Key points from the evidence

Summary

A Cochrane review of antiemetic treatment for children and young people with acute gastroenteritis found oral or intravenous ondansetron increased the proportion of children and young people who stopped vomiting compared with placebo. Oral ondansetron also reduced the proportion of children and young people needing intravenous fluid therapy and reduced the immediate hospital admission rate compared with placebo. Ondansetron was associated with increased episodes of diarrhoea.

Regulatory status: off‑label. This topic was prioritised because there was a high volume of requests from the NHS. In 2009, the guideline development group for the NICE clinical guideline on diarrhoea and vomiting caused by gastroenteritis: diagnosis, assessment and management in children younger than 5 years concluded that administration of antiemetics could not currently be recommended. However, further research on the use of ondansetron was needed, focusing particularly on the possible risk of worsened diarrhoea. This evidence summary reviews the evidence that is now available to support decision‑making in this area, but this summary is not NICE guidance.

Effectiveness

A Cochrane review of antiemetic treatment for children and young people with acute gastroenteritis found:

  • oral ondansetron increased the proportion of children and young people who stopped vomiting compared with placebo (relative risk [RR] 1.44, 95% CI 1.29 to 1.61, p<0.00001, number needed to treat [NNT] 4; 4 RCTs [n=574])

  • oral ondansetron reduced the proportion of children and young people needing intravenous fluid therapy compared with placebo (RR 0.41, 95% CI 0.29 to 0.59, p<0.00001, NNT 5; 3 RCTs [n=465])

  • oral ondansetron reduced the immediate hospital admission rate compared with placebo (RR 0.40, 95% CI 0.19 to 0.83, p=0.01; 3 RCTs [n=465])

  • intravenous ondansetron increased the proportion of children and young people who stopped vomiting compared with placebo (RR 2.01, 95% CI 1.49 to 2.71, p<0.00001, NNT 3; 3 RCTs [n=186]).

Safety

  • Ondansetron prolongs the QT interval in a dose‑dependent manner. It should be avoided in people with congenital long QT syndrome and used with caution in people who have or may develop prolongation of QTc, such as those with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or people taking other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration (July 2013 Drug Safety Update and ondansetron summaries of product characteristics).

Patient factors

  • A Cochrane review found oral and intravenous ondansetron increased the number of episodes of diarrhoea compared with placebo (p<0.05).

  • For children and young people who are unable to swallow tablets, oral ondansetron can be given as an orodispersible tablet which is placed on top of the tongue or as an oral solution.

Resource implications

  • Ondansetron tablets are £1.71 for 10×4 mg tablets, and £44.05 for 10×8 mg tablets (excluding VAT; Drug Tariff, September 2014).

  • Ondansetron orodispersible tablets are £35.97 to £37.76 for 10×4 mg tablets and £71.94 to £75.53 for 10×8 mg tablets (excluding VAT; Drug Tariff, September 2014).

  • Ondansetron 4 mg/5 ml oral solution is £36.82 for 50 ml (excluding VAT; Drug Tariff, September 2014).

  • Ondansetron (Zofran) 2 mg/ml injection is £29.97 for 5×2 ml (4 mg) ampoules and £59.95 for 5×4 ml (8 mg) ampoules (excluding VAT; MIMS September 2014).

Introduction and current guidance

NICE published a clinical guideline on diarrhoea and vomiting caused by gastroenteritis: diagnosis, assessment and management in children younger than 5 years in 2009. The management of gastroenteritis in children is multifaceted, and this guideline covers diagnosis, assessment of dehydration and shock, fluid management, nutritional management and the role of antibiotics and other therapies.

The evidence for the use of antiemetics was reviewed in the full NICE guideline. After reviewing this evidence, the guideline development group concluded that oral ondansetron could increase the success rate with oral rehydration therapy (thereby reducing the need to treat with intravenous fluid therapy), but there was a concern that it might worsen diarrhoea. There was no evidence to support other agents, including metoclopramide and dexamethasone. The guideline development group concluded that administration of antiemetics could not currently be recommended, but further research on the use of ondansetron was needed.

Full text of Introduction and current guidance.

Product overview

Ondansetron is a potent, highly selective 5HT3 receptor antagonist. It is licensed for use in children and young people for the management of chemotherapy‑induced nausea and vomiting and for the prevention and treatment of post‑operative nausea and vomiting (see individual summaries of product characteristics for details).

Ondansetron is not licensed for the management of vomiting in children and young people with gastroenteritis, therefore using it for this indication is off‑label.

Full text of Product overview.

Evidence review

This evidence summary is based on the evidence review of antiemetics for the full NICE guideline on diarrhoea and vomiting caused by gastroenteritis in children younger than 5 years published in 2009, an updated Cochrane review of antiemetics for acute gastritis in children and young people (Carter and Fedorowicz 2012) and a retrospective cohort study of ondansetron use in the emergency departments of children's hospitals in the USA (Freedman et al. 2014).

  • The updated Cochrane review (Carter and Fedorowicz 2012) included 10 randomised controlled trials (RCTs; n=1479) in children and young people aged 3 months to 13 years. Four of the included RCTs investigated oral ondansetron, 4 RCTs investigated intravenous ondansetron, 1 RCT investigated a dimenhydrinate suppository and 1 investigated oral granisetron.

  • Dosing regimens varied between the 8 RCTs which investigated ondansetron but most used a weight‑dependent dosage. In most studies a single oral or intravenous dose of ondansetron was given. Oral ondansetron (2 mg to 8 mg depending on weight or age) was given as an orodispersible tablet or a solution, and intravenous ondansetron was mainly given at a dose of 0.15 mg/kg (0.3 mg/kg in 1 study).

  • Pooled data from 4 RCTs (n=574) found oral ondansetron was more effective than placebo at stopping vomiting based on the proportion of children and young people who stopped vomiting (relative risk [RR] 1.44, 95% confidence interval [CI] 1.29 to 1.61, p<0.00001, number needed to treat [NNT] 4 [95% CI 4 to 6]).

  • Pooled data from 3 RCTs (n=465) found the proportion of children and young people needing intravenous fluid therapy was lower with oral ondansetron compared with placebo during the emergency department stay (RR 0.41, 95% CI 0.29 to 0.59, p<0.00001, NNT 5 [95% CI 4 to 8]) and up to 72 hours after discharge.

  • Pooled data from 3 RCTs (n=465) found oral ondansetron reduced the immediate hospital admission rate during the emergency department stay (RR 0.40, 95% CI 0.19 to 0.83, p=0.01) but not hospitalisation up to 72 hours after discharge, compared with placebo.

  • Pooled data from 3 RCTs (n=186) found intravenous ondansetron was more effective than placebo at stopping vomiting based on the proportion of children and young people who stopped vomiting (RR 2.01, 95% CI 1.49 to 2.71, p<0.00001, NNT 3 [95% CI 3 to 5]).

  • In 3 of the 4 RCTs that compared oral ondansetron with placebo there was an increase in the number of episodes of diarrhoea (p<0.05). In 1 of the 3 RCTs that compared intravenous ondansetron with placebo, more episodes of diarrhoea were reported in the ondansetron group in the first 24 hours compared with placebo (p=0.013).

  • The updated Cochrane review (Carter and Fedorowicz 2012) was well‑conducted, but it is limited by the quality of the trials it included. The authors suggest that study design in the included studies was adequate overall but there was an unclear or high risk of bias in some of the domains, which reflects the challenges faced in screening and following up children and young people presenting to emergency departments.

  • The 8 RCTs included in the updated Cochrane review that investigated ondansetron were conducted mostly in the emergency departments of children's hospitals in the USA, Canada, Turkey, Venezuela, Qatar and Thailand. The findings of these may not be generalisable to UK practice.

  • The retrospective cohort study of ondansetron use in emergency departments of children's hospitals in the USA (Freedman et al. 2014) found oral ondansetron use increased from a median institutional rate of 0.11% of patient visits in 2002 to 42.2% in 2011. However, this increased use of oral ondansetron was not associated with reductions in the rates of intravenous rehydration (18.7% of children or young people during the low ondansetron use period and 17.8% during the high ondansetron use period) or hospitalisation (6.0% during the low ondansetron use period and 6.7% during the high ondansetron use period).

  • This study is limited by its observational nature, and also reflects US not UK practice. However, it provides useful data to determine the clinical effectiveness of ondansetron in 'real‑world' conditions.

  • Ondansetron prolongs the QT interval in a dose‑dependent manner and cases of Torsade de Pointes have been reported in people using ondansetron. Ondansetron should be avoided in people with congenital long QT syndrome and should be used with caution in people who have or may develop prolongation of QTc, such as people with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or people taking other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration (see ondansetron summaries of product characteristics for details). Dose‑dependent QT interval prolongation with ondansetron is discussed in more detail in the July 2013 Drug Safety Update from the MHRA.

Full text of Evidence review.

Context and estimated impact for the NHS

For the full NICE guideline on diarrhoea and vomiting caused by gastroenteritis in children younger than 5 years published in 2009, a simple economic model was developed. This showed potential economic advantages of oral ondansetron if given to children with persistent vomiting in whom intravenous fluids are being considered. However, there was clinical uncertainty about possible effects of ondansetron on diarrhoea, and whether or not increased diarrhoea would lead to increased use of NHS resources. Therefore no firm conclusions regarding the cost‑effectiveness of ondansetron could be made.

  • Ondansetron tablets are £1.71 for 10×4 mg tablets and £44.05 for 10×8 mg tablets (excluding VAT; Drug Tariff, September 2014).

  • Ondansetron orodispersible tablets are £35.97 to £37.76 for 10×4 mg tablets and £71.94 to £75.53 for 10×8 mg tablets (excluding VAT; costs taken from the Drug Tariff, September 2014).

  • Ondansetron 4 mg/5 ml oral solution is £36.82 for 50 ml (excluding VAT; costs taken from the Drug Tariff, September 2014).

  • Ondansetron (Zofran) 2 mg/ml injection is £29.97 for 5×2 ml (4 mg) ampoules and £59.95 for 5×4 ml (8 mg) ampoules (excluding VAT; costs taken from MIMS September 2014).

Full text of Context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for parents, carers or children with gastroenteritis who are being offered ondansetron to manage nausea and vomiting.

About this evidence summary

'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.