Toxicology/original research
Ondansetron and the Risk of Cardiac Arrhythmias: A Systematic Review and Postmarketing Analysis

Presented as an abstract at the 2013 Pediatric Academic Society annual meeting, May 2013, Washington, DC.
https://doi.org/10.1016/j.annemergmed.2013.10.026Get rights and content

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.

Introduction

Ondansetron hydrochloride is a potent antiemetic that antagonizes serotonin at 5-hydroxytryptamine3 receptors.1 Between 1995 and 2009, administration in US emergency departments (EDs) increased more than 330-fold, from 38,000 to 12.6 million doses.2 Pediatric usage has also increased, with more than 2 million doses administered to children in US EDs each year, greater than 85% by the oral route.3 In September 2011, the Food and Drug Administration (FDA) issued a communication warning that ondansetron may induce fatal arrhythmias.4 In June 2012, the FDA issued an update linking the risk of QT prolongation to the administration of a 32-mg intravenous dose. Despite this, screening recommendations remain unchanged5, 6, 7 and continue to recommend that ondansetron be avoided in patients with congenital long-QT syndrome and that ECG monitoring and serum electrolyte screening be performed in all potentially susceptible patients (“electrolyte abnormalities, congestive heart failure, bradyarrhythmias, or patients taking other medicinal products that lead to QT prolongation”).4

Editor’s Capsule Summary

What is already known on this topic

Recently, the Food and Drug Administration issued a warning that ondansetron may induce fatal arrhythmias, leading to concerns about emergency department use.

What question this study addressed

This systematic review analyzed available sources to identify cases of arrhythmia temporally associated with the administration of a single oral ondansetron dose. A secondary outcome was identifying all cases associating ondansetron administration to an arrhythmia.

What this study adds to our knowledge

No reports describing an arrhythmia associated with single oral ondansetron dose administration were identified.

How this is relevant to clinical practice

This study supports the safety of the clinical practice of administering a single oral ondansetron dose to low-risk patients without the need for screening evaluations.

The identification of high-risk individuals is important because drugs are frequently administered in the ED without complete knowledge of a patient’s medication or medical history, and the opportunity for monitoring of adverse drug events may be limited.8, 9 Consequently, to identify at-risk individuals, diagnostic investigations that might not otherwise be indicated are often required. For example, individuals with vomiting may have electrolyte abnormalities; however, in practice, significant abnormalities are uncommon and testing is not routinely recommended.10 Similarly, long-QT syndrome, a rare and asymptomatic disorder,11 typically remains undiagnosed until a complication occurs. Approximately 16,000 screening ECGs need to be performed to identify a single asymptomatic long-QT syndrome case.12

Current regulatory agency communications have resulted in significant uncertainty and confusion among clinicians who use ondansetron frequently.13 Although the ability of high-dose intravenous ondansetron to prolong the QT interval is not in 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 oral dose administration, a common practice in EDs.

Section snippets

Search Strategy

We conducted a systematic review of the published literature, in accordance with Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines.14, 15 Additionally, we explored the grey literature (which includes reports, theses, conference proceedings, translations, bibliographies, and other documents that are “not available through the conventional, commercial distribution channels”)16 and global adverse drug reaction and pharmacovigilance registries to identify all relevant

Published Literature

The electronic database searches identified 1,120 citations (Figure). After removal of duplicates and review of titles and abstracts, 71 articles containing potentially eligible cases remained. Of these, 18 reports describing 21 eligible cases were identified. Reference and text review detected 2 additional cases. In total, 23 cases (6 pediatric; 17 adult) (Table E3, available online at http://www.annemergmed.com) were identified from 20 publications.23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,

Limitations

Our study has several potential limitations. First, it is possible that not all cases have been reported. To mitigate this, we used a comprehensive search strategy and a low inclusion threshold of all published and unpublished reports. Second, we used the Naranjo Scale to assess the causality of adverse reactions because it is the most widely accepted causality scoring system and has been in use for more than 30 years.44 During study planning, we conducted a literature search and identified its

Discussion

Despite extensive use for more than 22 years and several hundred million patient treatment-days,46 we did not find any reports of an arrhythmia occurring in a patient after the administration of a single oral ondansetron dose. Our findings indicate that universal ECG screening and electrolyte testing before ondansetron administration are likely unwarranted. The evidence is particularly weak as it relates to the typical pediatric ED scenario in which a single oral dose is often administered

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    Please see page 20 for the Editor’s Capsule Summary of this article.

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    Supervising editor: Matthew D. Sztajnkrycer, MD, PhD

    Author contributions: SBF and YF contributed equally to this article and are therefore co-Principal Investigators. SBF and YF had full access to all of the data in the study, take responsibility for the integrity of the data and the accuracy of the data analysis, serve as study guarantors, and were responsible for study concept, statistical analysis, and study supervision. SBF, MR, and YF were responsible for analysis and interpretation of data and administrative, technical, and material support. SBF, EU, and YF were responsible for drafting the article. All authors were responsible for acquisition of data and critical revision of the article for important intellectual content, had full access to all of the data (including statistical reports and tables) in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. SBF takes responsibility for the paper as a whole.

    Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that (1) none of the authors have received support for the conduct of the submitted work; (2) Dr. Freedman has a relationship with GlaxoSmithKline that might have an interest in the submitted work in the previous 3 years; (3) the authors’ spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) Drs. Freedman, Finkelstein, and Rumantir and Ms. Uleryk have no nonfinancial interests that may be relevant to the submitted work. Specifically, Dr. Freedman acknowledges receiving in-kind study drug/placebo from GlaxoSmithKline, the manufacturer of ondansetron, for the conduct of an independently funded (Bill and Melinda Gates Foundation and Thrasher Research Fund) clinical trial not related to the current study. No other form of funding or research support was provided by GlaxoSmithKline. The first draft of the article was written by Drs. Freedman and Finkelstein. No honorarium, grant, or other form of payment was given to anyone to conduct the study or produce the article. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

    The data provided by the WHO Collaborating Centre for International Drug Monitoring, Uppsala, are not homogeneous at least with respect to origin or likelihood that the pharmaceutical product caused the adverse reaction, and the information we report from the WHO Collaborating Centre does not represent the opinion of the World Health Organization.

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