Adverse event detection using the FDA post-marketing drug safety surveillance system: Cardiotoxicity associated with loperamide abuse and misuse.

OBJECTIVE: The purpose of this investigation was to identify and characterize post-marketing reports of cardiotoxicity, including torsades de pointes (TdP), associated with loperamide use. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database for post-marketing reports of serious cardiac adverse events associated with loperamide use from December 28, 1976 (U.S. drug approval date), through December 14, 2015. We also conducted a Pubmed and Google Scholar search to identify additional published reports of cardiotoxicity associated with loperamide in the medical literature through February 11, 2016. RESULTS: Forty-eight cases of serious cardiac adverse events associated with loperamide use composed the case series. The most frequently reported cardiac adverse events were syncope (n = 24), cardiac arrest (n = 13), QT-interval prolongation (n = 13), ventricular tachycardia (n = 10), and TdP (n = 7). There were 10 cases that resulted in death. Of the 48 cases, the most commonly reported reasons for use can be characterized as drug abuse (n = 22) and diarrhea treatment (n = 17). More than one-half of the 48 cases were reported after 2010. Of the 22 drug abuse cases, the median daily dose was 250 mg (range 70 mg to 1600 mg) and events occurred as early as 6 hours after a dose and as long as 18 months after initiation of loperamide. Thirteen of the 22 cases reported using loperamide for euphoric or analgesic effects, and 9 reported use to prevent opioid withdrawal symptoms. CONCLUSION: The FAERS case reports provide evidence to suggest that high doses of loperamide are associated with TdP and other serious cardiac adverse events. The majority of cases in this series occurred in the setting of drug abuse for the purpose of preventing opioid withdrawal or to produce euphoric effects. It is important for both clinicians and patients to be aware of this potential risk, because prompt therapy and discontinuation of the offending agent are often essential to management and prevention of loperamide-induced cardiac arrhythmias.

Pediatric post-marketing safety systems in North America: assessment of the current status.

PURPOSE: It is critical to have pediatric post-marketing safety systems that contain enough clinical and epidemiological detail to draw regulatory, public health, and clinical conclusions. The pediatric safety surveillance workshop (PSSW), coordinated by the Food and Drug Administration (FDA), identified these pediatric systems as of 2010. This manuscript aims to update the information from the PSSW and look critically at the systems currently in use. METHODS: We reviewed North American pediatric post-marketing safety systems such as databases, networks, and research consortiums found in peer-reviewed journals and other online sources. We detail clinical examples from three systems that FDA used to assess pediatric medical product safety. RESULTS: Of the 59 systems reviewed for pediatric content, only nine were pediatric-focused and met the inclusion criteria. Brief descriptions are provided for these nine. The strengths and weaknesses of three systems (two of the nine pediatric-focused and one including both children and adults) are illustrated with clinical examples. CONCLUSIONS: Systems reviewed in this manuscript have strengths such as clinical detail, a large enough sample size to capture rare adverse events, and/or a patient denominator internal to the database. Few systems include all of these attributes. Pediatric drug safety would be better informed by utilizing multiple systems to take advantage of their individual characteristics.

The Food and Drug Administration's (FDA's) Drug Safety Surveillance During the COVID-19 Pandemic.

INTRODUCTION: On 4 February, 2020, the Secretary of the Department of Health and Human Services declared a public health emergency related to coronavirus disease 2019 (COVID-19), and on 27 March, 2020 declared circumstances existed to justify the authorization of the emergency use of drug and biological products (hereafter, "drugs") for COVID-19. At the outset of the pandemic with uncertainty relating to the virus, many drugs were being used to treat or prevent COVID-19, resulting in the US Food and Drug Administration's (FDA's) need to initiate heightened surveillance across these drugs. OBJECTIVE: We aimed to describe the FDA's approach to monitoring the safety of drugs to treat or prevent COVID-19 across multiple data sources and the subsequent actions taken by the FDA to protect public health. METHODS: The FDA conducted surveillance of adverse event and medication error data using the FDA Adverse Event Reporting System, biomedical literature, FDA-American College of Medical Toxicology COVID-19 Toxicology Investigators Consortium Pharmacovigilance Project Sub-registry, and the American Association of Poison Control Centers National Poison Data System. RESULTS: From 4 February, 2020, through 31 January, 2022, we identified 22,944 unique adverse event cases worldwide and 1052 unique medication error cases domestically with drugs to treat or prevent COVID-19. These were from the FDA Adverse Event Reporting System (22,219), biomedical literature (1107), FDA-American College of Medical Toxicology COVID-19 Toxicology Investigator's Consortium Sub-registry (638), and the National Poison Data System (32), resulting in the detection of several important safety issues. CONCLUSIONS: Safety surveillance using near real-time data was critical during the COVID-19 pandemic because the FDA monitored an unprecedented number of drugs to treat or prevent COVID-19. Additionally, the pandemic prompted the FDA to accelerate innovation, forging new collaborations and leveraging data sources to conduct safety surveillance to respond to the pandemic.

ADE Eval: An Evaluation of Text Processing Systems for Adverse Event Extraction from Drug Labels for Pharmacovigilance.

INTRODUCTION: The US FDA is interested in a tool that would enable pharmacovigilance safety evaluators to automate the identification of adverse drug events (ADEs) mentioned in FDA prescribing information. The MITRE Corporation (MITRE) and the FDA organized a shared task-Adverse Drug Event Evaluation (ADE Eval)-to determine whether the performance of algorithms currently used for natural language processing (NLP) might be good enough for real-world use. OBJECTIVE: ADE Eval was conducted to evaluate a range of NLP techniques for identifying ADEs mentioned in publicly available FDA-approved drug labels (package inserts). It was designed specifically to reflect pharmacovigilance practices within the FDA and model possible pharmacovigilance use cases. METHODS: Pharmacovigilance-specific annotation guidelines and annotated corpora were created. Two metrics modeled the experiences of FDA safety evaluators: one measured the ability of an algorithm to identify correct Medical Dictionary for Regulatory Activities (MedDRA®) terms for the text from the annotated corpora, and the other assessed the quality of evidence extracted from the corpora to support the selected MedDRA® term by measuring the portion of annotated text an algorithm correctly identified. A third metric assessed the cost of correcting system output for subsequent training (averaged, weighted F1-measure for mention finding). RESULTS: In total, 13 teams submitted 23 runs: the top MedDRA® coding F1-measure was 0.79, the top quality score was 0.96, and the top mention-finding F1-measure was 0.89. CONCLUSION: While NLP techniques do not perform at levels that would allow them to be used without intervention, it is now worthwhile exploring making NLP outputs available in human pharmacovigilance workflows.