Download Ondansetron and the Risk of Cardiac Arrhythmias: A Systematic

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.
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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
Background
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 unchanged5-7 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
Volume 64, no. 1 : July 2014
(“electrolyte abnormalities, congestive heart failure,
bradyarrhythmias, or patients taking other medicinal products
that lead to QT prolongation”).4
Importance
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
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
(18 years) cases associating ondansetron administration (any
dose, frequency, or route) to the development of an arrhythmia
and to evaluate causality.
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.
Goals of This Investigation
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.
MATERIALS AND METHODS
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 reports.
Objectives
The primary objective of this study was to identify all reported
arrhythmias occurring in temporal association with the
20 Annals of Emergency Medicine
Study Selection
Eligible cases described a documented arrhythmia or event
perceived as an arrhythmia and ondansetron administration up to
24 hours preceding the event. We selected this timeframe to
ensure comprehensiveness and the inclusion of all potentially
relevant cases catalogued by global pharmacovigilance
registries, including those associated with long-term use. Two
investigators with expertise in outcomes-based research (S.B.F.)
and clinical pharmacology (Y.F.) independently screened all
abstracts to assess eligibility. Excluded cases were filed with a
reason. Disagreements were resolved through discussion until
achievement of consensus. Articles deemed appropriate
underwent detailed, full-text review. Adverse drug reaction
registry reports were reviewed manually.
Data Extraction
Cases underwent independent data abstraction by 2 authors
(S.B.F., M.R.) using a standardized form. Disagreements were
resolved through discussion until achievement of consensus.
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
providing clinical care and was focused on the presence of
preexisting cardiac disease (eg, heart failure, personal or family
history suggestive of long-QT syndrome, other arrhythmias) or
disorders associated with electrolyte abnormalities (eg, short-gut
syndrome, diuretic use, renal disease).
Data Sources
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
contained a broad series of subject headings and keywords
relating to ondansetron, arrhythmias, and cardiovascular disease.
We ran the initial searches (Appendix E1, Table E1, available
online at http://www.annemergmed.com) in October 2011
(most recent update, December 19, 2012), using the OvidSP,
Thomson Reuters, and SciVerse search platforms in the following
databases: MEDLINE, EMBASE, Web of Knowledge/Science
(Conference Proceedings Citation Index), and Scopus. Databases
were searched from creation to December 2012, with no
language restrictions. The reference lists of all included articles
and relevant reviews were hand-searched.
Grey Literature. The New York Academy of Medicine Grey
Literature Report, FDA Web site (http://www.fda.gov/drugs/
drugsafety/default.htm), OpenGrey (System for Information on
Volume 64, no. 1 : July 2014
Freedman et al
Grey Literature in Europe; http://www.opengrey.eu/), the
Canada Vigilance Adverse Reaction Online Database (http://
www.hc-sc.gc.ca/dhp-mps/medeff/databasdon/index-eng.php),
Google Scholar, and the Canadian Agency for Drugs and Health
Technologies (http://cadth.ca/en/products) were searched on
September 5, 2012, with the search term combination of
“ondansetron” AND (QT or arrhythmia*).
Global ADR Registries. The World Health Organization
(WHO) Global Individual Safety Case Reports Database
(VigiBase) registry, which holds more than 3,800,000 reports
from national pharmacovigilance centers and regulatory
authorities of more than 80 countries,18 was searched on August
30, 2012, with the WHO-adverse drug reaction terminology
preferred terms “arrhythmia,” “arrhythmia ventricular,” and
“arrhythmia atrial” to extract all suspected or interacting
arrhythmia reports occurring within 24 hours of ondansetron
administration.
A search of the FDA Adverse Events Reporting System was
conducted on November 26, 2012, using formal MedDRA
nomenclature (version 15.1; Glaxosmithkline, Brentford,
Middlesex, United Kingdom). Cases reporting “ondansetron,”
“ondansetron hydrochloride,” “ondansetron ODT” or “Zofran”
and “Arrhythmia,” including “Torsade de Pointes,” were retrieved.
We approached GlaxoSmithKline, the company that
developed and markets ondansetron (Zofran), to provide all
relevant postmarketing adverse drug reaction reports.
Data Synthesis and Analysis
The primary outcome was the number of reports describing
an arrhythmia after single oral ondansetron dose administration. Secondary outcomes included (1) cases linking the
administration of ondansetron by any route, dose, and frequency
to the development of an arrhythmia; and (2) the strength of
causality. To determine the optimal method of assessing
causality, we used the Naranjo ADR Probability Scale (Table E2,
available online at http://www.annemergmed.com).19 A boardcertified clinical pharmacologist (Y.F.) with previous experience
using the scale20,21 assigned probability scores to all published
cases. For cases identified in the WHO registry, we
documented the scores provided (ie, Council for International
Organizations of Medical Sciences scoring system)22; FDA
Adverse Events Reporting System did not provide causality scores.
RESULTS
Case Selection
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.23-42
Grey Literature. No additional eligible reports were
identified.
Volume 64, no. 1 : July 2014
Ondansetron and Risk of Cardiac Arrhythmias
1120 Articles identified and screened for retrieval from MEDLINE,
EMBASE, Web of Knowledge, SCOPUS
91
1029
Titles and abstracts screened for inclusion
958
71
2
Duplicate articles removed
Articles excluded based on
title/abstract review
Potentially relevant articles retrieved for full-text review
Relevant reports
identified in reference
review
20
53
Excluded
38 review articles
11 Ineligible reports
4 Letters/Comments (no case)
Articles (23 cases) describing an arrhythmia or an event
perceived as possibly being an arrhythmia in an individual
administered ondansetron up to 24 hours prior to the event.
Figure. Flow of reports identified in the published literature
through the systematic review process.
Global ADR Registries. A comprehensive VigiBase search
identified 25 reports, and the FDA Adverse Events Reporting
System identified 16; 4 were duplicates, resulting in 37 unique
reports. Because safety reports are shared by GlaxoSmithKline with
regulatory authorities (eg, the FDA), the company stated that
querying regulatory data sets would capture all relevant reports.
Primary Outcome
We did not identify any reports describing the occurrence
of an arrhythmia within 24 hours of the administration of a
single oral ondansetron dose in any of the sources searched.
Secondary Outcomes
Eleven (18%) pediatric and 49 (82%) adult cases were
identified (Tables 1 and 2). Forty-eight (80%) involved
intravenous administration and 2 (3%) involved long-term
oral use in patients with multiple arrhythmia risk factors. A
significant medical history (67%; 40/60) or concomitant use
of QT-prolonging medications (67%; 40/60) was identified in
83% (50/60). Unique (ie, nonoverlapping) indications for
use included prevention of postoperative (35%; 21/60) or
chemotherapy-induced (35%; 21/60) vomiting.
Adult Reports (n¼49). Published Literature (n¼17) Fifteen
(88%) of the cases had readily identifiable proarrhythmogenic
risk factors (ie, significant medical history or receiving other QTprolonging medications). Median patient age was 46 years
(interquartile range [IQR] 36, 60; range 24 to 67 years). Twelve
involved intravenous administration24,25,28-35,42; 1, oral
administration37; and 4, an unspecified route.36,38-40 The single
oral case involved long-term use37 in a patient with acute
cardiomyopathy and electrolyte imbalances. Two patients
received multiple intravenous doses24,31 and 1 received a large
intravenous dose.36 Nine individuals were treated to prevent
Annals of Emergency Medicine 21
Freedman et al
Ondansetron and Risk of Cardiac Arrhythmias
Table 1. Summary of all secondary outcome reports identified from all sources searched.
Pediatric (<18 Years) Reports
Source
Published literature
ADR databases
VigiBase
FAERS†
Grey literature
Total
Adult (‡18 Years) Reports
Intravenous
Oral
Intramuscular
Intravenous
Oral
Not Documented
Total
4
1*
1
12
1*
4
23
4
1
0
9
0
0
0
1
0
0
0
1
19
8
0
39
0
0
0
1
2
3
0
9
25
12
0
60
ADR, Adverse drug report; FAERS, FDA Adverse Event Reporting System.
*Involved long-term use (ie, multiple doses) in patients with significant arrhythmia risk factors.
†
A total of 16 cases were identified in FAERS; however, 4 were duplicates of previously identified cases in VigiBase, yielding 12 unique reports.
postoperative nausea and vomiting24,25,29,31-33,35,42 and 3 for
cancer chemotherapy-associated vomiting.34,36,39 Subjects were
receiving a median of 6 additional medications (IQR 2, 8); only
1 did not receive concomitant medications. Nine individuals
received other QT-prolonging medications43 and 2 were
receiving 3 such medications.28,40
ADR Registries (n¼32). The WHO VigiBase search identified
21 adult reports (patients aged 25 to 70 years; 9 men). Nineteen
patients received intravenous ondansetron (4 to 20 mg/day);
the other 2 lacked documentation of route of administration.
Twelve patients received long-term ondansetron. Nine were
oncology patients; 1 had a pacemaker. Nineteen (91%)
received concomitant medications (range 1, 7; median 3; IQR 2,
4); 14 (67%) received QT-prolonging agents. Four patients had an
ondansetron rechallenge, and none had arrhythmia recurrence.
The FDA Adverse Events Reporting System search identified
13 adult reports; 2 were duplicates and were excluded. The
11 remaining adults were aged 20 to 80 years. Eight patients
received intravenous ondansetron (1 both intravenously and
orally); 3 lacked documentation of route of administration. Ten
patients (91%) had significant underlying conditions, including
cardiac (eg, cardiomyopathy, myocarditis, long-QT syndrome),
oncologic, renal, and metabolic abnormalities. Ten patients
(91%) received additional medications (range 1, 24; median 8;
IQR 4, 13); 9 included a QT-prolonging medication. The sole
case without a reported risk factor involved a 62-year-old
administered ondansetron intravenously.
Pediatric Reports (n¼11). Published Literature (n¼6). The
mean age of pediatric patients was 12.2 years (SD 2.8 years). A
single case describing an arrhythmia in a child administered oral
ondansetron was identified. This 16-year-old with significant
medical problems (eg, leukemia, sepsis, acute tubular necrosis,
hypokalemia, hypomagnesaemia) had been administered longterm ondansetron,27 along with 8 additional QT-prolonging
agents. Additional cases were associated with intravenous
exposure: 3 described arrhythmias in the operating room in
children with long-QT syndrome after concomitant
administration of multiple QT-prolonging medications.26,41
Another report described a child becoming apneic and
bradycardic after intravenous administration.25 Atropine and
oxygen administration led to recovery. Last, 3 hours after
intramuscular ondansetron injection, a child developed
ventricular tachycardia and died.23 Because no other details were
provided in association with this report, causality is uncertain and
unlikely.
Global ADR Registries (n=5). VigiBase search identified 4
pediatric cases (age range 2 to 14 years; United States n¼2;
Germany n¼1, Chile n¼1) involving intravenous ondansetron
(1 to 24 mg/day). Three of these children received long-term
ondansetron; 2 were oncology patients receiving multiple
medications, including chemotherapeutics, whereas the third
received 3 general anesthetic agents. The FDA Adverse Events
Reporting System search identified 3 reports; 2 were duplicates
of cases identified in VigiBase. The unique case involved an
Table 2. Summary description of arrhythmia risk factors in all secondary outcome reports identified from all studied sources.
Pediatric (<18 Years) Reports (n[11)
Source
Published literature
ADR databases
VigiBase*
FAERS
Total (%)†
Adult (‡18 Years) Reports (n[49)
Significant
Medical
History
Concomitant
QT-Prolonging
Medication
Prevention
of PONV
Significant
Medical
History
Concomitant
QT-Prolonging
Medication
Prevention
of PONV
3
4
4
11
9
9
3
0
6 (55)
3
1
8 (73)
1
1
6 (55)
13
10
34 (69)
14
9
32 (65)
3
3
15 (31)
PONV, Postoperative nausea and vomiting.
*WHO global individual case safety report database system.
†
Totals may underrepresent actual frequency of occurrence because all cases with missing or unclear information, particularly the ADR databases, had the item under
consideration coded as negative (ie, not present).
22 Annals of Emergency Medicine
Volume 64, no. 1 : July 2014
Freedman et al
11-year-old child who received ondansetron and 8 concomitant
intravenous medications, including 4 arrhythmogenic
anesthetics.
Strength of Causality. There were no reported arrhythmias
that developed after administration of a single oral ondansetron
dose in any of the studied sources (primary outcome). All 23
secondary outcome reports from the literature were assigned low
probability Naranjo scores (pediatric 2 to 3, adult 2 to 4;
“possible” range). Council for International Organizations of
Medical Sciences probability scores were reported in VigiBase for
1 child (“possible”) and 6 adults (5 “possible” and 1 “probable”);
the remainder of adverse drug reaction registry cases could not be
assigned probability scores because of insufficient data provided
to the registry.
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 use in
938 publications, including 45 assessments of drug-induced
arrhythmias. However, this score was not designed to evaluate
adverse events resulting from the interaction of multiple drugs,45
as was often the case in our reports. Nonetheless, the associations
reported for the secondary outcomes were scarce and weak, with
original authors usually attributing causality to other factors, such
as baseline conditions or concomitant drugs. Although our ability
to assess causality related to reports in the unpublished literature
was limited because of missing data in some cases, our search
yielded a paucity of reports, with none involving a single oral
ondansetron dose. Although the FDA warning in 2011 may have
limited the use of ondansetron in patients with risk factors,
thereby decreasing the risk of complications since its publication,
the absence of reports associating single oral dose ondansetron
use with arrhythmia throughout the study period implies that
such events rarely if ever occur.
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
to an otherwise healthy individual who is not prescribed other
QT-interval prolonging medications. Individuals at risk of
developing an arrhythmia included those receiving ondansetron
intravenously in the setting of underlying arrhythmogenic
Volume 64, no. 1 : July 2014
Ondansetron and Risk of Cardiac Arrhythmias
conditions and those administered other QT-prolonging
medications concomitantly.
Ondansetron is routinely used, often off label, to treat a variety
of ambulatory conditions in the ED, such as gastroenteritisinduced vomiting47 and hyperemesis gravidarum.48-50 The
unwarranted withholding of ondansetron when clinically
indicated and the performance of universal ECG and electrolyte
screening may lead to increased morbidity, resource consumption,
impaired ED patient flow, and costs. Recently, a study of 100
children administered therapeutic doses of intravenous
ondansetron for the treatment of nausea and vomiting in the ED
found no statistical or clinically significant evidence of QT-interval
prolongation at peak (3 minutes) or 1 hour postpeak effect.51
The pharmacokinetic differences between oral and
intravenous ondansetron administration provide a biologically
plausible mechanistic explanation for the absence of reports of
arrhythmias after single oral dose administration. The peak serum
level after oral administration, the most relevant factor affecting
arrhythmia risk, is only 3% to 34% of that achieved after a
similar intravenous dose.52,53 Although the maximum QTc
lengthening is 17 to 20 msec after intravenous administration of
a 32-mg ondansetron dose, it is only 5.8 msec after an 8-mg
intravenous dose in adults,54-56 and to our knowledge there
are no reports documenting QTc prolongation after oral
administration. The time to peak serum level is much longer
after oral (2.3 hours) compared with intravenous (5 minutes)
administration.53 Recently, the intentional ingestion of 60 mg
of ondansetron by a child (ie, 8 times the therapeutic dose)
did not result in ECG changes.57 Thus, oral administration of
a therapeutic ondansetron dose is highly unlikely to cause a
clinically significant prolongation of the QT interval and even less
likely to cause an arrhythmia, a finding supported by our analysis.
Proposed Approach
In accordance with the data presented in this article, it is
our opinion that a patient-tailored, evidence-based approach to
risk-stratify patients would serve to optimize care. Consideration
should be given to performing ECG and electrolyte screening in
patients with known arrhythmia risk factors, including cardiac
(eg, heart failure, personal or family history suggestive of longQT syndrome, other arrhythmias), medication (eg, multiple dose
or intravenous ondansetron, concomitant QT-prolonging or
cardiac medications), or electrolyte (eg, short-gut syndrome,
diuretic use, renal disease); individuals receiving a single oral dose
in the absence of risk factors should not be screened. This
balanced approach enables the implementation of regulatory
agency recommendations without compromising or delaying
care. It minimizes the potential harms and costs (estimated at
$5.5 million per 1 true long-QT syndrome case) associated with
screening low-risk patients while allowing patients to benefit
from an effective medication.
In summary, we did not identify any reports of arrhythmias
developing in otherwise healthy patients after the
administration of a single oral ondansetron dose. Clinicians
should be cognizant of ondansetron’s potential to prolong
Annals of Emergency Medicine 23
Freedman et al
Ondansetron and Risk of Cardiac Arrhythmias
the QT interval when administered intravenously, particularly
in high doses and in high-risk patients. A risk-stratification
strategy should be used to individualize how these
recommendations are adapted into clinical practice to identify
potentially vulnerable patients who are likely to benefit from
screening. In patients with no known risk factors who are
administered a single oral ondansetron dose, routine ECG
and electrolyte screening are not warranted.
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.
Supervising editor: Matthew D. Sztajnkrycer, MD, PhD
Publication dates: Received for publication July 31, 2013.
Revision received October 2, 2013. Accepted for publication
October 24, 2013. Available online December 4, 2013.
Author affiliations: From the Sections of Pediatric Emergency
Medicine and Gastroenterology, Alberta Children’s Hospital,
Alberta Children’s Hospital Research Institute, University of
Calgary, Calgary, Alberta, Canada (Freedman); the Hospital Library
and Archives (Uleryk), Child Health Evaluative Sciences
(Finkelstein), Hospital for Sick Children Research Institute
(Finkelstein, Rumantir), and Divisions of Paediatric Emergency
Medicine and Clinical Pharmacology and Toxicology, Department of
Paediatrics (Finkelstein), The Hospital for Sick Children, Toronto,
Ontario, Canada; and the Faculty of Medicine, University of
Toronto, Toronto, Ontario, Canada (Uleryk, Finkelstein).
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
24 Annals of Emergency Medicine
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.
Presented as an abstract at the 2013 Pediatric Academic Society
annual meeting, May 2013, Washington, DC.
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healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/15080aeng.php. Accessed April 23, 2013.
7. Medicines and Healthcare Products Regulatory Agency. Ondansetron
(Zofran): risk of QTc prolongation—important new intravenous dose
restriction. Available at: http://www.mhra.gov.uk/Safetyinformation/
DrugSafetyUpdate/CON180635. Accessed April 23, 2013.
8. Hohl CM, Dankoff J, Colacone A, et al. Polypharmacy, adverse drugrelated events, and potential adverse drug interactions in elderly
patients presenting to an emergency department. Ann Emerg Med.
2001;38:666-671.
9. Banerjee A, Mbamalu D, Ebrahimi S, et al. The prevalence of polypharmacy
in elderly attenders to an emergency department—a problem with a
need for an effective solution. Int J Emerg Med. 2011;4:22.
10. Olshaker JS, Mason JD. The usefulness of serum electrolytes in the evaluation
of acute adult gastroenteritis. Ann Emerg Med. 1989;18:258-260.
11. Garson A Jr, Dick M 2nd, Fournier A, et al. The long QT syndrome in
children. An international study of 287 patients. Circulation.
1993;87:1866-1872.
12. Rodday AM, Triedman JK, Alexander ME, et al. Electrocardiogram
screening for disorders that cause sudden cardiac death in asymptomatic
children: a meta-analysis. Pediatrics. 2012;129:e999-e1010.
13. Bruzzese E, Vecchio AL, Guarino A. Hospital management of
children with acute gastroenteritis. Curr Opin Gastroenterol.
2013;29:23-30.
14. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. Ann
Intern Med. 2009;151:264-269, W64.
Volume 64, no. 1 : July 2014
Freedman et al
15. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for
reporting systematic reviews and meta-analyses of studies that
evaluate healthcare interventions: explanation and elaboration. BMJ.
2009;339:b2700.
16. Alberani V, De Castro Pietrangeli P, Mazza AM. The use of grey
literature in health sciences: a preliminary survey. Bull Med Libr Assoc.
1990;78:358-363.
17. Wahi G, Parkin PC, Beyene J, et al. Effectiveness of interventions aimed
at reducing screen time in children: a systematic review and metaanalysis of randomized controlled trials. Arch Pediatr Adolesc Med.
2011;165:979-986.
18. Lindquist M. VigiBase, the WHO Global ICSR Database System: basic
facts. Drug Inf J. 2008;42:409-419.
19. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability
of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
20. Avner M, Finkelstein Y, Hackam D, et al. Establishing causality in
pediatric adverse drug reactions: use of the Naranjo probability scale.
Paediatr Drugs. 2007;9:267-270.
21. Rezvani M, Finkelstein Y, Verjee Z, et al. Generalized seizures following
topical lidocaine administration during circumcision: establishing
causation. Paediatr Drugs. 2007;9:125-127.
22. Meyboom RH, Hekster YA, Egberts AC, et al. Causal or casual? the role
of causality assessment in pharmacovigilance. Drug Saf.
1997;17:374-389.
23. Chandrakala R, Vijayashankara C, Kumar K, et al. Ondansetron induced
fatal ventricular tachycardia. Indian J Pharmacol. 2008;40:186-187.
24. Havrilla PL, Kane-Gill SL, Verrico MM, et al. Coronary vasospasm and
atrial fibrillation associated with ondansetron therapy. Ann
Pharmacother. 2009;43:532-536.
25. Afonso N, Dang A, Namshikar V, et al. Intravenous ondansetron
causing severe bradycardia: two cases. Ann Card Anaesth.
2009;12:172-173.
26. McKechnie K, Froese A. Ventricular tachycardia after ondansetron
administration in a child with undiagnosed long QT syndrome. Can J
Anaesth. 2010;57:453-457.
27. Bagatell R, Hainstock M, Lowe MC, et al. The perfect storm: torsades
de pointes in a child with leukemia. Pediatr Blood Cancer.
2007;49:996-999.
28. Choo EK, Weber FS, Schmidt TA. Torsade de pointes after
administration of droperidol for nausea and vomiting. Prehosp Emerg
Care. 2009;13:261-265.
29. Baguley WA, Hay WT, Mackie KP, et al. Cardiac dysrhythmias
associated with the intravenous administration of ondansetron and
metoclopramide. Anesth Analg. 1997;84:1380-1381.
30. Chakraborti C, Egan J. The lesser of two adverse reactions. Joint
Commission J Qual Pat Saf. 2010;36:22-27.
31. Kasinath NS, Malak O, Tetzlaff J. Atrial fibrillation after ondansetron for
the prevention and treatment of postoperative nausea and vomiting:
a case report. Can J Anaesth. 2003;50:229-231.
32. Moazzam MS, Nasreen F, Bano S, et al. Symptomatic sinus
bradycardia: a rare adverse effect of intravenous ondansetron. Saudi J
Anaesth. 2011;5:96-97.
33. Dolenska S. Intraoperative cardiac arrest in acquired long QT
syndrome. Br J Anaesth. 2009;102:503-505.
34. Perez-Verdia A, Angulo F, Hardwicke FL, et al. Acute cardiac toxicity
associated with high-dose intravenous methotrexate therapy: case report
and review of the literature. Pharmacotherapy. 2005;25:1271-1276.
35. Bosek V, Hu P, Robinson LA. Acute myocardial ischemia after
administration of ondansetron hydrochloride. Anesthesiology.
2000;92:885-887.
36. Ballard HS, Bottino G, Bottino J. Ondansetron and chest pain. Lancet.
1992;340:1107.
37. Purvis JA, Cunningham EL, McGlinchey PG, et al. Drugs, electrolytes
and tako-tsubo cardiomyopathy: triple aetiology of acquired long QT
syndrome and torsades de pointes. Ulster Med J. 2009;78:188-189.
Volume 64, no. 1 : July 2014
Ondansetron and Risk of Cardiac Arrhythmias
38. Hussain A, Ghazal S. After more than 300 defibrillation shocks, patient
still alive 12 years later refractory torsade de pointes due to
polypharmacy and persistent vomiting. J Saudi Heart Assoc.
2010;22:149-151.
39. Philips JA, Marty FM, Stone RM, et al. Torsades de pointes associated
with voriconazole use. Transpl Infect Dis. 2007;9:33-36.
40. Boxall E, Milne J, Peters E, et al. Sudden unexplained death in a patient with
HIV and MDR-TB. Journal of the International AIDS Society Conference:
10th International Congress on Drug Therapy in HIV Infection; Conference
Start 2010; 20101107; Glasgow, Scotland, November 7-11, 2010.
41. Nathan AT, Berkowitz DH, Montenegro LM, et al. Implications of
anesthesia in children with long QT syndrome. Anesth Analg.
2011;112:1163-1168.
42. Saxena A, Chand T, Arya SK, et al. Ondansetron-induced ventricular
tachycardia in a patient of caesarian section. J Obstet Anaesth Crit
Care. 2012;2:103-104.
43. Roden DM. Drug-induced prolongation of the QT interval. N Engl J
Med. 2004;350:1013-1022.
44. Gallagher RM, Kirkham JJ, Mason JR, et al. Development and interrater reliability of the Liverpool adverse drug reaction causality
assessment tool. PLoS One. 2011;6:e28096.
45. Kane-Gill SL, Kirisci L, Pathak DS. Are the Naranjo criteria reliable and
valid for determination of adverse drug reactions in the intensive care
unit? Ann Pharmacother. 2005;39:1823-1827.
46. GlaxoSmithKline Inc., inventor Product Monograph - Zofran (ondansetron
hydrochloride dihydrate). Mississauga, ON January 26, 2012.
47. Kharbanda AB, Hall M, Shah SS, et al. Variation in resource utilization
across a national sample of pediatric emergency departments.
J Pediatr. 2013;163:230-236.
48. Madjunkova S, Maltepe C, Koren G. The leading concerns of American
women with nausea and vomiting of pregnancy calling Motherisk NVP
Helpline. Obstet Gynecol Int. 2013;2013:752980.
49. Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy
and risk of adverse fetal outcomes. N Engl J Med.
2013;368:814-823.
50. Raymond SH. A survey of prescribing for the management of nausea
and vomiting in pregnancy in Australasia. Aust N Z J Obstet Gynaecol.
2013;53:358-362.
51. The effect of intravenous ondansetron on the QT interval of
patients’ electrocardiograms in the pediatric emergency department.
Available at: http://www2.aap.org/sections/pem/PDF/
2013SOEMNCEProgram7-13.pdf. Accessed July 29, 2013.
52. Pritchard JF, Bryson JC, Kernodle AE, et al. Age and gender effects on
ondansetron pharmacokinetics: evaluation of healthy aged volunteers.
Clin Pharmacol Ther. 1992;51:51-55.
53. VanDenBerg CM, Kazmi Y, Stewart J, et al. Pharmacokinetics of three
formulations of ondansetron hydrochloride in healthy volunteers:
24-mg oral tablet, rectal suppository, and i.v. infusion. Am J Health
Syst Pharm. 2000;57:1046-1050.
54. Charbit B, Albaladejo P, Funck-Brentano C, et al. Prolongation of
QTc interval after postoperative nausea and vomiting treatment by
droperidol or ondansetron. Anesthesiology. 2005;102:1094-1100.
55. Charbit B, Alvarez JC, Dasque E, et al. Droperidol and ondansetroninduced QT interval prolongation: a clinical drug interaction study.
Anesthesiology. 2008;109:206-212.
56. GlaxoSmithKline Inc. A randomized, double-blind, four-period
crossover study to investigate the effect of intravenous ondansetron, a
5-HT3 antagonist, on cardiac conduction as compared to placebo
and moxifloxacin in healthy adult subjects. Available at: http://www.
gsk-clinicalstudyregister.com/result_detail.jsp?protocolId¼
115458&studyId¼9B2760D1-7F0C-4871-992F-EAF86227CE3E&
compound¼ondansetron. Accessed October 1, 2012.
57. Ghafouri N, Darracq MA, Cantrell FL. Ondansetron-associated
hypotension following pediatric self-poisoning. Pediatr Emerg Care.
2012;28:596-597.
Annals of Emergency Medicine 25
Ondansetron and Risk of Cardiac Arrhythmias
APPENDIX E1.
ONDANSETRON DRUG SAFETY COMMUNICATION
The U.S. Food and Drug Administration (FDA) is informing
the public of an ongoing safety review of the antinausea drug Zofran
(ondansetron, ondansetron hydrochloride, and their generics).
Ondansetron may increase the risk of developing abnormal changes
in the electrical activity of the heart, which can result in a potentially
fatal abnormal heart rhythm.
Changes in the electrical activity of the heart (prolongation of
the QT interval of the ECG)—see data summary below—can
lead to an abnormal and potentially fatal heart rhythm (including
torsade de pointes). Patients at particular risk for developing
torsade include those with underlying heart conditions, such as
congenital long-QT syndrome, those who are predisposed to low
levels of potassium and magnesium in the blood, and those
receiving other medications that lead to QT prolongation.
FDA has reviewed all available information and is making
interim changes to the drug labels. The manufacturer of Zofran
(GlaxoSmithKline) is being required to conduct a thorough QT
study to assess the potential for the drug to prolong the QT
interval. The results from this study are expected to be available in
the summer of 2012. Additional label changes may result after the
additional information has been reviewed. The Zofran
(ondansetron) drug labels already contain information about
the potential for QT prolongation. The labels are being revised
to include a warning to avoid use in patients with congenital
25.e1 Annals of Emergency Medicine
Freedman et al
long-QT syndrome because these patients are at particular risk
for torsade. Additionally, recommendations for ECG monitoring
in patients with electrolyte abnormalities (eg, hypokalemia,
hypomagnesemia), congestive heart failure, or bradyarrhythmias,
or in patients receiving other medications that can lead to
QT prolongation, are being included in the labels.
Additional Information for Health Care Professionals
ECG changes including QT-interval prolongation have been
observed in patients receiving Zofran (ondansetron). In
addition, torsade de pointes, an abnormal heart rhythm, has
been reported in some patients receiving ondansetron.
The use of Zofran (ondansetron) should be avoided in patients
with congenital long-QT syndrome.
ECG monitoring is recommended in patients with
electrolyte abnormalities (eg, hypokalemia, hypomagnesemia),
congestive heart failure, or bradyarrhythmias, or patients
receiving concomitant medications that prolong the QT
interval.
Advise patients to contact a health care professional
immediately if they experience signs and symptoms of an
abnormal pulse rate or rhythm while receiving Zofran
(ondansetron).
Report adverse events involving Zofran (ondansetron) to the
FDA MedWatch program, using the information in the
“Contact Us” box at the bottom of the page.
Volume 64, no. 1 : July 2014
Freedman et al
Volume 64, no. 1 : July 2014
Table E1. Search strategies.
Set
History
Results
Annals of Emergency Medicine 25.e2
Ondansetron and Risk of Cardiac Arrhythmias
Databases: OvidSP, MEDLINE, 1946 to April 13, 2012. Initial search: October 12, 2011. Update search: December 11, 2012.
1
Ondansetron/or Ondansetron (nm) or (ondansetron or “gr38032f” or “gr 38032f” or “sn 307” or sn307 or “gr-38032f” or “sn-307” or bryterol or
3,452
cedantron or ceramos or emeset or “c507 75” or narfoz or onsia or sakisozin or vomceran or zetron or zofran or zydis or zofrene or zofron or
zophran or zophren).mp.
2
exp Arrhythmias, Cardiac/or exp cardiovascular diseases/
1,775,166
3
1 and 2
87
Databases: OvidSP, EMBASE (1980 to 2012 week 14). Initial search: October 12, 2011. Update search: December 11, 2012.
2,862
1
Ondansetron/po or (po.fs. and (ondansetron or “gr38032f” or “gr 38032f” or “sn 307” or sn307 or “gr-38032f” or “sn-307” or bryterol or
cedantron or ceramos or emeset or “c507 75” or narfoz or onsia or sakisozin or vomceran or zetron or zofran or zydis or zofrene or zofron or
zophran or zophren).mp.)
2
exp heart arrhythmia/
2,634,057
3
1 and 2
2,387
Databases: ISI Web of Knowledge, conference proceedings, Citation Index–Science (CPCI-S) 1990 to present, and conference proceedings, Citation Index–Social Science & Humanities
(CPCI-SSH) 1990 to present. Initial search: October 12, 2011. Update search: December 11, 2012.
1
TS¼(ondansetron OR bryterol OR cedantron OR ceramos OR emeset OR narfoz OR onsia OR sakisozin OR vomceran OR zetron OR zofran OR zydis
404
OR zofrene OR zofron OR zophran OR zophren)
2
ts¼arrythmia*
80
3
#1 and #2
0
Databases: SciVerse, Scopus to October 12, 2011. Initial search: October 12, 2011. Update search: December 11, 2012.
1
(ondansetron OR “gr38032f” OR “gr 38032f” OR “sn 307” OR sn307 OR “gr-38032f” OR “sn-307” OR bryterol OR cedantron OR ceramos OR
17
emeset OR “c507 75” OR narfoz OR onsia OR sakisozin OR vomceran OR zetron OR zofran OR zydis OR zofrene OR zofron OR zophran OR
zophren) AND (arrhythmia*) AND (LIMIT-TO(DOCTYPE, “cp”))
Freedman et al
Ondansetron and Risk of Cardiac Arrhythmias
Table E2. Elements and point values of the Naranjo Adverse Drug Reaction Probability Scale.
Score
Criteria
Yes
No
Do Not Know
Are there previous conclusive reports on this reaction?
Did the adverse event occur after the suspected drug was administered?
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?
Did the adverse reaction reappear when the drug was readministered?
Are there alternative causes (other than the drug) that could have on their own caused the reaction?
Did the reaction reappear when a placebo was given?
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
Was the adverse event confirmed by any objective evidence?
þ1
þ2
þ1
þ2
1
1
þ1
þ1
þ1
þ1
0
1
0
1
þ2
þ1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
25.e3 Annals of Emergency Medicine
Volume 64, no. 1 : July 2014
Age, Years
Past Medical History
Indication
Dose
Route
Prevention of PONV
0.1 mg/kg
825
None
Prevention of PONV
0.13 mg/kg IV
1423
None
1627
ALL, pseudomonas
bacteremia, acute
tubular necrosis,
Clostridium difficile
colitis
Vomiting, abdominal
4 mg
pain8 h
Intractable emesis
N/A
secondary to C difficile
colitis and
Helicobacter pylori
1341
LQTS, Andersen-Tawil
(LQTS 7) syndrome
Prevention of PONV
N/A
IV
1141
Jervell and LangeNielsen (LQTS)
syndrome
Prevention of PONV
N/A
Prevention of PONV
Adult cases
2442
Pregnancy
IV
Time to Event
Event
Explanation
Sevoflurane, nitrous
oxide, remifentanil,
rocuronium,
dexamethasone,
dimenhydrinate
Not documented
2 min
PVCs developing into VT
Congenital LQTS
2 min
Unconscious, apnea,
severe bradycardia
IM
Antacid
300 min
VT then VF
Bradycardia as a result of
attenuation of BezoldJarisch reflex
Autopsy declined
PO
Clarithromycin,
amoxicillin,
metronidazole,
trimethoprimsulfamethoxazole,
diphenhydramine,
hydroxyzine,
pantoprazole,
potassium
Sevoflurane, desflurane,
vecuronium,
anticholinesterase,
anticholinergic
“Several hours”
PVCs, prolonged QT
Hypokalemia (2.0 mEq/L)
interval, ventricular
and hypomagnesemia
(1.1 mg/dL) as a result
ectopy; 60 min later
developed VT then TdP
of renal dysfunction,
diuretic use, diarrhea;
multiple medications
“Close proximity”
Bigeminy, VT
IV
Sodium pentothal,
propofol, isoflurane,
pancuronium
anticholinesterase,
anticholinergic
“Close proximity”
TdP
4 mg
IV
Bupivacaine
Within 1 min
VT
4728
Hypertension, aortic
stenosis, GERD,
anxiety, depression
Abdominal pain, nausea, 4 mg
vomiting
IV
HRT, morphine sulphate,
“Shortly after”
cimetidine, nortriptyline,
droperidol; 30 min
fluoxetine, droperidol
after ondansetron
3729
Leg injury,
hematocrit¼24%
Prevention of PONV
IV
Oxycodone,
metoclopramide
4 mg
Preoperative
During emergence
(increased
sympathetic activity),
in LQTS patient, with
multiple QT-prolonging
medications
During emergence
(increased
sympathetic activity),
in LQTS patient, with
multiple QT-prolonging
medications
Adverse effect of
ondansetron or
inadvertent
intravascular injection
of bupivacaine
Ventricular ectopy
Stress cardiomyopathy,
followed by VT or TdP
coronary artery
disease with TdP
related to droperidol
administration
Bigeminy, ST depression, Concurrent
T-wave inversion
administration of
metoclopramide
Ondansetron and Risk of Cardiac Arrhythmias
Annals of Emergency Medicine 25.e4
Pediatric cases
1126
None
Concomitant
Medications
Freedman et al
Volume 64, no. 1 : July 2014
Table E3. Pediatric and adult case reports identified in the literature.
Age, Years
Past Medical History
Indication
Dose
Route
Concomitant
Medications
Time to Event
Event
Reduction of bilateral
calcaneal fractures,
palpitations
Prevention of PONV
2 mg
IV
6025
Gastric carcinoma,
hemoglobin¼7 g/dL
Erosive gastritis, GERD,
hypertension
Prevention of PONV
4 mg
IV
Nausea, vomiting,
anorexia
N/A
IV
5124
Hyperlipidemia
Prevention of PONV
4 mg2
IV
4731
Benign breast lump
Prevention of PONV
4 mg2
IV
4332
Cholecystitis
Prevention of PONV
4 mg
IV
3533
Asthma
Prevention of PONV
4 mg
IV
Fentanyl, propofol,
Immediately after 5 mL
cocaine paste, nitrous
of 2% lidocaine with
oxide, sevoflurane,
epinephrine (1 in
diclofenac, lidocaine
80,000)
with epinephrine
VT, VF
3634
Osteosarcoma
Medication induced
nausea and vomiting
8 mg
IV
Bradycardia, junctional
escape beats, VT
6035
Pulmonary
adenocarcinoma
Prevention of PONV
2 mg
IV
Cisplatin, doxorubicin,
2 h postinitiation of
sodium bicarbonate,
methotrexate infusion
methotrexate,
leucovorin, lorazepam,
dexamethasone,
enoxaparin,
pantoprazole,
sertraline, zolpidem
Ropivacaine, fentanyl,
Immediate
droperidol
6236
Locally advanced
pancreatic carcinoma
Medication-induced
nausea and vomiting
15 mg
N/A
4630
Propofol, lidocaine,
Immediate
fentanyl, nitrous oxide,
succinylcholine,
cefazolin, desflurane,
metoclopramide
Glycopyrrolate
2 min
Valsartan, pantoprazole,
hydrochlorothiazide,
midazolam, fentanyl
Atorvastatin, midazolam,
multivitamin,
glucosamine,
chondroitin, cefazolin,
rocuronium,
isoflurane, propofol,
fentanyl, glycopyrrolate
Midazolam, propofol,
isoflurane, nitrous
oxide, fentanyl,
ketorolac
None
Explanation
Bradycardia, junctional
rhythm, VT, SVT
Previous administration
of metoclopramide
Bradycardia
Attenuated BezoldJarisch reflex
Idiosyncratic adverse
effect
60 min
Second-degree AV block
Immediately after
second dose
ST-segment elevation
and alternans, atrial
fibrillation
Coronary artery
vasospasm “probably”
related to ondansetron
15 min after second
dose
Atrial fibrillation
Cannot conclusively
establish causality
2 to 3 min
Sinus bradycardia
Attenuated BezoldJarisch reflex
Injection of epinephrine
after recent cocaine
paste application,
during volatile
anesthetic
administration in
patient with LQTS
“Probable” relationship
between cardiotoxicity
and methotrexate
Fluorouracil, doxorubicin, N/A
dexamethasone,
diphenhydramine
SVT, PVCs, VT
Ventricular arrhythmia
Ondansetron-induced
acute myocardial
ischemia
Association is not proof
of a relationship to
ondansetron
Freedman et al
Volume 64, no. 1 : July 2014
3429
Ondansetron and Risk of Cardiac Arrhythmias
25.e5 Annals of Emergency Medicine
Table E3. Continued.
Depression, ileostomy,
diverticular disease
Long-term nausea
treatment
4 mg
BID
PO
Fluoxetine
N/A
TdP
3638
Hysterectomy, nonulcer
dyspepsia, GERD
Infected rectus sheath
hematoma
N/A
N/A
N/A
VT, TdP
6239
AML, invasive Aspergillus Medication-induced
nausea and vomiting
infection, pleural
effusions,
cardiomyopathy
8 mg Qday
N/A
N/A
TdP
2540
TB, HIV
N/A
N/A
Loperamide,
metronidazole,
nitrofurantoin,
trimethoprimsulfamethoxazole,
tetracycline,
metoclopramide,
ranitidine, cisapride
Daunorubicin,
cytarabine,
furosemide,
amphotericin b,
voriconazole,
esomeprazole
Amikacin, linezolid,
moxifloxacin,
prothionamide,
ethambutol,
cycloserine,
pyrazinamide,
darunavir-ritonavir,
clofazamine,
enoxaparin,
valganciclovir,
fluconazole
N/A
Fatal arrhythmia
Long-term nausea
treatment
Hypomagnesemia, daily
ondansetron and
fluoxetine,
cardiomyopathy
Multifactorial cause
including cisapride,
drug-drug interaction,
and electrolyte
disturbance
Freedman et al
Volume 64, no. 1 : July 2014
6737
Voriconazole caused QT
prolongation in setting
of cardiomyopathy,
electrolyte
disturbance, and
esomeprazole
Medications causing QT
prolongation, HIV, and
TB infection
IV, Intravenous; PVC, premature ventricular contraction; VT, ventricular tachycardia; LQTS, long-QT syndrome; IM, intramuscular; VF, ventricular fibrillation; ALL, acute lymphoblastic leukemia; N/A, not available; PO, per os; TdP,
torsades de pointes; GERD, gastroesophageal reflux; HRT, hormone replacement therapy; SVT, supraventricular tachycardia; AV, atrioventricular; BID, twice daily; AML, acute myelogenous leukemia; Qday, daily; TB, tuberculosis.
Ondansetron and Risk of Cardiac Arrhythmias
Annals of Emergency Medicine 25.e6