TOXICOLOGY/ORIGINAL RESEARCH Ondansetron and the Risk of Cardiac Arrhythmias: A Systematic Review and Postmarketing Analysis Stephen B. Freedman, MDCM, MSc; Elizabeth Uleryk, BA, MLS; Maggie Rumantir, MD; Yaron Finkelstein, MD* *Corresponding Author. E-mail: yaron.fi[email protected]. Study objective: To explore the risk of cardiac arrhythmias associated with ondansetron administration in the context of recent recommendations for identification of high-risk individuals. Methods: We conducted a postmarketing analysis and systematically reviewed the published literature, grey literature, manufacturer’s database, Food and Drug Administration Adverse Events Reporting System, and the World Health Organization Individual Safety Case Reports Database (VigiBase). Eligible cases described a documented (or perceived) arrhythmia within 24 hours of ondansetron administration. The primary outcome was arrhythmia occurrence temporally associated with the administration of a single, oral ondansetron dose. Secondary objectives included identifying all cases associating ondansetron administration (any dose, frequency, or route) to an arrhythmia. Results: Primary: No reports describing an arrhythmia associated with single oral ondansetron dose administration were identified. Secondary: Sixty unique reports were identified. Route of administration was predominantly intravenous (80%). A significant medical history (67%) or concomitant use of a QT-prolonging medication (67%) was identified in 83% of reports. Approximately one third occurred in patients receiving chemotherapeutic agents, many of which are known to prolong the QT interval. An additional third involved administration to prevent postoperative vomiting. Conclusion: Current evidence does not support routine ECG and electrolyte screening before single oral ondansetron dose administration to individuals without known risk factors. Screening should be targeted to high-risk patients and those receiving ondansetron intravenously. [Ann Emerg Med. 2014;64:19-25.] Please see page 20 for the Editor’s Capsule Summary of this article. A feedback survey is available with each research article published on the Web at www.annemergmed.com. A podcast for this article is available at www.annemergmed.com. 0196-0644/$-see front matter Copyright © 2013 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2013.10.026 INTRODUCTION (“electrolyte abnormalities, congestive heart failure, Background bradyarrhythmias, or patients taking other medicinal products ” 4 Ondansetron hydrochloride is a potent antiemetic that that lead to QT prolongation ). 1 antagonizes serotonin at 5-hydroxytryptamine3 receptors. Between 1995 and 2009, administration in US emergency Importance departments (EDs) increased more than 330-fold, from 38,000 The identification of high-risk individuals is important because to 12.6 million doses.2 Pediatric usage has also increased, with drugs are frequently administered in the ED without complete more than 2 million doses administered to children in US EDs knowledge of a patient’s medication or medical history, and the each year, greater than 85% by the oral route.3 In September opportunity for monitoring of adverse drug events may be limited.8,9 2011, the Food and Drug Administration (FDA) issued a Consequently, to identify at-risk individuals, diagnostic investigations communication warning that ondansetron may induce fatal that might not otherwise be indicated are often required. For example, arrhythmias.4 In June 2012, the FDA issued an update linking individuals with vomiting may have electrolyte abnormalities; the risk of QT prolongation to the administration of a 32-mg however, in practice, significant abnormalities are uncommon and intravenous dose. Despite this, screening recommendations testing is not routinely recommended.10 Similarly, long-QT remain unchanged5-7 and continue to recommend that syndrome, a rare and asymptomatic disorder,11 typically remains ondansetron be avoided in patients with congenital long-QT undiagnosed until a complication occurs. Approximately 16,000 syndrome and that ECG monitoring and serum electrolyte screening ECGs need to be performed to identify a single screening be performed in all potentially susceptible patients asymptomatic long-QT syndrome case.12 Volume 64, no. 1 : July 2014 Annals of Emergency Medicine 19 Ondansetron and Risk of Cardiac Arrhythmias Freedman et al Editor’s Capsule Summary administration of a single oral ondansetron dose. Our secondary objectives were to identify all pediatric (<18 years) and adult What is already known on this topic (18 years) cases associating ondansetron administration (any Recently, the Food and Drug Administration issued a dose, frequency, or route) to the development of an arrhythmia warning that ondansetron may induce fatal and to evaluate causality. arrhythmias, leading to concerns about emergency department use. Study Selection Eligible cases described a documented arrhythmia or event What question this study addressed perceived as an arrhythmia and ondansetron administration up to This systematic review analyzed available sources to 24 hours preceding the event. We selected this timeframe to identify cases of arrhythmia temporally associated ensure comprehensiveness and the inclusion of all potentially with the administration of a single oral ondansetron relevant cases catalogued by global pharmacovigilance dose. A secondary outcome was identifying all cases registries, including those associated with long-term use. Two associating ondansetron administration to an investigators with expertise in outcomes-based research (S.B.F.) arrhythmia. and clinical pharmacology (Y.F.) independently screened all abstracts to assess eligibility. Excluded cases were filed with a What this study adds to our knowledge reason. Disagreements were resolved through discussion until No reports describing an arrhythmia associated with achievement of consensus. Articles deemed appropriate single oral ondansetron dose administration were underwent detailed, full-text review. Adverse drug reaction identified. registry reports were reviewed manually. How this is relevant to clinical practice Data Extraction This study supports the safety of the clinical practice Cases underwent independent data abstraction by 2 authors of administering a single oral ondansetron dose to (S.B.F., M.R.) using a standardized form. Disagreements were low-risk patients without the need for screening resolved through discussion until achievement of consensus. evaluations. Information extracted included age, indication, dose, route, concomitant medications, event description and timing, and causal association. The presence of a significant medical history was assessed by the 2 reviewers and required a consensus opinion based on the assumptions that would be expected by a physician Goals of This Investigation providing clinical care and was focused on the presence of Current regulatory agency communications have resulted in preexisting cardiac disease (eg, heart failure, personal or family significant uncertainty and confusion among clinicians who 13 history suggestive of long-QT syndrome, other arrhythmias) or use ondansetron frequently. Although the ability of high-dose disorders associated with electrolyte abnormalities (eg, short-gut intravenous ondansetron to prolong the QT interval is not in syndrome, diuretic use, renal disease). dispute, the need for universal screening is. We sought to identify all reports describing an association between ondansetron administration and arrhythmia occurrence, with a focus on single Data Sources oral dose administration, a common practice in EDs. Published Literature. The search strategy was developed through consultation with a professional research librarian (E.U.) with experience in conducting systematic reviews.17 The strategy MATERIALS AND METHODS contained a broad series of subject headings and keywords Search Strategy relating to ondansetron, arrhythmias, and cardiovascular disease. We conducted a systematic review of the published literature, in We ran the initial searches (Appendix E1, Table E1, available accordance with Preferred Reporting Items for Systemic Reviews online at http://www.annemergmed.com) in October 2011 14,15 and Meta-Analyses guidelines. Additionally, we explored the (most recent update, December 19, 2012), using the OvidSP, grey literature (which includes reports, theses, conference Thomson Reuters, and SciVerse search platforms in the following proceedings, translations, bibliographies, and other documents databases: MEDLINE, EMBASE, Web of Knowledge/Science “ that are not available through the conventional, commercial (Conference Proceedings Citation Index), and Scopus. Databases ” 16 distribution channels ) and global adverse drug reaction and were searched from creation to December 2012, with no pharmacovigilance registries to identify all relevant reports. language restrictions. The reference lists of all included articles and relevant reviews were hand-searched. Objectives Grey Literature. The New York Academy of Medicine Grey The primary objective of this study was to identify all reported Literature Report, FDA Web site (http://www.fda.gov/drugs/ arrhythmias occurring in temporal association with the drugsafety/default.htm), OpenGrey (System for Information on 20 Annals of Emergency Medicine Volume 64, no. 1 : July 2014 Freedman et al Ondansetron and Risk of Cardiac Arrhythmias Grey Literature in Europe; http://www.opengrey.eu/), the 1120 Articles