Evidence review

This evidence review is based on a meta-analysis (Lehert et al. 2011) that assessed the efficacy of racecadotril as an adjunct to oral rehydration salt (ORS) solution, compared with ORS solution alone or with placebo in children with acute gastroenteritis (see table 2). The meta-analysis summarised the safety data by reporting the percentage of children experiencing an adverse event but the authors state that racecadotril safety was not an objective of the meta-analysis. Additional safety data have been obtained from the Hidrasec summaries of product characteristics for infants and children.

Racecadotril for childhood gastroenteritis: an individual patient data meta-analysis ( Lehert et al. 2011 )

  • Design: an individual patient data meta-analysis of 9 randomised controlled trials, 4 in inpatients and 5 in outpatients. Trials were conducted in France, Guatemala, India, Mexico, Peru and Spain.

  • Population: 1384 children aged from 1 to 71 months (median 12 months) with acute gastroenteritis and at least 3 watery stools in the previous 24 hours (mean number of diarrhoeic stools 8; mean duration of diarrhoea 41 hours).

  • Intervention and comparison: racecadotril in combination with ORS solution (1.5 mg/kg 3 times per day in 8 studies, dose imprecise in 1 study) compared with ORS solution alone or with placebo for up to 7 days.

  • Outcomes: using individual patient raw data from the studies, duration of diarrhoea and number of diarrhoeic stools were calculated for the period between first drug intake and the last unformed stool before recovery. Recovery was defined as the occurrence of 2 consecutive formed stools or no stool for 12 hours. Duration of diarrhoea was the primary end point. Stool output for the first 24 hours was considered for inpatient studies. Total number of diarrhoeic stools until recovery was considered for outpatient studies.

Table 2 Summary of the meta-analysis: Lehert et al. (2011)

Racecadotril plus ORS

ORS alone or with placebo

Analysis a

Randomised

n=692

n=692

Efficacy

n=692

n=692

Primary outcome: median duration of diarrhoea

1.75 days

2.81 days

HR 2.04 (95% CI 1.85 to 2.32)

p<0.001

Selected secondary outcomes:

n=692

n=692

Responders (% with diarrhoea for less than 48 hours) after adjusting for baseline dehydration and rotavirus

50.3%

25.8%

RR 1.98 (95% CI 1.71 to 2.28) p value not stated

NNT: 4

Stool output in first 24 hours (inpatient studies only n=637)

(ratio of mean stool output racecadotril/placebo)

GMR 0.59 (95% CI 0.51 to 0.74) p<0.001

Number of diarrhoeic stools until recovery (outpatient studies only n=695)

(ratio of the mean number of diarrhoeic stools racecadotril/placebo)

RR 0.63 (95% CI 0.51 to 0.74) p<0.001

Safety b

n=698

n=695

Children experiencing adverse events

11.6% (81/698)

10.1% (70/695)

No significant difference (p value not stated)

Abbreviations: CI, confidence interval; GMR, geometric mean ratio; HR, hazard ratio; NNT, number needed to treat; ORS, oral rehydration salt; RR, relative risk.

a Analysis was carried out on the intention to treat population of all children randomised. In 2 studies, some children were lost to follow-up: these were included assuming that therapy had been ineffective.

b It is unclear why the number of children in the safety population is higher than the number of children randomised.

Clinical effectiveness

The meta-analysis found that, when taken with ORS solution, racecadotril significantly reduced the duration of diarrhoea compared with ORS solution alone or with placebo. Median duration of diarrhoea was 1.75 days in the racecadotril group and 2.81 days in the comparator group: twice as many children recovered at any time with racecadotril (hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.85 to 2.32). Overall, 50% of children taking racecadotril and ORS solution recovered within 48 hours, compared with 26% of children taking ORS solution alone or with placebo (relative risk [RR] 1.98, 95% CI 1.71 to 2.28). Four children would need to be treated with racecadotril rather than placebo for 1 extra child to recover in 2 days.

In the 4 inpatient studies, a statistically significant 41% relative reduction in stool output was seen in the racecadotril group compared with the comparator group. Similarly, in the 5 outpatient studies, racecadotril statistically significantly reduced the number of stools recorded by 37% in relative terms.

The efficacy of racecadotril for the primary outcome was found to be independent of the level of dehydration, the presence or absence of rotavirus, the age of the children, the setting (inpatient or outpatient) and the country or cultural context.

Safety

The number of adverse events did not differ significantly between the groups. 11.6% of children in the racecadotril group had an adverse event compared with 10.1% in the comparator group (p value not stated).

More than 27 million children have been treated with racecadotril in Europe and overall exposure is 32 million children worldwide (Abbott Healthcare Products Limited: personal communication January 2013). According to the summaries of product characteristics for infants and children, tonsillitis, rash and erythema have been reported more often with racecadotril than with placebo. However, these adverse effects are uncommon (frequency between 1 in 1000 and 1 in 100). The summaries of product characteristics for infants and children state that in studies during its clinical development racecadotril caused secondary constipation at a rate comparable to placebo.

Evidence strengths and limitations

The results of the meta-analysis showed that racecadotril plus ORS solution statistically significantly improves recovery rate and reduces the duration of diarrhoea and the volume and frequency of stool output compared with ORS solution alone or with placebo. However, it is unclear whether racecadotril reduces the rate of inpatient or outpatient visits, or the need for intravenous rehydration even though 3 unblinded studies (n=164, 170 and 179) included in the meta-analysis considered these outcomes.

The 9 studies included in the meta-analysis have various limitations, which affect its validity. For example, allocation concealment was judged adequate by the meta-analysis authors in only 3 studies, and only 5 studies were blinded. Follow-up was incomplete in 2 studies, but children lost to follow-up were included in the meta-analysis as therapy failure. There were heterogeneities in terms of inclusion criteria, treatment setting and study end points, although individual patient data were used to address heterogeneity for the end points studied in the meta-analysis.

The studies included in the meta-analysis were carried out in a range of developed and developing countries where the aetiology and severity of diarrhoea may differ, which may raise the applicability to UK practice. However, the meta-analysis found that the results for the primary outcome were independent of whether the studies were conducted in Europe or elsewhere.

The meta-analysis included hospital inpatient and outpatient studies of children with a range of baseline severities of acute diarrhoea. Some children received hospital treatment with intravenous fluids before racecadotril and/or ORS solution (Cojocaru et al. 2002 and Cézard et al. 2001).

Few studies have been carried out in older children. The median age of children in this meta-analysis was 12 months and the maximum age was 6 years.

A French study (Turck et al. 1999) compared the efficacy and safety of racecadotril and loperamide in 102 children aged 2 to 10 years (mean age 4.7 years) with acute diarrhoea (note, the BNF for children does not recommend loperamide in children aged under 12 years). The study concluded that racecadotril and loperamide were similarly effective in treating diarrhoea. There was no significant difference between the drugs in terms of number of diarrhoeic stools passed before recovery (mean 2.7 with racecadotril compared with 2.1 with loperamide) or duration of diarrhoea (mean duration 10.7 hours with racecadotril compared with 8.8 hours with loperamide). Adverse events were seen in 6 children (11.5%) taking racecadotril and 11 children (22%) taking loperamide. Statistically significantly more children taking loperamide had constipation (58% compared with 36.5%, p=0.03).