12月2日，美国食品和药物管理局（FDA）向马萨诸塞州的Alkermes公司发出了一封警告信。今日，据药智新闻记者获悉，FDA发布公告并公开了警告信具体内容，称该公司在宣传材料中遗漏了与该药物相关的最严重风险的警告，从而误导了该药物Vivitrol（一种纳曲酮的缓释注射制剂）的使用。

Vivitrol被批准用于预防阿片类药物依赖的复发，众所周知药物辅助治疗，使用像Vivitrol这样的药物，结合咨询和行为疗法，对阿片类药物使用障碍（OUD）的治疗是有效的，可以帮助一些人维持康复。

FDA药物评估和研究中心FDA处方药推广办公室主任Thomas Abrams在公告中表示：“FDA保护公众健康的一个方法是确保药品赞助商传播的处方药信息是真实、平衡和准确的。我们通过审查处方药广告和宣传标签来做到这一点，以确保这些宣传材料中包含的信息不虚假或误导，Vivitrol的推广方式没有以真实和非误导性的方式充分展示重要的风险信息。从公共卫生的角度来看，这是令人担忧的，因为在这个脆弱的病人群体中，可能会出现致命的阿片类药物过量。”

以下是警告信具体内容：

Dear Mr. Pops:

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration (FDA) has reviewed a print advertisement (print ad) (VIV-003460-v2) for VIVITROL (naltrexone for extended-release injectable suspension) for intramuscular use (Vivitrol) submitted by Alkermes, Inc. (Alkermes) under cover of Form FDA 2253. The print ad is false or misleading because it omits important risk information associated with the use of Vivitrol. Thus, the print ad misbrands Vivitrol within the meaning of the Federal Food, Drug and Cosmetic Act (FD&C Act) and makes its distribution violative. 21 U.S.C. 352(n); 321(n); 331(a).  See 21 CFR 202.1(e)(5).  This violation is concerning from a public health perspective because it creates a misleading impression regarding the overall safety of  Vivitrol.  Opioid dependence and misuse is a significant public health concern and a national crisis that impacts millions of lives in the United States.  When used as provided in the FDA approved product labeling, Vivitrol is safe and effective for the prevention of relapse to opioid dependence, following opioid detoxification. However, those utilizing Vivitrol for the treatment of opioid dependence should be made aware of the vulnerability to potentially fatal overdose at the end of a dosing interval, after missing a dose, or after discontinuing Vivitrol treatment. Attempts to overcome blockade may also lead to fatal overdose.

美国食品和药物管理局（FDA）处方药推广办公室（OPDP）审查了Alkermes公司用于肌肉注射的Vivitrol（纳曲酮缓释注射液）的印刷广（VIV-003460-v2）。印刷广告有虚假的或误导性的信息，因为它忽略了与使用Vivitrol相关的重要风险信息。因此，他在FD&C法规定的范围内印刷Vivitrol错误的广告，并使其销售违法。从公共卫生的角度来看，这一违规行为令人担忧，因为它对Vivitrol的整体安全性造成了误导性的印象。阿片类药物依赖和滥用是一个重大的公共卫生问题，也是影响美国数百万人生命的国家危机。当在FDA批准的产品标签中使用时，Vivitrol预防阿片类药物依赖的复发和阿片类药物解毒是安全有效的。然而，那些使用Vivitrol治疗阿片依赖性的患者应意识到，在给药间隔结束时、错过给药后或停止Vivitrol治疗后，存在潜在危险。试图克服依赖性也可能导致致命的过量用药。

Background

Below is the indication and the summary of the most serious and most common risks associated with the use of Vivitrol.1   According to the INDICATIONS AND USAGE section of the FDA-approved product labeling (PI) for Vivitrol:

以下是与使用Vivitrol相关的最严重和最常见风险的适应症和总结。（此信息仅用于背景目的，不一定代表应包含在本函所述促销品中的风险信息。）根据FDA批准的Vivitrol产品标签（PI）的适应症和使用部分：

      Treatment with VIVITROL should be part of a comprehensive management program that includes psychosocial support.

      VIVITROL is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL.  Patients should not be actively drinking at the time of initial VIVITROL administration.

      VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification.

Vivitrol治疗应该是包括心理社会支持在内的综合管理计划的一部分。

Vivitrol适用于在开始使用Vivitrol治疗之前在门诊戒酒的酒精依赖患者。患者在初次使用Vivitrol时不应主动饮酒。

在阿片类药物戒毒后，可预防阿片依赖复发。

Vivitrol is contraindicated in patients receiving opioid analgesics, patients with current physiologic opioid dependence, patients in acute opioid withdrawal, any individual who has failed the naloxone challenge test or has a positive urine screen for opioids, and patients who have previously exhibited hypersensitivity to naltrexone, polylactide-co-glycolide (PLG), carboxymethylcellulose, or any other components of the diluent.  The PI for Vivitrol includes warnings and precautions regarding vulnerability to opioid overdose, injection site reactions, precipitation of opioid withdrawal, hepatotoxicity, depression and suicidality, when reversal of Vivitrol blockade is required for pain management, eosinophilic pneumonia, hypersensitivity reactions including anaphylaxis, intramuscular injections, alcohol withdrawal, and interference with laboratory tests.  The most common adverse reactions observed with Vivitrol therapy in opioid-dependent patients were hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache.

接受阿片类镇痛药的患者、目前生理性阿片依赖的患者、急性阿片类戒断的患者、纳洛酮激发试验失败或阿片类尿检呈阳性的任何个人以及以前对纳曲酮过敏的患者禁用Vivitrol，聚乙丙交酯（PLG）、羧甲基纤维素或稀释剂的任何其他成分。Vivitrol的PI包括警告和预防阿片类药物过量、注射部位反应、阿片类药物沉淀、肝脏毒性、抑郁和自杀的预防措施，当维他命阻断剂逆转疼痛需要时，嗜酸性粒细胞肺炎、过敏反应包括过敏反应、肌肉注射、酒精戒断和实验室检查干扰。Vivitrol治疗阿片依赖患者最常见的不良反应是肝酶异常、注射部位疼痛、鼻咽炎、失眠和牙痛。

False or Misleading Risk Presentation 虚假或误导性风险陈述

Promotional materials misbrand a drug if they are false or misleading with respect to risk. The determination of whether promotional materials are misleading includes, among other things, not only representations made or suggested in promotional materials, but also failure to reveal facts material in light of the representations made or with respect to consequences that may result from the use of the drug as recommended or suggested in the materials.

如果宣传材料在副作用方面是虚假或误导性的，宣传材料则会给药品打上了错误的表情。确定宣传材料是否具有误导性，包括宣传材料中作出或建议的陈述，未能根据所作的陈述或材料中所建议或建议的药物使用可能造成的后果。

The print ad contains claims and representations about the benefits of Vivitrol.  However, the print ad fails to communicate information from the WARNINGS AND PRECAUTIONS section of the PI concerning vulnerability to opioid overdose, a potentially fatal risk. Specifically, the PI states that after opioid detoxification, patients are likely to have reduced tolerance to opioids.  Vivitrol blocks the effects of exogenous opioids for approximately 28 days after administration.  However, as the blockade wanes and eventually dissipates completely, patients who have been treated with Vivitrol may respond to lower doses of opioids than previously used, just as they would have shortly after completing detoxification. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment. Furthermore, there is also the possibility that a patient who is treated with Vivitrol could overcome the opioid blockade effect of Vivitrol.  Patients should be told of the serious consequences of trying to overcome the opioid blockade.

印刷广告包含Vivitrol利益的声明和陈述。然而，印刷广告未能传达来自PI的警告和预防部分关于阿片类药物过量（一种潜在的致命风险）的信息。具体而言，PI表示阿片类药物解毒后，患者可能对阿片类药物的耐受性降低。Vivitrol给药后大约28天阻断外源阿片类药物的作用。然而，随着依赖性的减弱最终完全消失，接受过Vivitrol治疗的患者可能对较低剂量的阿片类药物产生反应。如果患者使用以前容忍剂量的阿片类药物，可能会导致潜在的危及生命的阿片类药物中毒（呼吸衰竭或停止，循环衰竭等）。据报道，在给药间隔结束、错过预定剂量或停止治疗后使用阿片类药物的患者中，出现了阿片类药物过量并导致死亡的病例。此外，使用Vivitrol治疗的患者也有可能克服Vivitrol的类阿片阻滞作用。病人应该被告知试图克服阿片类药物的依懒性所造成的严重后果。

By omitting this serious and potentially fatal risk, the print ad fails to provide material information about the consequences that may result from the use of the drug and creates a misleading impression about the drug’s safety. This is extremely concerning from a public health perspective because of the potential for fatal overdose in this vulnerable patient population.

由于忽略了这一严重和潜在的致命风险，印刷广告未能提供有关使用该药物可能产生的后果的重要信息，并对该药物的安全性造成误导性印象。从公共卫生的角度来看，这是极为令人担忧的，因为在这个脆弱的病人群体中，可能会出现致命的过量用药。

In addition, the print ad omits other important warnings and precautions, including the risk of injection site reactions (one of the risks addressed by the Vivitrol Risk Evaluation and Mitigation Strategy (REMS)), and the most common adverse reactions associated with the use of drug.

此外，印刷广告省略了其他重要的警告和预防措施，包括注射部位反应的风险（Vivitrol风险评估和缓解策略（REMS）解决的风险之一），以及与药物使用相关的最常见不良反应。

We note the statement, “For additional Important Safety Information, please see the Brief Summary of Prescribing Information on adjacent pages” (emphasis in original) in small print at the bottom of the print ad; however, this statement and the inclusion of the brief summary on adjacent pages do not mitigate the misleading omissions of material risk information from the main body of the print ad.

我们注意到这样一条声明：“关于其他重要的安全信息，请参阅印刷广告底部小字体的“相邻页面处方信息摘要”（强调原文）；但是，本声明以及在相邻页面中包含简要摘要并没有减轻印刷广告正文中重大风险信息的误导性遗漏。

Prior Communications

OPDP

OPDP refers Alkermes to OPDP’s advisory letter, dated March 9, 2011, on proposed promotional materials for Vivitrol, wherein OPDP advised Alkermes that the proposed material (b)(4)

OPDP请Alkermes参阅OPDP于2011年3月9日就Vivitrol的拟议宣传材料发出的咨询函，其中OPDP告知Alkermes拟议材料

Office of New Drugs

On October 12, 2018, the Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) sent an information request to Alkermes requesting that Alkermes “describe any efforts you have made to ensure that prescribers and patients are aware of the risk of overdose” for patients exposed to Vivitrol.  On October 29, 2018, Alkermes responded in part stating that they have “undertaken numerous efforts to ensure that prescribers and patients are aware of the risk of overdose,” and that one such measure undertaken by Alkermes was the “[i]nclusion of the risk of opioid overdose within the text of promotional materials for healthcare professionals, caregivers and consumers...”

2018年10月12日，麻醉、镇痛和成瘾产品部（DAAAP）向Alkermes发送了一份信息请求，要求Alkermes描述为确保处方医生和患者意识到服用Vivitrol的患者的过量用药风险所做的措施。2018年10月29日，Alkermes在一部分指出，他们作出了许多努力，以确保处方医生和患者意识到过量用药的风险，而Alkermes采取的一项措施是“在保健专业人员、护理人员和消费者的宣传材料中纳入阿片类药物过量的风险……”

OPDP is concerned that Alkermes continues to promote Vivitrol in a manner that fails to adequately present this important risk information in a truthful and non-misleading manner.

OPDP担心，Alkermes继续以一种虚假和误导性的方式呈现这一重要风险信息的方式销售Vivitrol。

Conclusion and Requested Action

For the reasons discussed above, the print ad misbrands Vivitrol within the meaning of the FD&C Act and makes its distribution violative. 21 U.S.C. 352(n); 321(n); 331(a). See 21 CFR 202.1(e)(5).

基于上述原因，宣传材料误导了Vivitrol的使用，并使其销售违规。

OPDP requests that Alkermes immediately cease misbranding Vivitrol and/or cease introducing the misbranded drug into interstate commerce.  Please submit a written response to this letter on or before December 16, 2019, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Vivitrol that contain statements such as those described above, and explaining your plan for discontinuing use of such materials, or, in the alternative, for ceasing distribution of Vivitrol. Because the violations described above are serious, we request, further, that your  submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the  audience(s) that received the violative promotional materials.  In order to clearly identify the violative promotional piece(s) and/or activity and focus on the corrective message(s), OPDP recommends that corrective piece(s) include a description of the violative promotional piece(s) and/or activity, include a summary of the violative message(s), provide information to correct each of the violative message(s), and be free of promotional claims and presentations.  To the extent possible, corrective messaging should be distributed using the same media, and generally for the same duration of time and with the same frequency that the violative promotional material was disseminated.  If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.

OPDP要求Alkermes立即停止Vivitrol的错误商标和/或停止将错误商标的药物投入市场。请在2019年12月16日或之前提交对本函的书面回复，说明是否打算遵守此要求，列出包含上述声明的Vivitrol的所有宣传材料，并解释停止使用此类材料的计划，或者，作为替代，停止销售Vivitrol。由于上述违规行为严重，FDA进一步要求贵公司提交的文件包括一份全面的行动计划，以传播真实、无误导性的信息，并向收到违规宣传材料的消费者填写关于本函所讨论问题的纠正信息。为了明确识别违规宣传品和活动，并专注于纠正信息，OPDP建议纠正件包括对违规宣传品的描述宣传片和活动，包括违规信息的摘要，提供纠正违规信息的信息，并且没有宣传声明和演示。在可能的情况下，应使用相同的媒体宣传纠正信息，一般来说，在相同的时间和频率下，违规宣传材料被传播。如果您认为您的产品没有违反FD&C法案，请提供您的理由和任何支持信息，以供我们考虑。

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, 5901- B Ammendale Road, Beltsville, Maryland 20705-1266.  A courtesy copy can be sent by facsimile to (301) 847-8444.  To ensure timely delivery of your submissions, please use the full address above and include a prominent directional notation (e.g. a sticker) to indicate that the submission is intended for OPDP.  Please refer to MA 864 in addition to the NDA number in all future correspondence relating to this particular matter. All correspondence should include a subject line that clearly identifies the submission as a Response to Warning Letter.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Vivitrol comply with each applicable requirement of the FD&C Act and FDA implementing regulations.

Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.

Sincerely,

{See appended electronic signature page}

Andrew S.T. Haffer, Pharm.D. Director

Division of Advertising & Promotion Review 1

Office of Prescription Drug Promotion

来源：

1、http://suo.im/63fOXA

2、http://suo.im/5zaYUC

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