاً بنزوديازپين يا ساير داروهاي مضعف CNS مصرف مي‌كند، داروي ضددرد شبه افيوني شروع شود، دوز اوليه كمتري از مسكن اپيوييدي را تجويز كنيد و بر اساس پاسخ باليني آن را تيتر كنيد. بیماران را از نظر علائم و نشانه‌های افسردگی تنفسی و آرام‌بخشی از نزدیک تحت نظر بگیرید. سندرم ترک مواد افیونی نوزادان استفاده از بوپرنورفین برای مدت طولانی در دوران بارداری می تواند منجر به ترک اعتیاد در نوزاد شود. سندرم ترک مواد افیونی نوزادان، بر خلاف سندرم ترک مواد افیونی در بزرگسالان، در صورت عدم شناسایی و درمان ممکن است تهدید کننده زندگی باشد و نیاز به مدیریت بر اساس پروتکل های توسعه یافته توسط متخصصان نوزادان دارد. نوزادان را از نظر علائم سندرم ترک مواد افیونی نوزادان مشاهده کنید و بر اساس آن مدیریت کنید. به زنان باردار که برای مدت طولانی از مواد افیونی استفاده می کنند در مورد خطر سندرم ترک مواد افیونی نوزادان توصیه کنید و اطمینان حاصل کنید که درمان توسط متخصصان نوزادان هنگام زایمان در دسترس خواهد بود [به هشدارها، اقدامات احتیاطی: اطلاعات برای بیماران، بارداری مراجعه کنید]. پردردی ناشی از مواد افیونی و آلودینیا پردردی ناشی از مواد افیونی (OIH) زمانی رخ می دهد که یک مسکن مخدر به طور متناقضی باعث افزایش درد یا افزایش حساسیت به درد شود. این شرایط با تحمل متفاوت است، که نیاز به افزایش دوز مواد افیونی برای حفظ یک اثر مشخص است (به وابستگی مراجعه کنید). علائم OIH عبارتند از (اما ممکن است محدود به آن نباشد) افزایش سطح درد با افزایش دوز مواد افیونی، کاهش سطح درد پس از کاهش دوز مواد افیونی، یا درد ناشی از محرک های معمولی غیر دردناک (آلوداینیا). این علائم تنها در صورتی ممکن است OIH را نشان دهند که هیچ مدرکی دال بر پیشرفت بیماری زمینه ای، تحمل به مواد افیونی، ترک مواد افیونی یا رفتار اعتیادآور وجود نداشته باشد. موارد OIH گزارش شده است، هم با استفاده کوتاه مدت و هم طولانی مدت از مسکن های مخدر. اگرچه مکانیسم OIH به طور کامل شناخته نشده است، مسیرهای بیوشیمیایی متعددی دخیل هستند. ادبیات پزشکی وجود یک معقول بیولوژیکی قوی بین مسکن های مخدر و OIH و آلوداینیا را نشان می دهد. اگر بیمار مشکوک به تجربه OIH است، به دقت کاهش دوز ضددرد یا چرخش اپیوئیدی فعلی را به دقت در نظر بگیرید (به طور ایمن بیمار را به یک گروه دیگر مواد افیونی تغییر دهید) (به دوز و تجویز، هشدارها مراجعه کنید). افسردگي تنفسي تهديد كننده حيات در بيماران مبتلا به بيماري مزمن ريوي يا در بيماران مسن، كاككتيك يا ناتوان استفاده از بوپرنورفين در بيماران مبتلا به آسم برونشيال حاد يا شديد در محيط بدون نظارت يا در غياب تجهيزات احيا منع مصرف دارد. بیماران مبتلا به بیماری مزمن ریوی: بیماران تحت درمان با بوپرنورفین با بیماری انسدادی مزمن ریه یا کورپولمونال، و آنهایی که به طور قابل توجهی ذخیره تنفسی، هیپوکسی، هیپرکاپنیا، یا دپرسیون تنفسی از قبل موجود کاهش یافته است، حتی در دوزهای توصیه شده بوپرنورفین (WARNINGS) در معرض خطر کاهش نیروی تنفسی از جمله آپنه هستند. بیماران مسن، کشکتیک یا ناتوان: افسردگی تنفسی تهدید کننده زندگی بیشتر در بیماران مسن، کشکتیک یا ناتوان رخ می دهد، زیرا ممکن است در مقایسه با بیماران جوانتر و سالم تر، فارماکوکینتیک یا کلیرانس را تغییر داده باشند. چنین بیمارانی را به‌ویژه هنگام شروع و تیتراسیون بوپرنورفین و هنگامی که بوپرنورفین همزمان با سایر داروهایی که تنفس را کاهش می‌دهند تجویز می‌شود، به دقت تحت نظر داشته باشید [به هشدارها مراجعه کنید]. روش دیگر، استفاده از مسکن های غیر مخدر در این بیماران را در نظر بگیرید. نارسایی آدرنال مواردی از نارسایی آدرنال با مصرف مواد افیونی گزارش شده است که اغلب پس از مصرف بیش از یک ماه می باشد. تظاهر نارسایی آدرنال ممکن است شامل علائم و نشانه های غیر اختصاصی از جمله تهوع، استفراغ، بی اشتهایی، خستگی، ضعف، سرگیجه و فشار خون پایین باشد. در صورت مشکوک بودن به نارسایی آدرنال، در اسرع وقت با آزمایش های تشخیصی، تشخیص را تایید کنید. اگر نارسایی آدرنال تشخیص داده شد، با دوزهای جایگزین فیزیولوژیک کورتیکواستروئیدها درمان کنید. بیمار را از مواد افیونی جدا کنید تا عملکرد آدرنال بهبود یابد و درمان کورتیکواستروئید را تا بهبود عملکرد آدرنال ادامه دهید. سایر مواد افیونی ممکن است آزمایش شوند زیرا برخی موارد استفاده از یک مخدر دیگر را بدون عود نارسایی آدرنال گزارش کرده اند. اطلاعات موجود هیچ گونه افیونی خاصی را که بیشتر با نارسایی آدرنال مرتبط است شناسایی نمی کند. افت فشار خون شدید بوپرنورفین ممکن است باعث افت فشار خون شدید از جمله افت فشار خون ارتواستاتیک و سنکوپ در بیماران سرپایی شود. در بیمارانی که توانایی آنها در حفظ فشار خون قبلاً به دلیل کاهش حجم خون یا تجویز همزمان برخی داروهای مضعف CNS (مانند فنوتیازین ها یا داروهای بیهوشی عمومی) به خطر افتاده است، افزایش می یابد. پس از شروع یا افزایش دوز بوپرنورفین، این بیماران را از نظر علائم افت فشار خون تحت نظر بگیرید. در بیماران مبتلا به شوک گردش خون، بوپرنورفین ممکن است باعث اتساع عروق شود که می تواند برون ده قلبی و فشار خون را بیشتر کاهش دهد. از مصرف بوپرنورفین در بیماران مبتلا به شوک گردش خون خودداری کنید. خطرات استفاده در بیماران با افزایش فشار داخل جمجمه ای، تومورهای مغزی، آسیب به سر، یا اختلال هوشیاری در بیمارانی که ممکن است مستعد اثرات داخل جمجمه ای احتباس CO 2 باشند (مانند کسانی که شواهدی از افزایش فشار داخل جمجمه یا تومورهای مغزی دارند)، بوپرنورفین می تواند باعث افزایش بیشتر CO2 شده و منجر به کاهش مجدد شود. فشار داخل جمجمه این بیماران را از نظر علائم آرامبخشی و افسردگی تنفسی، به ویژه در هنگام شروع درمان با بوپرنورفین، تحت نظر بگیرید. مواد افیونی همچنین ممکن است سیر بالینی را در بیمار مبتلا به آسیب سر پنهان کند. از مصرف بوپرنورفین در بیماران مبتلا به اختلال هوشیاری یا کما خودداری کنید. طولانی شدن QTc مطالعات QT کامل با فرآورده های بوپرنورفین نشان دهنده طولانی شدن QT ≤ 15 میلی ثانیه است. به نظر نمی رسد این اثر طولانی شدن QTc توسط کانال های hERG واسطه شود. بر اساس این دو یافته، زمانی که بوپرنورفین به تنهایی در بیماران بدون فاکتورهای خطر استفاده شود، بعید است که پرو آریتمی باشد. خطر ترکیب بوپرنورفین با سایر عوامل طولانی کننده QT شناخته شده نیست. این مشاهدات را در تصمیم گیری های بالینی هنگام تجویز بوپرنورفین برای بیماران مبتلا به عوامل خطر مانند هیپوکالمی، برادی کاردی، تبدیل اخیر ناشی از فیبریلاسیون دهلیزی، نارسایی احتقانی قلب، درمان دیجیتالی، طولانی شدن QT پایه، سندرم طولانی QT تحت بالینی، یا هیپومنیزیمی شدید در نظر بگیرید. واکنش های آنافیلاکتیک/آلرژیک مواردی از حساسیت حاد و مزمن به بوپرنورفین هم در کارآزمایی های بالینی و هم در تجربه پس از بازاریابی گزارش شده است. شایع ترین علائم و نشانه ها شامل بثورات، کهیر و خارش است. مواردی از اسپاسم برونش، ادم آنژیونورتیک و شوک آنافیلاکتیک گزارش شده است. بوپرنورفین در بیماران با سابقه حساسیت به بوپرنورفین منع مصرف دارد. خطرات عوارض گوارشی تزریق بوپرنورفین هیدروکلراید در بیماران مبتلا به انسداد شناخته شده یا مشکوک دستگاه گوارش، از جمله ایلئوس فلج، منع مصرف دارد. بوپرنورفین موجود در تزریق بوپرنورفین هیدروکلراید ممکن است باعث اسپاسم اسفنکتر اودی شود. مواد افیونی ممکن است باعث افزایش آمیلاز سرم شوند. بیماران مبتلا به بیماری مجاری صفراوی، از جمله پانکراتیت حاد، را برای تشدید علائم به طور منظم ارزیابی کنید. مواردی از اختلال عملکرد مری ناشی از مواد افیونی (OIED): در بیماران مصرف کننده مواد افیونی گزارش شده است. خطر OIED ممکن است با افزایش دوز و/یا مدت مواد افیونی افزایش یابد. بیماران را به طور منظم از نظر علائم و نشانه های OIED (مانند دیسفاژی، نارسایی، درد قفسه سینه غیر قلبی) ارزیابی کنید و در صورت لزوم، درمان با مواد افیونی را مطابق بالینی مناسب تنظیم کنید [به فارماکولوژی بالینی مراجعه کنید. افزایش خطر تشنج در بیماران مبتلا به اختلالات تشنج بوپرنورفین در تزریق بوپرنورفین هیدروکلراید ممکن است دفعات تشنج را در بیماران مبتلا به اختلالات تشنج افزایش دهد و ممکن است خطر تشنج را در سایر محیط های بالینی مرتبط با تشنج افزایش دهد. بیماران با سابقه اختلالات تشنج را برای تشدید کنترل تشنج در طول درمان با بوپرنورفین کنترل کنید. خطرات رانندگی و کار با ماشین آلات بوپرنورفین ممکن است توانایی های ذهنی یا فیزیکی مورد نیاز برای انجام فعالیت های بالقوه خطرناک مانند رانندگی ماشین یا کار با ماشین آلات را مختل کند. به بیماران هشدار دهید که از رانندگی یا کار با ماشین آلات خطرناک خودداری کنند، مگر اینکه نسبت به اثرات بوپرنورفین تحمل کنند و بدانند که چگونه به دارو واکنش نشان خواهند داد [به اقدامات احتیاطی: اطلاعات برای بیماران مراجعه کنید].

General: Buprenorphine hydrochloride should be administered with caution in the elderly, debilitated patients, in children and those with severe impairment of hepatic, pulmonary, or renal function; myxedema or hypothyroidism; adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis. Because buprenorphine hydrochloride is metabolized by the liver, the activity of buprenorphine hydrochloride may be increased and/or extended in those individuals with impaired hepatic function or those receiving other agents known to decrease hepatic clearance. Buprenorphine hydrochloride has been shown to increase intracholedochal pressure to a similar degree as other opioid analgesics, and thus should be administered with caution to patients with dysfunction of the biliary tract. Information for Patients Addiction, Abuse, and Misuse Inform patients that the use of buprenorphine, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS ]. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting buprenorphine or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS ]. Hyperalgesia and Allodynia Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see WARNINGS , ADVERSE REACTIONS ] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions ]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see CLINICAL PHARMACOLOGY: Pharmacodynamics , ADVERSE REACTIONS ]. Drug Interactions Clinically significant drug interactions with Buprenorphine Hydrochloride Injection Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients closely for signs of respiratory depression and sedation [see WARNINGS] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids, alcohol. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. Intervention: If concomitant use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see CLINICAL PHARMACOLOGY: Pharmacokinetics ], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see CLINICAL PHARMACOLOGY: Pharmacokinetics ], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine dosage reduction and monitor for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma). Intervention: The use of buprenorphine is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of buprenorphine and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected, decrease the dosage of buprenorphine and/or the muscle relaxant as necessary. Examples: Cyclobenzaprine, metaxalone. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with anticholinergic drugs. Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Intervention: None Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs ) Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. Intervention: If prescribing an NNRTI to a patient taking buprenorphine, frequently reevaluate for this interaction and adjust dosing as necessary. Examples: efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Intervention: Monitor patients taking buprenorphine and atazanavir with and without ritonavir, and dose reduction of buprenorphine may be warranted. Examples: atazanavir, ritonavir Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day for 27 months in rats. These doses were approximately equivalent to 5.7, 52, and 534 times the recommended human dose (1.2 mg) on a mg/m 2 body surface area basis. Statistically significant dose-related increases in testicular interstitial (Leydig's) cell tumors occurred, according to the trend test adjusted for survival. Pairwise comparison of the high dose against control failed to show statistical significance. In the mouse study, buprenorphine was administered in the diet at doses of 8, 50, and 100 mg/kg/day for 86 weeks. The high dose was approximately equivalent to 477 times the recommended human dose (1.2 mg) on a mg/m 2 basis. Buprenorphine was not carcinogenic in mice. Mutagenesis Buprenorphine was studied in a series of tests. Results were negative in Chinese hamster bone marrow and spermatogonia cells, and negative in mouse lymphoma L5178Y assay. Results were equivocal in the Ames test: negative in studies in two laboratories, but positive in frame shift mutation at high dose (5 mg/plate) in a third study. Impairment of Fertility Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg (approximately 763 times the recommended human daily dose of 1.2 mg on a mg/m 2 basis) or up to 5 mg/kg I.M. or S.C. (approximately 48 times the recommended human daily dose of 1.2 mg on a mg/m 2 basis). Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS: Neonatal Opioid Withdrawal Syndrome ]. Available data with buprenorphine in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Reproductive and developmental studies in rats and rabbits identified adverse events at approximately 2 times the maximum recommended human dose (MRHD) of 1.8 mg/day of buprenorphine. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 54 and 2.2 times, respectively, the MRHD of 1.8 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 2.7 times and above and dystocia at approximately 27 times the MRHD of 1.8 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 5 times or greater than the MRHD of 1.8 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 5.4 and 10.8 times the MRHD of 1.8 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS: Neonatal Opioid Withdrawal Syndrome ]. Labor and Delivery The safety of buprenorphine hydrochloride given during labor and delivery has not been established. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, should be available for reversal of opioid induced respiratory depression in the neonate. Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship. Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m 2 ) to MRHD of 1.8 mg buprenorphine via buprenorphine hydrochloride injection. Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 1351 times the MRHD of 1.8 mg) in the presence of maternal toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 432 times the MRHD of 1.8 mg) in the absence of clear maternal toxicity. No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 161 times and 324 times, respectively, the MRHD of 1.8 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 54 times the MRHD of 1.8 mg). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 54 times, respectively, the MRHD of 1.8 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4.3 and 8.7 times, respectively, the MRHD of 1.8 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 865 times the MRHD of 1.8 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 270 times the MRHD of 1.8 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 5.4 times the MRHD of 1.8 mg), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 54 times the MRHD of 1.8 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately 10.8 times the MRHD of 1.8 mg) were not statistically significant. In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 2.2 times the MRHD of 1.8 mg). No maternal toxicity was noted at doses causing post-implantation loss in this study. Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 27 times the MRHD of 1.8 mg). Fertility, pre-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 4.3 times the MRHD of 1.8 mg), after IM doses of 0.5 mg/kg/day and up (approximately 2.7 times the MRHD of 1.8 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD of 1.8 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 432 times the MRHD of 1.8 mg). Lactation Risk Summary An apparent lack of milk production during general reproduction studies with buprenorphine in rats caused decreased viability and lactation indices. Use of high doses of sublingual buprenorphine in pregnant women showed that buprenorphine passes into the mother's milk. Clinical Considerations Breast-feeding is not advised in nursing mothers treated with buprenorphine. Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS ]. Pediatric Use The safety and effectiveness of buprenorphine hydrochloride have been established for children between 2 and 12 years of age. Use of buprenorphine hydrochloride in children is supported by evidence from adequate and well controlled trials of buprenorphine hydrochloride in adults, with additional data from studies of 960 children ranging in age from 9 months to 18 years of age. Data is available from a pharmacokinetic study, several controlled clinical trials, and several large post-marketing studies and case series. The available information provides reasonable evidence that buprenorphine hydrochloride may be used safely in children ranging from 2 to 12 years of age, and that it is of similar effectiveness in children as in adults. Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to buprenorphine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of buprenorphine slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression [see WARNINGS , PRECAUTIONS ]. Buprenorphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Clinically significant drug interactions with Buprenorphine Hydrochloride Injection Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients closely for signs of respiratory depression and sedation [see WARNINGS] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids, alcohol. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. Intervention: If concomitant use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see CLINICAL PHARMACOLOGY: Pharmacokinetics ], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see CLINICAL PHARMACOLOGY: Pharmacokinetics ], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine dosage reduction and monitor for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma). Intervention: The use of buprenorphine is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of buprenorphine and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected, decrease the dosage of buprenorphine and/or the muscle relaxant as necessary. Examples: Cyclobenzaprine, metaxalone. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with anticholinergic drugs. Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Intervention: None Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs ) Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. Intervention: If prescribing an NNRTI to a patient taking buprenorphine, frequently reevaluate for this interaction and adjust dosing as necessary. Examples: efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Intervention: Monitor patients taking buprenorphine and atazanavir with and without ritonavir, and dose reduction of buprenorphine may be warranted. Examples: atazanavir, ritonavir

Postmarketing Experience The most frequent side effect in clinical studies involving 1,133 patients was sedation which occurred in approximately two-thirds of the patients. Although sedated, these patients could easily be aroused to an alert state. Other less frequent adverse reactions occurring in 5 to 10% of the patients were: Nausea Dizziness/Vertigo Occurring in 1 to 5% of the patients: Sweating Headache Hypotension Nausea/Vomiting Vomiting Hypoventilation Miosis The following adverse reactions were reported to have occurred in less than 1% of the patients: CNS Effect: confusion, blurred vision, euphoria, weakness/fatigue, dry mouth, nervousness, depression, slurred speech, paresthesia. Cardiovascular: hypertension, tachycardia, bradycardia. Gastrointestinal: constipation. Respiratory: dyspnea, cyanosis. Dermatological: pruritus. Ophthalmological: diplopia, visual abnormalities. Miscellaneous: injection site reaction, urinary retention, dreaming, flushing/warmth, chills/cold, tinnitus, conjunctivitis, Wenckebach block, and psychosis. Other effects observed infrequently include malaise, hallucinations, depersonalization, coma, dyspepsia, flatulence, apnea, rash, amblyopia, tremor, and pallor. The following reactions have been reported to occur rarely: loss of appetite, dysphoria/agitation, diarrhea, urticaria, and convulsions/lack of muscle coordination. Allergic Reactions: Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the postmarketing experience of buprenorphine hydrochloride injection and other buprenorphine-containing products. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to buprenorphine hydrochloride. In the United Kingdom, buprenorphine hydrochloride was made available under monitored release regulation during the first year of sale, and yielded data from 1,736 physicians on 9,123 patients (17,120 administrations). Data on 240 children under the age of 18 years were included in this monitored release program. No important new adverse effects attributable to buprenorphine hydrochloride were observed. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time (see CLINICAL PHARMACOLOGY: Pharmacodynamics ) . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration ( see WARNINGS ) . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term (see WARNINGS ) . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in DRUG ABUSE AND DEPENDENCE ], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Controlled Substance Buprenorphine hydrochloride injection contains buprenorphine, a Schedule III controlled substance. Abuse Buprenorphine hydrochloride injection contains buprenorphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see WARNINGS ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Buprenorphine increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Buprenorphine with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of buprenorphine abuse include those with a history of prolonged use of any opioid, including products containing buprenorphine, those with drug or alcohol abuse, or those who use Buprenorphine in combination with other abused drugs. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Buprenorphine, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Buprenorphine Abuse of buprenorphine poses a risk of overdose and death. The risk is increased with concurrent abuse of buprenorphine with alcohol and/or other CNS depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Buprenorphine hydrochloride should not be rapidly reduced or abruptly discontinued [see DOSAGE AND ADMINISTRATION ]. If buprenorphine hydrochloride is rapidly reduced or abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Pregnancy ].

Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS: Neonatal Opioid Withdrawal Syndrome ]. Available data with buprenorphine in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Reproductive and developmental studies in rats and rabbits identified adverse events at approximately 2 times the maximum recommended human dose (MRHD) of 1.8 mg/day of buprenorphine. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 54 and 2.2 times, respectively, the MRHD of 1.8 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 2.7 times and above and dystocia at approximately 27 times the MRHD of 1.8 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 5 times or greater than the MRHD of 1.8 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 5.4 and 10.8 times the MRHD of 1.8 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS: Neonatal Opioid Withdrawal Syndrome ]. Labor and Delivery The safety of buprenorphine hydrochloride given during labor and delivery has not been established. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, should be available for reversal of opioid induced respiratory depression in the neonate. Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship. Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m 2 ) to MRHD of 1.8 mg buprenorphine via buprenorphine hydrochloride injection. Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 1351 times the MRHD of 1.8 mg) in the presence of maternal toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 432 times the MRHD of 1.8 mg) in the absence of clear maternal toxicity. No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 161 times and 324 times, respectively, the MRHD of 1.8 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 54 times the MRHD of 1.8 mg). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 54 times, respectively, the MRHD of 1.8 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4.3 and 8.7 times, respectively, the MRHD of 1.8 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 865 times the MRHD of 1.8 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 270 times the MRHD of 1.8 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 5.4 times the MRHD of 1.8 mg), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 54 times the MRHD of 1.8 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately 10.8 times the MRHD of 1.8 mg) were not statistically significant. In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 2.2 times the MRHD of 1.8 mg). No maternal toxicity was noted at doses causing post-implantation loss in this study. Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 27 times the MRHD of 1.8 mg). Fertility, pre-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 4.3 times the MRHD of 1.8 mg), after IM doses of 0.5 mg/kg/day and up (approximately 2.7 times the MRHD of 1.8 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD of 1.8 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 432 times the MRHD of 1.8 mg).

Mechanism of Action Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. One unusual property of buprenorphine observed in vitro studies is its very slow rate of dissociation from its receptor. This could account for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence. Pharmacodynamics Buprenorphine hydrochloride is a parenteral opioid analgesic with 0.3 mg buprenorphine being approximately equivalent to 10 mg morphine sulfate in analgesic and respiratory depressant effects in adults. Pharmacological effects occur as soon as 15 minutes after intramuscular injection and persist for 6 hours or longer. Peak pharmacologic effects usually are observed at 1 hour. When used intravenously, the times to onset and peak effect are shortened. Buprenorphine demonstrates narcotic antagonist activity and has been shown to be equipotent with naloxone as an antagonist of morphine in the mouse tail flick test. Effect s on the Central Nervous System The principal action of therapeutic value of buprenorphine is analgesia and is thought to be due to buprenorphine binding with high affinity to opioid receptors on neurons in the brain and spinal cord. Buprenorphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Under usual conditions of use in adults, both buprenorphine and morphine show similar dose-related respiratory depressant effects. At adult therapeutic doses, buprenorphine (0.3 mg buprenorphine) can decrease respiratory rate in an equivalent manner to an equianalgesic dose of morphine (10 mg). [see WARNINGS ]. Buprenorphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Buprenorphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effec ts on the Cardiovascular System Buprenorphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Buprenorphine may cause a decrease or, rarely, an increase in pulse rate and blood pressure in some patients. Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of buprenorphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance. Concentration–Adverse Reaction Relationships There is a relationship between increasing buprenorphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. Pharmacokinetics The limits of sensitivity of available analytical methodology precluded demonstration of bioequivalence between intramuscular and intravenous routes of administration. Elimination In postoperative adults, pharmacokinetic studies have shown elimination half-lives ranging from 1.2 to 7.2 hours (mean 2.2 hours) after intravenous administration of 0.3 mg of buprenorphine. A single, ten-patient, pharmacokinetic study of doses of 3 μg/kg in children (age 5 to 7 years) showed a high inter-patient variability, but suggests that the clearance of the drug may be higher in children than in adults. This is supported by at least one repeat-dose study in postoperative pain that showed an optimal inter-dose interval of 4 to 5 hours in pediatric patients as opposed to the recommended 6 to 8 hours in adults. Metabolism Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Its clearance is related to hepatic blood flow. Studies in patients anesthetized with 0.5% halothane have shown that this anesthetic decreases hepatic blood flow by about 30%.