Open Society Foundations, New York, NY, USA.
University of North Carolina at Chapel Hill, Suite 500, CB 7505, 137 E. Franklin St., Chapel Hill, NC, 27599, USA.
Drug Saf. 2018 Oct;41(10):981-988. doi: 10.1007/s40264-018-0653-3.
An extended-release injectable naltrexone suspension (Vivitrol) was approved in USA in 2010 for the prevention of relapse to opioid dependence. Concerns, raised at the time of approval, about rebound overdose risk following the last dose, have not been adequately studied. We sought to determine the time period of concern for fatal overdose associated with Vivitrol.
We performed a retrospective case review of Vivitrol spontaneous reports (October 2010-March 2016) in the US Food and Drug Administration Adverse Event Reporting System via the Freedom of Information Act. Case narratives were manually reviewed to identify overdose deaths amongst current and former patients, extracting information on the time from discontinuation, followed by causality assessment.
Narratives on 263 deaths and overdose-related outcomes were obtained. One hundred and forty-five death reports were assessed for causality. Among these reports, cause of death was unknown in 46%, while 52 fatal overdoses met the case definition. Of 52 overdoses, time between the last dose and death was known for 28; 22 (84.6%) occurred within 2 months of the last Vivitrol injection [median 46 days (interquartile range 29.5-82)]. The sponsor's causality assessment in 75% of fatal overdoses repeated verbatim text that placed responsibility on underlying opioid dependence and precluded a link between medication and overdose or ignored rebound risk following treatment discontinuation.
Vivitrol adverse event reports suggest the need to investigate two months following the last medicine injection as a period of particular concern for overdose. A registry study would best quantify risk. Providers should report suspected post-discontinuation overdoses to government authorities.
一种长效纳曲酮混悬注射液（Vivitrol）于 2010 年在美国获得批准，用于预防阿片类药物依赖的复发。在获得批准时，人们对最后一次用药后出现反弹过量风险的担忧尚未得到充分研究。我们旨在确定与 Vivitrol 相关的致命性过量风险的关注时间段。
我们通过信息自由法案在美国食品和药物管理局不良事件报告系统中对 Vivitrol 自发报告（2010 年 10 月至 2016 年 3 月）进行了回顾性病例审查。通过手动审查病例叙述，确定当前和以前患者中的过量死亡病例，提取停药后时间的信息，并进行因果关系评估。
获得了 263 例死亡和与过量相关的结果的叙述。对 145 份死亡报告进行了因果关系评估。在这些报告中，46%的死因未知，而 52 例致命性过量符合病例定义。在 52 例过量中，已知最后一次用药与死亡之间的时间间隔的有 28 例；22 例（84.6%）发生在最后一次 Vivitrol 注射后 2 个月内[中位数 46 天（四分位距 29.5-82）]。在 75%的致命性过量中，赞助商的因果关系评估逐字重复了文本，将责任归咎于潜在的阿片类药物依赖，并排除了药物与过量之间的联系或忽视了治疗停药后的反弹风险。
Vivitrol 不良事件报告表明，需要在最后一次用药后两个月内进行调查，这是特别关注过量的时间段。注册研究最能量化风险。提供者应向政府当局报告疑似停药后过量。
