sign in sign up
<<
Home , Ondansetron, Zydis

TOXICOLOGY/ORIGINAL RESEARCH 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 .

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 , Background bradyarrhythmias, or patients taking other medicinal products ” 4 Ondansetron hydrochloride is a potent that that lead to QT prolongation ). 1 antagonizes 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 identified and screened for retrieval from MEDLINE, Canada Vigilance Adverse Reaction Online Database (http:// EMBASE, Web of Knowledge, SCOPUS www.hc-sc.gc.ca/dhp-mps/medeff/databasdon/index-eng.php), 91 Duplicate articles removed Google Scholar, and the Canadian Agency for Drugs and Health Technologies (http://cadth.ca/en/products) were searched on 1029 Titles and abstracts screened for inclusion September 5, 2012, with the search term combination of “ondansetron” AND (QT or arrhythmia*). 958 Articles excluded based on Global ADR Registries. The World Health Organization title/abstract review (WHO) Global Individual Safety Case Reports Database (VigiBase) registry, which holds more than 3,800,000 reports 71 Potentially relevant articles retrieved for full-text review from national pharmacovigilance centers and regulatory 53 Excluded authorities of more than 80 countries,18 was searched on August 2 Relevant reports 38 review articles identified in reference 11 Ineligible reports 30, 2012, with the WHO-adverse drug reaction terminology review 4 Letters/Comments (no case) preferred terms “arrhythmia,”“arrhythmia ventricular,” and “arrhythmia atrial” to extract all suspected or interacting arrhythmia reports occurring within 24 hours of ondansetron 20 Articles (23 cases) describing an arrhythmia or an event perceived as possibly being an arrhythmia in an individual administration. administered ondansetron up to 24 hours prior to the event. A search of the FDA Adverse Events Reporting System was conducted on November 26, 2012, using formal MedDRA Figure. Flow of reports identified in the published literature nomenclature (version 15.1; Glaxosmithkline, Brentford, through the systematic review process. Middlesex, United Kingdom). Cases reporting “ondansetron,” “ondansetron hydrochloride,”“ondansetron ODT” or “Zofran” Global ADR Registries. A comprehensive VigiBase search and “Arrhythmia,” including “Torsade de Pointes,” were retrieved. identified 25 reports, and the FDA Adverse Events Reporting We approached GlaxoSmithKline, the company that System identified 16; 4 were duplicates, resulting in 37 unique developed and markets ondansetron (Zofran), to provide all reports. Because safety reports are shared by GlaxoSmithKline with relevant postmarketing adverse drug reaction reports. regulatory authorities (eg, the FDA), the company stated that querying regulatory data sets would capture all relevant reports. Data Synthesis and Analysis The primary outcome was the number of reports describing an arrhythmia after single oral ondansetron dose admini- Primary Outcome stration. Secondary outcomes included (1) cases linking the We did not identify any reports describing the occurrence administration of ondansetron by any route, dose, and frequency of an arrhythmia within 24 hours of the administration of a to the development of an arrhythmia; and (2) the strength of single oral ondansetron dose in any of the sources searched. causality. To determine the optimal method of assessing causality, we used the Naranjo ADR Probability Scale (Table E2, Secondary Outcomes 19 available online at http://www.annemergmed.com). A board- Eleven (18%) pediatric and 49 (82%) adult cases were certified clinical pharmacologist (Y.F.) with previous experience identified (Tables 1 and 2). Forty-eight (80%) involved 20,21 using the scale assigned probability scores to all published intravenous administration and 2 (3%) involved long-term cases. For cases identified in the WHO registry, we oral use in patients with multiple arrhythmia risk factors. A documented the scores provided (ie, Council for International significant medical history (67%; 40/60) or concomitant use 22 Organizations of Medical Sciences scoring system) ; FDA of QT-prolonging medications (67%; 40/60) was identified in Adverse Events Reporting System did not provide causality scores. 83% (50/60). Unique (ie, nonoverlapping) indications for use included prevention of postoperative (35%; 21/60) or RESULTS -induced (35%; 21/60) vomiting. Case Selection Adult Reports (n¼49). Published Literature (n¼17) Fifteen Published Literature. The electronic database searches (88%) of the cases had readily identifiable proarrhythmogenic identified 1,120 citations (Figure). After removal of duplicates risk factors (ie, significant medical history or receiving other QT- and review of titles and abstracts, 71 articles containing prolonging medications). Median patient age was 46 years potentially eligible cases remained. Of these, 18 reports (interquartile range [IQR] 36, 60; range 24 to 67 years). Twelve describing 21 eligible cases were identified. Reference and text involved intravenous administration24,25,28-35,42; 1, oral review detected 2 additional cases. In total, 23 cases (6 pediatric; administration37; and 4, an unspecified route.36,38-40 The single 17 adult) (Table E3, available online at http://www. oral case involved long-term use37 in a patient with acute annemergmed.com) were identified from 20 publications.23-42 cardiomyopathy and electrolyte imbalances. Two patients Grey Literature. No additional eligible reports were received multiple intravenous doses24,31 and 1 received a large identified. intravenous dose.36 Nine individuals were treated to prevent

Volume 64, no. 1 : July 2014 Annals of Emergency Medicine 21 Ondansetron and Risk of Cardiac Arrhythmias Freedman et al

Table 1. Summary of all secondary outcome reports identified from all sources searched. Pediatric (<18 Years) Reports Adult (‡18 Years) Reports Source Intravenous Oral Intramuscular Intravenous Oral Not Documented Total Published literature 4 1* 1121* 423 ADR databases VigiBase 4 0 0 19 0 2 25 FAERS† 10 0 80 3 12 Grey literature 0 0 0 0 0 0 0 Total 91 1 391 9 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 and vomiting24,25,29,31-33,35,42 and 3 for Pediatric Reports (n¼11). Published Literature (n¼6). The cancer chemotherapy-associated vomiting.34,36,39 Subjects were mean age of pediatric patients was 12.2 years (SD 2.8 years). A receiving a median of 6 additional medications (IQR 2, 8); only single case describing an arrhythmia in a child administered oral 1 did not receive concomitant medications. Nine individuals ondansetron was identified. This 16-year-old with significant received other QT-prolonging medications43 and 2 were medical problems (eg, leukemia, sepsis, acute tubular necrosis, receiving 3 such medications.28,40 hypokalemia, hypomagnesaemia) had been administered long- ADR Registries (n¼32). The WHO VigiBase search identified term ondansetron,27 along with 8 additional QT-prolonging 21 adult reports (patients aged 25 to 70 years; 9 men). Nineteen agents. Additional cases were associated with intravenous patients received intravenous ondansetron (4 to 20 mg/day); exposure: 3 described arrhythmias in the operating room in the other 2 lacked documentation of route of administration. children with long-QT syndrome after concomitant Twelve patients received long-term ondansetron. Nine were administration of multiple QT-prolonging medications.26,41 oncology patients; 1 had a pacemaker. Nineteen (91%) Another report described a child becoming apneic and received concomitant medications (range 1, 7; median 3; IQR 2, bradycardic after intravenous administration.25 and 4); 14 (67%) received QT-prolonging agents. Four patients had an oxygen administration led to recovery. Last, 3 hours after ondansetron rechallenge, and none had arrhythmia recurrence. intramuscular ondansetron injection, a child developed The FDA Adverse Events Reporting System search identified ventricular tachycardia and died.23 Because no other details were 13 adult reports; 2 were duplicates and were excluded. The provided in association with this report, causality is uncertain and 11 remaining adults were aged 20 to 80 years. Eight patients unlikely. received intravenous ondansetron (1 both intravenously and Global ADR Registries (n=5). VigiBase search identified 4 orally); 3 lacked documentation of route of administration. Ten pediatric cases (age range 2 to 14 years; United States n¼2; patients (91%) had significant underlying conditions, including Germany n¼1, Chile n¼1) involving intravenous ondansetron cardiac (eg, cardiomyopathy, myocarditis, long-QT syndrome), (1 to 24 mg/day). Three of these children received long-term oncologic, renal, and metabolic abnormalities. Ten patients ondansetron; 2 were oncology patients receiving multiple (91%) received additional medications (range 1, 24; median 8; medications, including chemotherapeutics, whereas the third IQR 4, 13); 9 included a QT-prolonging medication. The sole received 3 general anesthetic agents. The FDA Adverse Events case without a reported risk factor involved a 62-year-old Reporting System search identified 3 reports; 2 were duplicates administered ondansetron intravenously. 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) Adult (‡18 Years) Reports (n[49) Significant Concomitant Significant Concomitant Medical QT-Prolonging Prevention Medical QT-Prolonging Prevention Source History Medication of PONV History Medication of PONV Published literature 3 4 4 11 9 9 ADR databases VigiBase* 33113143 FAERS 0 1 1 10 9 3 Total (%)† 6 (55) 8 (73) 6 (55) 34 (69) 32 (65) 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 Ondansetron and Risk of Cardiac Arrhythmias

11-year-old child who received ondansetron and 8 concomitant conditions and those administered other QT-prolonging intravenous medications, including 4 arrhythmogenic medications concomitantly. anesthetics. Ondansetron is routinely used, often off label, to treat a variety Strength of Causality. There were no reported arrhythmias of ambulatory conditions in the ED, such as - that developed after administration of a single oral ondansetron induced vomiting47 and .48-50 The dose in any of the studied sources (primary outcome). All 23 unwarranted withholding of ondansetron when clinically secondary outcome reports from the literature were assigned low indicated and the performance of universal ECG and electrolyte probability Naranjo scores (pediatric 2 to 3, adult 2 to 4; screening may lead to increased morbidity, resource consumption, “possible” range). Council for International Organizations of impaired ED patient flow, and costs. Recently, a study of 100 Medical Sciences probability scores were reported in VigiBase for children administered therapeutic doses of intravenous 1 child (“possible”) and 6 adults (5 “possible” and 1 “probable”); ondansetron for the treatment of nausea and vomiting in the ED the remainder of adverse drug reaction registry cases could not be found no statistical or clinically significant evidence of QT-interval assigned probability scores because of insufficient data provided prolongation at peak (3 minutes) or 1 hour postpeak effect.51 to the registry. The pharmacokinetic differences between oral and intravenous ondansetron administration provide a biologically LIMITATIONS plausible mechanistic explanation for the absence of reports of arrhythmias after single oral dose administration. The peak serum Our study has several potential limitations. First, it is possible level after oral administration, the most relevant factor affecting that not all cases have been reported. To mitigate this, we used a arrhythmia risk, is only 3% to 34% of that achieved after a comprehensive search strategy and a low inclusion threshold of similar intravenous dose.52,53 Although the maximum QTc all published and unpublished reports. Second, we used the lengthening is 17 to 20 msec after intravenous administration of Naranjo Scale to assess the causality of adverse reactions because a 32-mg ondansetron dose, it is only 5.8 msec after an 8-mg it is the most widely accepted causality scoring system and has intravenous dose in adults,54-56 and to our knowledge there been in use for more than 30 years.44 During study planning, are no reports documenting QTc prolongation after oral we conducted a literature search and identified its use in administration. The time to peak serum level is much longer 938 publications, including 45 assessments of drug-induced after oral (2.3 hours) compared with intravenous (5 minutes) arrhythmias. However, this score was not designed to evaluate administration.53 Recently, the intentional ingestion of 60 mg adverse events resulting from the interaction of multiple drugs,45 of ondansetron by a child (ie, 8 times the therapeutic dose) as was often the case in our reports. Nonetheless, the associations did not result in ECG changes.57 Thus, oral administration of reported for the secondary outcomes were scarce and weak, with a therapeutic ondansetron dose is highly unlikely to cause a original authors usually attributing causality to other factors, such clinically significant prolongation of the QT interval and even less as baseline conditions or concomitant drugs. Although our ability likely to cause an arrhythmia, a finding supported by our analysis. to assess causality related to reports in the unpublished literature was limited because of missing data in some cases, our search Proposed Approach yielded a paucity of reports, with none involving a single oral In accordance with the data presented in this article, it is ondansetron dose. Although the FDA warning in 2011 may have our opinion that a patient-tailored, evidence-based approach to limited the use of ondansetron in patients with risk factors, risk-stratify patients would serve to optimize care. Consideration thereby decreasing the risk of complications since its publication, should be given to performing ECG and electrolyte screening in the absence of reports associating single oral dose ondansetron patients with known arrhythmia risk factors, including cardiac use with arrhythmia throughout the study period implies that (eg, heart failure, personal or family history suggestive of long- such events rarely if ever occur. QT syndrome, other arrhythmias), medication (eg, multiple dose or intravenous ondansetron, concomitant QT-prolonging or DISCUSSION cardiac medications), or electrolyte (eg, short-gut syndrome, Despite extensive use for more than 22 years and several diuretic use, renal disease); individuals receiving a single oral dose hundred million patient treatment-days,46 we did not find any in the absence of risk factors should not be screened. This reports of an arrhythmia occurring in a patient after the balanced approach enables the implementation of regulatory administration of a single oral ondansetron dose. Our findings agency recommendations without compromising or delaying indicate that universal ECG screening and electrolyte testing care. It minimizes the potential harms and costs (estimated at before ondansetron administration are likely unwarranted. The $5.5 million per 1 true long-QT syndrome case) associated with evidence is particularly weak as it relates to the typical pediatric screening low-risk patients while allowing patients to benefit ED scenario in which a single oral dose is often administered from an effective medication. to an otherwise healthy individual who is not prescribed other In summary, we did not identify any reports of arrhythmias QT-interval prolonging medications. Individuals at risk of developing in otherwise healthy patients after the developing an arrhythmia included those receiving ondansetron administration of a single oral ondansetron dose. Clinicians intravenously in the setting of underlying arrhythmogenic should be cognizant of ondansetron’s potential to prolong

Volume 64, no. 1 : July 2014 Annals of Emergency Medicine 23 Ondansetron and Risk of Cardiac Arrhythmias Freedman et al the QT interval when administered intravenously, particularly to conduct the study or produce the article. The funders had no in high doses and in high-risk patients. A risk-stratification role in study design, data collection and analysis, decision to strategy should be used to individualize how these publish, or preparation of the article. recommendations are adapted into clinical practice to identify The data provided by the WHO Collaborating Centre for potentially vulnerable patients who are likely to benefit from International Drug Monitoring, Uppsala, are not homogeneous at screening. In patients with no known risk factors who are least with respect to origin or likelihood that the pharmaceutical administered a single oral ondansetron dose, routine ECG product caused the adverse reaction, and the information we and electrolyte screening are not warranted. report from the WHO Collaborating Centre does not represent the opinion of the World Health Organization.

Supervising editor: Matthew D. Sztajnkrycer, MD, PhD Publication dates: Received for publication July 31, 2013. Revision received October 2, 2013. Accepted for publication Author affiliations: From the Sections of Pediatric Emergency October 24, 2013. Available online December 4, 2013. Medicine and Gastroenterology, Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, University of Presented as an abstract at the 2013 Pediatric Academic Society Calgary, Calgary, Alberta, Canada (Freedman); the Hospital Library annual meeting, May 2013, Washington, DC. and Archives (Uleryk), Child Health Evaluative Sciences (Finkelstein), Hospital for Sick Children Research Institute (Finkelstein, Rumantir), and Divisions of Paediatric Emergency REFERENCES Medicine and Clinical Pharmacology and Toxicology, Department of 1. Bryson JC. Clinical safety of ondansetron. Semin Oncol. 1992;19:26-32. Paediatrics (Finkelstein), The Hospital for Sick Children, Toronto, 2. Tay KY, Ewald MB, Bourgeois FT. Use of QT-prolonging medications in Ontario, Canada; and the Faculty of Medicine, University of US emergency departments, 1995-2009. Pharmacoepidemiol Drug Toronto, Toronto, Ontario, Canada (Uleryk, Finkelstein). Saf. 2013;. http://dx.doi.org/10.1002/pds.3455. 3. Sturm JJ, Hirsh DA, Schweickert A, et al. Ondansetron use in the Author contributions: SBF and YF contributed equally to this article pediatric emergency department and effects on hospitalization and and are therefore co-Principal Investigators. SBF and YF had full return rates: are we masking alternative diagnoses? Ann Emerg Med. access to all of the data in the study, take responsibility for the 2010;55:415-422. integrity of the data and the accuracy of the data analysis, serve as 4. Food and Drug Administration. FDA drug safety communication: study guarantors, and were responsible for study concept, statistical abnormal heart rhythms may be associated with use of Zofran analysis, and study supervision. SBF, MR, and YF were responsible (ondansetron). Available at: http://www.fda.gov/Drugs/DrugSafety/ ucm271913.htm. Accessed April 23, 2013. for analysis and interpretation of data and administrative, technical, 5. FDA drug safety podcast for healthcare professionals: new information and material support. SBF, EU, and YF were responsible for drafting regarding QT prolongation with ondansetron (Zofran). Available at: the article. All authors were responsible for acquisition of data and http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ critical revision of the article for important intellectual content, had ucm310546.htm. Accessed September 5, 2012. full access to all of the data (including statistical reports and tables) 6. Zofran (ondansetron)—association with changes in electrical activity in in the study, and take responsibility for the integrity of the data and the heart—for health professionals. Available at: http://www. the accuracy of the data analysis. SBF takes responsibility for the healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2012/15080a- paper as a whole. eng.php. Accessed April 23, 2013. 7. Medicines and Healthcare Products Regulatory Agency. Ondansetron Funding and support: By Annals policy, all authors are required to (Zofran): risk of QTc prolongation—important new intravenous dose disclose any and all commercial, financial, and other relationships restriction. Available at: http://www.mhra.gov.uk/Safetyinformation/ in any way related to the subject of this article as per ICMJE conflict DrugSafetyUpdate/CON180635. Accessed April 23, 2013. of interest guidelines (see www.icmje.org). All authors have 8. Hohl CM, Dankoff J, Colacone A, et al. Polypharmacy, adverse drug- completed the Unified Competing Interest form at www.icmje.org/ related events, and potential adverse drug interactions in elderly coi_disclosure.pdf (available on request from the corresponding patients presenting to an emergency department. Ann Emerg Med. 2001;38:666-671. author) and declare that (1) none of the authors have received 9. Banerjee A, MbamaluD,Ebrahimi S, etal. The prevalence of polypharmacy support for the conduct of the submitted work; (2) Dr. Freedman in elderly attenders to an emergency department—a problem with a has a relationship with GlaxoSmithKline that might have an need for an effective solution. Int J Emerg Med. 2011;4:22. interest in the submitted work in the previous 3 years; (3) the 10. Olshaker JS, Mason JD. The usefulness of serum electrolytes in the evaluation authors’ spouses, partners, or children have no financial of acute adult gastroenteritis. Ann Emerg Med. 1989;18:258-260. relationships that may be relevant to the submitted work; and 11. Garson A Jr, Dick M 2nd, Fournier A, et al. The long QT syndrome in (4) Drs. Freedman, Finkelstein, and Rumantir and Ms. Uleryk have children. An international study of 287 patients. Circulation. no nonfinancial interests that may be relevant to the submitted 1993;87:1866-1872. work. Specifically, Dr. Freedman acknowledges receiving in-kind 12. Rodday AM, Triedman JK, Alexander ME, et al. Electrocardiogram study drug/placebo from GlaxoSmithKline, the manufacturer of screening for disorders that cause sudden cardiac death in asymptomatic children: a meta-analysis. Pediatrics. 2012;129:e999-e1010. ondansetron, for the conduct of an independently funded (Bill and 13. Bruzzese E, Vecchio AL, Guarino A. Hospital management of Melinda Gates Foundation and Thrasher Research Fund) clinical children with acute gastroenteritis. Curr Opin Gastroenterol. trial not related to the current study. No other form of funding or 2013;29:23-30. research support was provided by GlaxoSmithKline. The first draft 14. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for of the article was written by Drs. Freedman and Finkelstein. No systematic reviews and meta-analyses: the PRISMA statement. Ann honorarium, grant, or other form of payment was given to anyone Intern Med. 2009;151:264-269, W64.

24 Annals of Emergency Medicine Volume 64, no. 1 : July 2014 Freedman et al Ondansetron and Risk of Cardiac Arrhythmias

15. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for 38. Hussain A, Ghazal S. After more than 300 defibrillation shocks, patient reporting systematic reviews and meta-analyses of studies that still alive 12 years later refractory torsade de pointes due to evaluate healthcare interventions: explanation and elaboration. BMJ. polypharmacy and persistent vomiting. J Saudi Heart Assoc. 2009;339:b2700. 2010;22:149-151. 16. Alberani V, De Castro Pietrangeli P, Mazza AM. The use of grey 39. Philips JA, Marty FM, Stone RM, et al. associated literature in health sciences: a preliminary survey. Bull Med Libr Assoc. with voriconazole use. Transpl Infect Dis. 2007;9:33-36. 1990;78:358-363. 40. Boxall E, Milne J, Peters E, et al. Sudden unexplained death in a patient with 17. Wahi G, Parkin PC, Beyene J, et al. Effectiveness of interventions aimed HIV and MDR-TB. Journal of the International AIDS Society Conference: at reducing screen time in children: a systematic review and meta- 10th International Congress on Drug Therapy in HIV Infection; Conference analysis of randomized controlled trials. Arch Pediatr Adolesc Med. Start 2010; 20101107; Glasgow, Scotland, November 7-11, 2010. 2011;165:979-986. 41. Nathan AT, Berkowitz DH, Montenegro LM, et al. Implications of 18. Lindquist M. VigiBase, the WHO Global ICSR Database System: basic anesthesia in children with long QT syndrome. Anesth Analg. facts. Drug Inf J. 2008;42:409-419. 2011;112:1163-1168. 19. NaranjoCA,BustoU,SellersEM,etal.Amethod for estimating the probability 42. Saxena A, Chand T, Arya SK, et al. Ondansetron-induced ventricular of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245. tachycardia in a patient of caesarian section. J Obstet Anaesth Crit 20. Avner M, Finkelstein Y, Hackam D, et al. Establishing causality in Care. 2012;2:103-104. pediatric adverse drug reactions: use of the Naranjo probability scale. 43. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Paediatr Drugs. 2007;9:267-270. Med. 2004;350:1013-1022. 21. Rezvani M, Finkelstein Y, Verjee Z, et al. Generalized seizures following 44. Gallagher RM, Kirkham JJ, Mason JR, et al. Development and inter- topical lidocaine administration during circumcision: establishing rater reliability of the Liverpool adverse drug reaction causality causation. Paediatr Drugs. 2007;9:125-127. assessment tool. PLoS One. 2011;6:e28096. 22. Meyboom RH, Hekster YA, Egberts AC, et al. Causal or casual? the role 45. Kane-Gill SL, Kirisci L, Pathak DS. Are the Naranjo criteria reliable and of causality assessment in pharmacovigilance. Drug Saf. valid for determination of adverse drug reactions in the intensive care 1997;17:374-389. unit? Ann Pharmacother. 2005;39:1823-1827. 23. Chandrakala R, Vijayashankara C, Kumar K, et al. Ondansetron induced 46. GlaxoSmithKline Inc., inventor Product Monograph - Zofran (ondansetron fatal ventricular tachycardia. Indian J Pharmacol. 2008;40:186-187. hydrochloride dihydrate). Mississauga, ON January 26, 2012. 24. Havrilla PL, Kane-Gill SL, Verrico MM, et al. Coronary vasospasm and 47. Kharbanda AB, Hall M, Shah SS, et al. Variation in resource utilization atrial fibrillation associated with ondansetron therapy. Ann across a national sample of pediatric emergency departments. Pharmacother. 2009;43:532-536. J Pediatr. 2013;163:230-236. 25. Afonso N, Dang A, Namshikar V, et al. Intravenous ondansetron 48. Madjunkova S, Maltepe C, Koren G. The leading concerns of American causing severe : two cases. Ann Card Anaesth. women with nausea and vomiting of calling Motherisk NVP 2009;12:172-173. Helpline. Obstet Gynecol Int. 2013;2013:752980. 26. McKechnie K, Froese A. Ventricular tachycardia after ondansetron 49. Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy administration in a child with undiagnosed long QT syndrome. Can J and risk of adverse fetal outcomes. N Engl J Med. Anaesth. 2010;57:453-457. 2013;368:814-823. 27. Bagatell R, Hainstock M, Lowe MC, et al. The perfect storm: torsades 50. Raymond SH. A survey of prescribing for the management of nausea de pointes in a child with leukemia. Pediatr Blood Cancer. and vomiting in pregnancy in Australasia. Aust N Z J Obstet Gynaecol. 2007;49:996-999. 2013;53:358-362. 28. Choo EK, Weber FS, Schmidt TA. Torsade de pointes after 51. The effect of intravenous ondansetron on the QT interval of administration of for nausea and vomiting. Prehosp Emerg patients’ electrocardiograms in the pediatric emergency department. Care. 2009;13:261-265. Available at: http://www2.aap.org/sections/pem/PDF/ 29. Baguley WA, Hay WT, Mackie KP, et al. Cardiac dysrhythmias 2013SOEMNCEProgram7-13.pdf. Accessed July 29, 2013. associated with the intravenous administration of ondansetron and 52. Pritchard JF, Bryson JC, Kernodle AE, et al. Age and gender effects on . Anesth Analg. 1997;84:1380-1381. ondansetron : evaluation of healthy aged volunteers. 30. Chakraborti C, Egan J. The lesser of two adverse reactions. Joint Clin Pharmacol Ther. 1992;51:51-55. Commission J Qual Pat Saf. 2010;36:22-27. 53. VanDenBerg CM, Kazmi Y, Stewart J, et al. Pharmacokinetics of three 31. Kasinath NS, Malak O, Tetzlaff J. Atrial fibrillation after ondansetron for formulations of ondansetron hydrochloride in healthy volunteers: the prevention and treatment of postoperative nausea and vomiting: 24-mg oral tablet, rectal suppository, and i.v. infusion. Am J Health a case report. Can J Anaesth. 2003;50:229-231. Syst Pharm. 2000;57:1046-1050. 32. Moazzam MS, Nasreen F, Bano S, et al. Symptomatic sinus 54. Charbit B, Albaladejo P, Funck-Brentano C, et al. Prolongation of bradycardia: a rare adverse effect of intravenous ondansetron. Saudi J QTc interval after postoperative nausea and vomiting treatment by Anaesth. 2011;5:96-97. droperidol or ondansetron. . 2005;102:1094-1100. 33. Dolenska S. Intraoperative cardiac arrest in acquired long QT 55. Charbit B, Alvarez JC, Dasque E, et al. Droperidol and ondansetron- syndrome. Br J Anaesth. 2009;102:503-505. induced QT interval prolongation: a clinical drug interaction study. 34. Perez-Verdia A, Angulo F, Hardwicke FL, et al. Acute cardiac toxicity Anesthesiology. 2008;109:206-212. associated with high-dose intravenous methotrexate therapy: case report 56. GlaxoSmithKline Inc. A randomized, double-blind, four-period and review of the literature. Pharmacotherapy. 2005;25:1271-1276. crossover study to investigate the effect of intravenous ondansetron, a 35. Bosek V, Hu P, Robinson LA. Acute myocardial ischemia after 5-HT3 antagonist, on cardiac conduction as compared to placebo administration of ondansetron hydrochloride. Anesthesiology. and moxifloxacin in healthy adult subjects. Available at: http://www. 2000;92:885-887. gsk-clinicalstudyregister.com/result_detail.jsp?protocolId¼ 36. Ballard HS, Bottino G, Bottino J. Ondansetron and chest pain. Lancet. 115458&studyId¼9B2760D1-7F0C-4871-992F-EAF86227CE3E& 1992;340:1107. compound¼ondansetron. Accessed October 1, 2012. 37. Purvis JA, Cunningham EL, McGlinchey PG, et al. Drugs, electrolytes 57. Ghafouri N, Darracq MA, Cantrell FL. Ondansetron-associated and tako-tsubo cardiomyopathy: triple aetiology of acquired long QT hypotension following pediatric self-poisoning. Pediatr Emerg Care. syndrome and torsades de pointes. Ulster Med J. 2009;78:188-189. 2012;28:596-597.

Volume 64, no. 1 : July 2014 Annals of Emergency Medicine 25 Ondansetron and Risk of Cardiac Arrhythmias Freedman et al

APPENDIX E1. long-QT syndrome because these patients are at particular risk ONDANSETRON DRUG SAFETY COMMUNICATION for torsade. Additionally, recommendations for ECG monitoring in patients with electrolyte abnormalities (eg, hypokalemia, The U.S. Food and Drug Administration (FDA) is informing hypomagnesemia), congestive heart failure, or bradyarrhythmias, the public of an ongoing safety review of the antinausea drug Zofran or in patients receiving other medications that can lead to (ondansetron, ondansetron hydrochloride, and their generics). QT prolongation, are being included in the labels. 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. Additional Information for Health Care Professionals Changes in the electrical activity of the heart (prolongation of ECG changes including QT-interval prolongation have been the QT interval of the ECG)—see data summary below—can observed in patients receiving Zofran (ondansetron). In lead to an abnormal and potentially fatal heart rhythm (including addition, torsade de pointes, an abnormal heart rhythm, has torsade de pointes). Patients at particular risk for developing been reported in some patients receiving ondansetron. torsade include those with underlying heart conditions, such as The use of Zofran (ondansetron) should be avoided in patients congenital long-QT syndrome, those who are predisposed to low with congenital long-QT syndrome. levels of potassium and magnesium in the blood, and those ECG monitoring is recommended in patients with receiving other medications that lead to QT prolongation. electrolyte abnormalities (eg, hypokalemia, hypomagnesemia), FDA has reviewed all available information and is making congestive heart failure, or bradyarrhythmias, or patients interim changes to the drug labels. The manufacturer of Zofran receiving concomitant medications that prolong the QT (GlaxoSmithKline) is being required to conduct a thorough QT interval. study to assess the potential for the drug to prolong the QT Advise patients to contact a health care professional interval. The results from this study are expected to be available in immediately if they experience signs and symptoms of an the summer of 2012. Additional label changes may result after the abnormal pulse rate or rhythm while receiving Zofran additional information has been reviewed. The Zofran (ondansetron). (ondansetron) drug labels already contain information about Report adverse events involving Zofran (ondansetron) to the the potential for QT prolongation. The labels are being revised FDA MedWatch program, using the information in the to include a warning to avoid use in patients with congenital “Contact Us” box at the bottom of the page.

25.e1 Annals of Emergency Medicine Volume 64, no. 1 : July 2014 remne al et Freedman Volume 4 o : 1 no. 64, July 2014

Table E1. Search strategies. Set History Results 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 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. 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 2,862 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. 1TS¼(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) 2ts¼arrythmia* 80

3 #1 and #2 0 Arrhythmias Cardiac of Risk and Ondansetron 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”)) Annals of mrec Medicine Emergency 25.e2 Ondansetron and Risk of Cardiac Arrhythmias Freedman et al

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? þ10 0 Did the adverse event occur after the suspected drug was administered? þ2 10 Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? þ10 0 Did the adverse reaction reappear when the drug was readministered? þ2 10 Are there alternative causes (other than the drug) that could have on their own caused the reaction? 1 þ20 Did the reaction reappear when a placebo was given? 1 þ10 Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? þ10 0 Was the reaction more severe when the dose was increased or less severe when the dose was decreased? þ10 0 Did the patient have a similar reaction to the same or similar drugs in any previous exposure? þ10 0 Was the adverse event confirmed by any objective evidence? þ10 0

25.e3 Annals of Emergency Medicine Volume 64, no. 1 : July 2014 remne al et Freedman Volume Table E3. Pediatric and adult case reports identified in the literature. Concomitant 4 o : 1 no. 64, Age, Years Past Medical History Indication Dose Route Medications Time to Event Event Explanation Pediatric cases 1126 None Prevention of PONV 0.1 mg/kg IV Sevoflurane, nitrous 2 min PVCs developing into VT Congenital LQTS oxide, remifentanil, July rocuronium,

2014 , 825 None Prevention of PONV 0.13 mg/kg IV Not documented 2 min Unconscious, apnea, Bradycardia as a result of severe bradycardia attenuation of Bezold- Jarisch reflex 1423 None Vomiting, abdominal 4 mg IM Antacid 300 min VT then VF Autopsy declined pain8h 1627 ALL, pseudomonas Intractable emesis N/A PO Clarithromycin, “Several hours” PVCs, prolonged QT Hypokalemia (2.0 mEq/L) bacteremia, acute secondary to C difficile amoxicillin, interval, ventricular and hypomagnesemia tubular necrosis, colitis and metronidazole, ectopy; 60 min later (1.1 mg/dL) as a result Clostridium difficile Helicobacter pylori trimethoprim- developed VT then TdP of renal dysfunction, colitis sulfamethoxazole, diuretic use, ; , multiple medications , pantoprazole, potassium 1341 LQTS, Andersen-Tawil Prevention of PONV N/A IV Sevoflurane, desflurane, “Close proximity” Bigeminy, VT During emergence (LQTS 7) syndrome vecuronium, (increased anticholinesterase, sympathetic activity), in LQTS patient, with multiple QT-prolonging medications 1141 Jervell and Lange- Prevention of PONV N/A IV Sodium pentothal, “Close proximity” TdP During emergence Nielsen (LQTS) , isoflurane, (increased

syndrome pancuronium sympathetic activity), Arrhythmias Cardiac of Risk and Ondansetron anticholinesterase, in LQTS patient, with anticholinergic multiple QT-prolonging medications Adult cases Annals 2442 Pregnancy Prevention of PONV 4 mg IV Bupivacaine Within 1 min VT Adverse effect of ondansetron or

of inadvertent intravascular injection mrec Medicine Emergency of bupivacaine 4728 Hypertension, aortic Abdominal pain, nausea, 4 mg IV HRT, morphine sulphate, “Shortly after” Ventricular ectopy Stress cardiomyopathy, stenosis, GERD, vomiting , , droperidol; 30 min followed by VT or TdP coronary artery , depression fluoxetine, droperidol after ondansetron disease with TdP related to droperidol administration 3729 Leg injury, Prevention of PONV 4 mg IV Oxycodone, Preoperative Bigeminy, ST depression, Concurrent ¼

25.e4 hematocrit 24% metoclopramide T-wave inversion administration of metoclopramide nasto n iko ada Arrhythmias Cardiac of Risk and Ondansetron 25.e5

Table E3. Continued.

Annals Concomitant Age, Years Past Medical History Indication Dose Route Medications Time to Event Event Explanation of 3429 Reduction of bilateral Prevention of PONV 2 mg IV Propofol, lidocaine, Immediate Bradycardia, junctional Previous administration mrec eiieVolume Medicine Emergency calcaneal fractures, fentanyl, , rhythm, VT, SVT of metoclopramide palpitations succinylcholine, cefazolin, desflurane, metoclopramide 6025 Gastric carcinoma, Prevention of PONV 4 mg IV Glycopyrrolate 2 min Bradycardia Attenuated Bezold- hemoglobin¼7 g/dL Jarisch reflex 4630 Erosive gastritis, GERD, Nausea, vomiting, N/A IV Valsartan, pantoprazole, 60 min Second-degree AV block Idiosyncratic adverse hypertension anorexia hydrochlorothiazide, effect , fentanyl 5124 Hyperlipidemia Prevention of PONV 4 mg2 IV Atorvastatin, midazolam, Immediately after ST-segment elevation Coronary artery multivitamin, second dose and alternans, atrial vasospasm “probably” glucosamine, fibrillation related to ondansetron chondroitin, cefazolin, rocuronium, isoflurane, propofol, fentanyl, glycopyrrolate 4731 Benign breast lump Prevention of PONV 4 mg2 IV Midazolam, propofol, 15 min after second Atrial fibrillation Cannot conclusively isoflurane, nitrous dose establish causality oxide, fentanyl, ketorolac 4332 Cholecystitis Prevention of PONV 4 mg IV None 2 to 3 min Sinus bradycardia Attenuated Bezold- Jarisch reflex 3533 Asthma Prevention of PONV 4 mg IV Fentanyl, propofol, Immediately after 5 mL VT, VF Injection of epinephrine cocaine paste, nitrous of 2% lidocaine with after recent cocaine oxide, sevoflurane, epinephrine (1 in paste application, diclofenac, lidocaine 80,000) during volatile with epinephrine anesthetic administration in patient with LQTS 3634 Osteosarcoma Medication induced 8 mg IV , doxorubicin, 2 h postinitiation of Bradycardia, junctional “Probable” relationship nausea and vomiting sodium bicarbonate, methotrexate infusion escape beats, VT between cardiotoxicity methotrexate, and methotrexate leucovorin, , dexamethasone, enoxaparin, pantoprazole, , zolpidem 35

4 o : 1 no. 64, 60 Pulmonary Prevention of PONV 2 mg IV Ropivacaine, fentanyl, Immediate SVT, PVCs, VT Ondansetron-induced adenocarcinoma droperidol acute myocardial ischemia 6236 Locally advanced Medication-induced 15 mg N/A Fluorouracil, doxorubicin, N/A Ventricular arrhythmia Association is not proof al et Freedman pancreatic carcinoma nausea and vomiting dexamethasone, of a relationship to

July diphenhydramine ondansetron 2014 remne al et Freedman Volume 6737 Depression, ileostomy, Long-term nausea 4mg PO N/A TdP Hypomagnesemia, daily diverticular disease treatment BID ondansetron and fluoxetine, 4 o : 1 no. 64, cardiomyopathy 3638 Hysterectomy, nonulcer Infected rectus sheath N/A N/A , N/A VT, TdP Multifactorial cause dyspepsia, GERD hematoma metronidazole, including , nitrofurantoin, drug-drug interaction, trimethoprim- and electrolyte July sulfamethoxazole, disturbance

2014 tetracycline, metoclopramide, , cisapride 6239 AML, invasive Aspergillus Medication-induced 8 mg Qday N/A Daunorubicin, N/A TdP Voriconazole caused QT infection, pleural nausea and vomiting cytarabine, prolongation in setting effusions, furosemide, of cardiomyopathy, cardiomyopathy amphotericin b, electrolyte voriconazole, disturbance, and esomeprazole esomeprazole 2540 TB, HIV Long-term nausea N/A N/A Amikacin, linezolid, N/A Fatal arrhythmia Medications causing QT treatment moxifloxacin, prolongation, HIV, and prothionamide, TB infection ethambutol, cycloserine, pyrazinamide, darunavir-ritonavir, clofazamine, enoxaparin, valganciclovir, fluconazole

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. nasto n iko ada Arrhythmias Cardiac of Risk and Ondansetron Annals of mrec Medicine Emergency 25.e6