Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence
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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.
The authors thank the US Food and Drug Administration employees involved in responding to Freedom of Information Act requests.
Compliance with Ethical Standards
This study was funded by Open Society Foundations.
Conflict of interest
Daniel Wolfe is an employee of Open Society Foundations and Roxanne Saucier is a consultant to Open Society Foundations. Nabarun Dasgupta is a part-time employee of the RADARS System, which had no involvement in this study. The RADARS System is supported by subscriptions from pharmaceutical manufacturers, and governmental and non-governmental agencies for data, research, and reporting services. The RADARS System is the property of the Denver Health and Hospital Authority, a political subdivision of the State of Colorado (USA). Employees are prohibited from financial relationships with any biopharmaceutical company.
All data used in this analysis were publicly available and redacted of identifying information by the US Food and Drug Administration, therefore no external institutional review board approval was needed.
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