Ephedrine Sulfate

近日，FDA召开了非处方药咨询委员会会议，专门讨论口服去氧肾上腺素作为非处方咳嗽和感冒产品活性成分的有效性。委员会讨论了口服去氧肾上腺素有效性的新数据，最终得出一致结论：当前的科学数据，并不支持口服去氧肾上腺素作为鼻减充血剂的有效性（投票结果16：0）。虽然FDA没有明确说明剂量，但大量文献指出，口服去氧肾上腺素（40毫克）无效【1】。这意味着Sudafed PE这样的名牌药物(Sudafed PE约占去氧肾上腺素市场的五分之一)，可能并没有像广告宣传的那样发挥减轻鼻塞的效果。FDA认定这一感冒成分无效，哪些药品受影响？01去氧肾上腺素的「生前身后名」去氧肾上腺素是一种α-1肾上腺素能受体激动剂。它通过刺激鼻道血管内壁平滑肌上的受体，导致血管收缩（变窄）。去氧肾上腺素通常用于缓解由普通感冒、过敏或鼻窦炎等疾病引起的鼻塞和不适。去氧肾上腺素的作用是缩小鼻道中的血管，从而减少肿胀和充血，使呼吸更容易。尽管对于口服去氧肾上腺素的有效性提出了否定，但这是否等同于”无效“，最终还需要FDA拍板定夺。咨询委员会只负责向FDA提供独立的意见和建议，但最终的决定权在FDA手中。笔者在药智数据库查询发现，国内上市药品中，含有去氧肾上腺素的口服非处方药，包含柳酚咖敏片等品种，其去氧肾上腺素的剂量大多在2.5mg-5mg之间。尽管FDA咨询委员会给出了“无法证明有效性”的结论，但仍然存在很多不确定因素：FDA是否会正式将去氧肾上腺素除名？下架的药物，仅限于去氧肾上腺素作为唯一有效物质的药物，还是牵连所有包含去氧肾上腺素的复方制剂？美国以外的监管机构会做出如何反应？通常来说，当一种OTC药物从OTC monograph中删除，可能会对消费者、制造商和监管环境产生重大影响。这些影响可能会因具体药物、除名原因以及可用替代品而异。如果去氧肾上腺素最终遭到FDA除名的话，可以想象，伪麻黄碱的需求量可能会出现激增，以填补去氧肾上腺素身后留下的巨大空缺。而如何在确保伪麻黄碱这种管控药物不流向甲基苯丙胺的方向，将成为美国政府需要重点关心的事情。对于患者来说，如何更容易地获得伪麻黄碱这种所谓的behind-the-counter药物（柜台后药物），也是一件关乎顺利过渡的事情。除了化学减充血剂药物之外，桉树油、薄荷醇、生姜、大蒜、蜂蜜等自然疗法也具有缓解鼻塞的潜力。不知道这对于拥有悠久草本入药历史的中国来说，是否意味着一个机遇？FDA的声明中还涉及到一项关键内容，即咨询委员会的建议仅涉及“口服”去氧肾上腺素（片剂或胶囊），而不针对鼻喷雾剂。含去氧肾上腺素的鼻喷雾剂不会受到任何连带影响。对此，佛罗里达大学药学博士Leslie Hendeles表示，“只有口服途径是无效的，因为99%的母体药物在肠道和肝首过代谢时就失活了”。Hendeles领导了佛罗里达大学2015年提交的公民请愿书，要求从OTC鼻减充血剂产品的OTC monograph中删除口服去氧肾上腺素。FDA还表示，含有去氧肾上腺素的药物，对于散瞳和手术期间使用同样有效，并不受到此次决定的影响。02除名去氧肾上腺素，哪些品种将受影响？在FDA官方网站上发布的声明称，有些产品仅含有去氧肾上腺素，而某些产品则含有去氧肾上腺素和另一种活性成分（例如对乙酰氨基酚或布洛芬），可针对鼻塞之外的其它症状，例如头痛或肌肉酸痛等，这些产品中的去氧肾上腺素的存在，并不会影响其他活性成分治疗这些症状。但在FDA正式将去氧肾上腺素认定对缓解鼻塞无效，并将其从OTC monograph中除名之后，含有去氧肾上腺素成分的复方药物的命运目前仍待观察。FDA表示，含有去氧肾上腺素成分的产品大约有250种，其在2022年的销售额约为18亿美元。受到去氧肾上腺素牵连的知名药物包括Tylenol,NyQuil,Mucinex,Theraflu和Benadryl等感冒和流感产品。如果FDA最终做出下架的决定，将有250种以上的产品受到影响。如果FDA遵循咨询小组的建议，强生、拜耳和其他制药商可能会被要求从商店货架上撤下含有去氧肾上腺素的口服药物。这可能会迫使消费者转而使用非处方药，或者使用含有去氧肾上腺素的鼻喷雾剂和滴剂。图片来源：SUDAFED PE、DrugSupplyStore.com、Walmart、amazon、HEB美国消费者保健产品协会(CHPA，The Consumer Healthcare Products Association)于9月12日发表声明，对FDA咨询委员会的调查结果表示失望，并敦促FDA将去氧肾上腺素继续留在市场上。CHPA表示，撤销去氧肾上腺素的非处方药资格将对医药市场造成明显的破坏性。除名去氧肾上腺素的决定将增加消费者负担，原本可以轻松从药店购买到的OTC可能会无迹可寻。患者需要寻求替代疗法，或者向医生寻求处方，这将导致就诊次数和医疗费用增加。CHPA还认为，除名去氧肾上腺素，无论对医药成本、患者依从性、供应链，都将造成意义深远的影响。FDA数据显示，去年美国零售店销售了2.42亿瓶含有去氧肾上腺素的药物，比2021年增长了30%。这些产品去年的销售额为18亿美元。03剥夺非处方药资格后，巨大空缺谁来填补？如果去氧肾上腺素最终被FDA剥夺了非处方药资格，那么它身后留下的巨大空缺将由谁来填补？伪麻黄碱(Pseudo-ephedrine)算得上一号。伪麻黄素是一种去除鼻塞和鼻窦充血的药物，通常用于治疗感冒、过敏性鼻炎和鼻窦炎等呼吸道疾病的症状。它可以有效收缩鼻腔和鼻窦中的血管，从而减轻鼻塞和流感症状。而且作为鼻减充血剂，伪麻黄碱比去氧肾上腺素更加有效。但更有效的药物却没有获得相应的市场份额，其中必有蹊跷。实际上，伪麻黄碱因为可以当作合成甲基苯丙胺的原料而无法做到洁身自好。甲基苯丙胺就是俗称的冰毒。受到甲基苯丙胺瓜田李下的影响，许多国家对伪麻黄素的销售和购买都有限制，并要求购买者提供身份信息，以确保合法使用。含有伪麻黄碱的产品仍然可以作为非处方药购买，但获取伪麻黄素药物不可能像去氧肾上腺素那样轻而易举。相比于去氧肾上腺素2022年2.42亿瓶和18亿美元的销售额，同期伪麻黄素的销量估计为5100万件，销售额为5.42亿美元。除了去氧肾上腺素和伪麻黄素之外，获批的nasal decongestant还包括：Levomethamphetamine（左旋甲基苯丙胺，甲基苯丙胺的L-对映体，亦称左旋甲基安非他命）:一种拟交感神经血管收缩剂，用于美国的一些非处方(OTC)鼻减充血剂。不同于右旋甲基苯丙胺，它在低剂量没有造成欣快或成瘾的特性。Oxymetazoline（羟甲唑啉）：一种α-1A肾上腺素受体激动剂，可用于治疗鼻充血、眼睛过敏反应以及与红斑痤疮相关的面部红斑。羟甲唑啉可作为鼻减充血剂用于非处方鼻用产品中。羟甲唑啉具有良好的外周血管收缩作用，直接激动血管α-1受体，引起鼻腔黏膜血管收缩，从而减轻炎症所致的充血和水肿。它起效迅速，在几分钟内即可发生作用，可维持数小时，能有效地解除鼻充血。Ephedrine（麻黄碱）：一种α和β肾上腺素能激动剂，用于治疗麻醉下低血压、过敏性疾病、支气管哮喘和鼻塞。Propylhexedrine（丙己定）：一种α-肾上腺素能激动剂，常用于鼻减充血吸入剂。它用于暂时缓解感冒、过敏性鼻炎或过敏引起的鼻塞。Xylometazoline（丁苄唑啉，亦称赛洛唑啉）：一种直接作用的α-肾上腺素能激动剂，用于对过敏或感冒引起的鼻充血和轻微炎症的对症治疗。不建议使用超过七天。同样，不建议三个月以下的婴儿使用，有的说法甚至建议不要在6岁以下儿童使用。04小结虽然当前的科学数据，并不支持口服去氧肾上腺素作为鼻减充血剂的有效性，但缺乏有效性支持，不等同于“无效确认”。等待FDA的下一步动作。参考来源：1.https://time.com/6314120/fda-decongestant-phenylephrine-decision/2.FDA clarifies results of recent advisory committee meeting on oral phenylephrine.FDA.14.09.2023.3.Sartain,M.FDA advisers say oral phenylephrine is not effective as a nasal decongestant.Pharmacist.com.13.09.2023.4.Dunleavy,K.It's unanimous:FDA panel says decongestant drug phenylephrine does not work.FiercePharma.13.09.2023.5.Constantino,A.K.Decongestant found in many cold,allergy medicines doesn’t actually work,FDA advisors say.CNBC.12.09.2023.6.Cerullo,M.Ineffective ingredient could make Dayquil,Sudafed and others disappear from store shelves.CBS News.12.09.2023.7.Drug Bank:Nasal Decongestant声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 八角转载开白 | 马老师 18996384680（同微信）商务合作 |  张武龙 13368443108（同微信） 阅读原文，是受欢迎的文章哦

LINCOLNSHIRE, Ill.--(BUSINESS WIRE)-- Nexus Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) issued a notice in the Federal Register that ephedrine sulfate should not be bulked by compounding facilities. Bulking is the practice of an outsourcing facility to “compound a drug using a bulk drug substance.”1 The FDA explained that bulk compounding is allowed only where there is a drug shortage or “the bulk drug substance appears on a list” set by the FDA called “the 503B Bulks List.”2 Section 503B refers to the portion of the Drug Quality and Security Act setting forth requirements when certain compounded products may be allowed. On August 21, 2023, the FDA published its conclusion as to ephedrine sulfate that the FDA “now decided not to place [it] on the 503B Bulks List.”3 The FDA confirmed that companies including Nexus with its EMERPHED® product already have FDA-approved products available for both the vial and syringe presentations of ephedrine sulfate, including “as a 5 mL single dose, prefilled syringe that contains 25 mg/5 mL (5 mg/mL) ephedrine sulfate, preservative-free, for intravenous administration, and as a 10 mL single dose, prefilled syringe that contains 50 mg/10 mL (5 mg/mL) ephedrine sulfate, preservative-free, for intravenous administration.”4 In its notice this week, the FDA also confirmed that “the products available as prefilled syringes are premixed formulations and do not require dilution prior to administration for their labeled indications.”5 The FDA concluded that “there is no clinical need for outsourcing facilities to compound using the bulk substance[] ephedrine sulfate” and “therefore we are not including these bulk drug substances on the 503B Bulks List.”6 “We are pleased that the FDA properly decided bulk compounding for ephedrine sulfate is not authorized,” said Chief Executive Officer and President, Usman Ahmed. “The FDA needs to continue to step up as a champion for compliance with the substantial restrictions Congress set forth for when compounded products may be tolerated.” Nexus’ EMERPHED® product is and remains available as an FDA-approved ephedrine sulfate product in both vial and syringe presentations. EMERPHED® was the first 10 mL ephedrine sulfate prefilled syringe approved by the FDA. About EMERPHED® (ephedrine sulfate injection) INDICATIONS AND USAGE EMERPHED® (ephedrine sulfate injection) is an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent that is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. WARNINGS AND PRECAUTIONS EMERPHED® (ephedrine sulfate injection) can cause pressor effects with concomitant use with oxytocic drugs. It can also cause tachyphylaxis with repeated administration of ephedrine. CONTRAINDICATIONS None. OVERDOSAGE Overdose of EMERPHED® (ephedrine sulfate injection) can cause a rapid rise in blood pressure. In the case of an overdose, careful monitoring of blood pressure is recommended. If blood pressure continues to rise to an unacceptable level, parenteral antihypertensive agents can be administered at the discretion of the clinician. ADVERSE REACTIONS Most common adverse reactions during treatment: nausea, vomiting, and tachycardia. To report SUSPECTED ADVERSE REACTIONS, contact Nexus Pharmaceuticals at (855) 642-2594 or FDA at 1-800-FDA-1088 or . About Nexus Pharmaceuticals LLC Nexus Pharmaceuticals LLC, a US-based healthcare company and certified diverse supplier, specializes in innovative processes to make difficult-to-manufacture specialty and generic drugs that are easier to use, less labor-intensive, and more streamlined in practice. Nexus ensures that its high-quality FDA-approved drugs fulfill a critical unmet medical need and delivers dependable life-saving treatment options when and where they’re needed most. For more information about Nexus Pharmaceuticals and its state-of-the-art manufacturing facility in Wisconsin, visit . ________________________________ 1 FDA Register, Vol. 88, No. 160, at 56838 (available at ). 2 Id. at 56839. 3 Id. 4 Id. at 56840. 5 Id. 6 Id. at 56t843.