Safety updates on the risk of QT prolongation and cardiac arrhythmia, including Torsades de Pointes with intravenous ondansetron

HSA would like to update healthcare professionals on the new dose restriction for intravenous (IV) ondansetron. The new maximum single IV dose for the management of chemotherapy-induced nausea and vomiting (CINV) in adults is 16mg, infused over at least 15 minutes. This new restriction is in response to concerns raised by the results of a new study demonstrating a dose-dependent prolongation of the QT interval with IV ondansetron, which could predispose patients to develop Torsades de Pointes.

Background

Ondansetron is a 5-HT₃ receptor antagonist, indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy as well as for the prevention and treatment of post-operative nausea and vomiting in adults and children 2 years and older. Three ondansetron-containing injections (2mg/mL) are registered in Singapore, namely Zofran® (GlaxoSmithKline), Ondansetron Hexal (Novartis) and Setronax (Drug Houses of Australia) since 1990, 2007 and 2009, respectively.

In 2011, HSA strengthened the local package inserts (PIs) to alert healthcare professionals to the risk of QT interval prolongation and cardiac arrhythmia, including Torsade de Pointes which were observed from postmarketing surveillance.

Further information on the degree of QT interval prolongation associated with ondansetron was reported in a recently completed study conducted by GSK. This was a double-blind, randomised, placebo- and active- (moxifloxacin 400mg) controlled crossover study to evaluate the effect of ondansetron on the QT interval in 58 healthy adult men and women. Ondansetron doses included 8mg and 32mg infused intravenously over 15 minutes. The preliminary results demonstrated that at the highest tested dose of 32mg IV, the maximum mean difference in QT duration corrected for heart rate by the Fridericia's formula (QTcF) compared to placebo after baseline-correction was 19.6ms (upper limit of 90% CI: 21.5). This degree of prolongation showed that the dose of 32mg IV could be clinically significant in certain individuals at risk for ventricular proarrhythmia. After exposure to a lower tested dose of 8mg IV, the maximum mean difference in QTcF compared to placebo after baseline-correction was 5.8ms (upper limit of 90% CI: 7.8), which is generally considered to be associated with a lower risk of proarrhythmia. Based on exposure-response modelling, it was predicted that an IV dosing regimen of 16mg, given over 15 minutes would result in a QTcF prolongation of 9.1ms (upper 95% CI: 11.2), an extent that is not expected to be associated with an increased risk of cardiac arrhythmias. No clinically important changes were observed in the measured electrocardiographic PR intervals, QRS duration or the heart rate across all treatment groups.

Actions by other regulatory agencies

The UK Medicine and Healthcare products Regulatory Agency (MHRA) has also issued a new dose restriction for IV ondansetron, with a maximum single IV dose of 16mg for the management of CINV in adults.¹ The US Food and Drug Administration (FDA) has informed healthcare professionals and the public about the risk of QT interval prolongation with the use of a single IV dose of 32mg ondansetron and recommended that a single IV dose of ondansetron should not exceed 16mg.²

Local situation

To date HSA has not received any local adverse reaction report on QT prolongation with the use of ondansetron. HSA will continue to work with the companies to update the local PIs for Zofran®, Ondansetron Hexal® and Setronax® injections to reflect the new dosing and warning recommendations.

HSA's advisory

Healthcare professionals should be aware of the following dose restrictions and precautions to minimise the risk of QT prolongation and cardiac arrhythmia, including Torsade de Pointes with the use of IV ondansetron:

1. A single dose of IV ondansetron given for the management of CINV in adults must not exceed 16mg (infused over at least 15 minutes)

2. Ondansetron should be avoided in patients with congenital long QT syndrome

3. Caution must be used if administering ondansetron to patients with risk factors for QT interval prolongation or cardiac arrhythmias. These include:

4. Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration

There are no changes to the recommended dosing for the following indications or patient populations:

• IV dosing for the prevention and treatment of post-operative nausea and vomiting in adult patients

• IV dosing for any indication in the paediatric population

• dosing for CINV using oral ondansetron formulations in adults and paediatric patients

Healthcare professionals are also encouraged to report any adverse reactions suspected to be related to the use of ondansetron to the Vigilance Branch of HSA.

References

1. http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON178189

2. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm310219.htm