Effect of Intravenous Ondansetron on QT Interval Prolongation

By: Raymond Wu, Pharm.D. Candidate c/o 2013

 

The 5-hydroxytryptamine type 3 (5HT3) antagonists (e.g. ondansetron [Zofran^®]) are commonly used in the prevention and treatment of nausea and vomiting in the inpatient setting.¹  Overall, ondansetron is a well-tolerated medication with few side effects.¹  Constipation, dizziness, and headache are the most commonly reported side effects associated with its use.¹  However, on September 15, 2011, the FDA issued a Medwatch Safety Alert for ondansetron in patients with congenital long QT syndrome, a cardiac arrhythmia.²  The FDA further required GlaxoSmithKline to conduct a thorough study to determine the degree to which ondansetron causes QT interval prolongation.²

Similarly, in 2001, droperidol received a black box warning against prolonging the QT interval and inducing arrhythmias.³  In response to this warning, providers in the United States began prescribing 5HT3 antagonists more widely, particularly due to the perceived safety profile of these agents.³  It now seems that ondansetron shares the same mechanism for QTc interval prolongation.⁴  Ondansetron is involved in the blockade of the human Ether-à-go-go-Related Gene (hERG) potassium channel in the myocardium, leading to a disruption of the rapid delayed rectifier potassium current (Ikr).⁴  This characteristic is shared by several other medications that are more notorious for their QT prolonging effects, including class III antiarrhythmics, cisapride, and droperidol.^4,5

Hafermann et. al. performed a prospective, observational study in 2001 observing the risk of QT prolongation with ondansetron.³  Their inclusion criteria for the study were:³

• numerous risk factors for drug-induced QT interval prolongation potentially leading to torsades de pointes
  • hypomagnesemia (<1.0 mEq/L)
  • hypokalemia  (<3.2 mEq/L)
  • congenital long QT syndrome
  • baseline QTc >500 msec
  • female gender
  • heart failure (ejection fraction <40%)
  • acute coronary syndromes
  • old myocardial infarction
  • bradycardia (<50 beats per minute)
  • use of drugs that either:
    • prolong the QT interval
    • disrupt the metabolism or distribution of QT-prolonging drugs

The study’s investigators defined QTc prolongation as 450 msec for men and 470 msec for women.³

Patients in the study received a primary cardiovascular diagnosis and had a baseline 12-lead electrocardiogram (ECG) on admission conducted in the ward or emergency department.³  About 120 minutes after the first dose of slow-push intravenous ondansetron, patients underwent a second ECG.³

The mean interval between obtaining the two ECGs was 3.5 ± 2.14 hours.³  In the total population, the QTc interval was prolonged by 19.3 ± 18 msec (P < 0.0001) within 120 minutes of ondansetron administration.³  For patients with an acute coronary syndrome and those with heart failure, QTc was prolonged by 18.3 ± 20 msec (P < 0.0001) and 20.6 ± 20 msec (P < 0.0012), respectively.³  Following ondansetron exposure, 31% and 46% in the heart failure and acute coronary syndromes groups, respectively, met the gender-related thresholds for a prolonged QTc.^3,5

This study found that QTc prolongation due to ondansetron administration was similar to that found in previous studies.³  When used in patients with cardiovascular disease, such as heart failure or acute coronary syndromes, with one or more risk factors for torsades de pointes, ondansetron may significantly increase the QTc interval for up to 120 minutes after administration.³

Hence, from a patient safety perspective, patients who are at high risk for torsades de pointes and receiving ondansetron ought to receive continuous ECG monitoring when receiving ondansetron in the inpatient setting.³

SOURCES:

1. Lexi-Comp Online^TM, Lexi-Drugs Online^TM, Hudson, Ohio: Lexi-Comp, Inc.; March 13, 2012.
2. U.S. Food and Drug Administration.  Zofran (ondansetron): Drug Safety Communication – Risk of Abnormal Heart Rhythms. Website. Available online: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm272041.htm. Sep 15, 2011.  Accessed Mar 13, 2012
3. Hafermann MJ, Namdar R, Seibold GE, Page RL 2nd. Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study. Drug Healthc Patient Saf. 2011;3:53-8.
4. Kuryshev YA, Brown AM, Wang L, Benedict CR, Rampe D. Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels. J Pharmacol Exp Ther. 2000 Nov;295(2):614-20.
5. Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J. 2007 Jun;153(6):891-9.