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Racecadotril: new acute diarrhoea treatment for adults and children

Steve Chaplin BPharm, MSc, Hossam Al-Hilou MRCP, Kamal Patel BSc, MRCP and Mark Wilkinson BSc, MD, FRCP

Racecadotril (Hidrasec) is a KEY POINTS new class of drug for the treatment of acute diar - n racecadotril (Hidrasec) reduces intestinal hypersecretion of water and electrolytes; it does not affect transit time rhoea. In our New products n it is licensed for the symptomatic treatment of acute diar - review, Steve Chaplin pres - rhoea in adults when causal treatment is not possible, or as a complementary treat - ents the clinical data relating ment; in infants >3 months and children it is licensed as a complementary treatment to oral rehydration to its efficacy and adverse n available as capsules (adults) and granules in sachets (children) taken 3 times daily; events, and Drs Al-Hilou, granules can be added to food or dispersed in water (see SPC for dosage) Patel and Wilkinson discuss n 20 doses (all formulations) cost £8.42 its place in therapy. n in combination with oral rehydration solution in infants and toddlers, racecadotril reduces the duration of diarrhoea by about 1 day and doubles the rate of recovery at 48 hours, regardless of the severity of dehydration or rotavirus infection he management of acute uncompli - n in adults, it is as effective as loperamide but causes less constipation cated diarrhoea in adults involves T n for children and infants >3 months of age racecadotril could be used as first-line maintenance of fluid intake and, if treatment; it may be of use in adult patients where there is a known intolerance to required, the reduction of stool frequency loperamide using an antimotility agent. 1 Loperamide is the agent of choice 1 and can be supplied without a prescription for patients aged when causal treatment is not possible. In over 12. Co-phenotrope (also available infants over three months old and in chil - without a prescription for patients aged dren, it is licensed as a complementary over 16) and codeine phosphate are other symptomatic treatment together with oral options. Probiotics may also be effective. 2 rehydration and the usual support meas - In children under five with acute diar - ures when these measures alone are rhoea due to gastroenteritis, NICE recom - insufficient to control the clinical condi - mends treatment of dehydration and fluid tion, and when causal treatment is not management but does not recommend possible. In both age groups, racecadotril antidiarrhoeal drugs. 3 can be given as a complementary treat - ment if causal treatment is possible. The technology In adults, the recommended dose is Racecadotril (Hidrasec – Abbott) has initially 100mg, then 100mg three times been available on the continent for sev - daily, preferably before the main meals. eral years. It is a prodrug that undergoes Treatment should continue until two nor - hydrolysis to thiorphan, which inhibits mal stools are recorded but should not enkephalinase and prolongs the actions exceed seven days. Dosage adjustment of enkephalins. In the small intestine, this is not necessary for elderly patients but reduces hypersecretion of water and elec - caution is required in patients with trolytes induced by cholera toxin or hepatic or renal impairment because inflammation. Racecadotril does not there is little experience of its use in affect intestinal transit time. such cases. It is licensed for the symptomatic Racecadotril is formulated as treatment of acute diarrhoea in adults granules for suspension for infants and prescriber.co.uk Prescriber 19 September 2013 z 37 n NEW PRODUCTS l Racecadotril

in elderly nursing home residents (mean Racecadotril ORS alone or Analysis (intent-to- age 82–83), found that diarrhoea was less plus ORS with placebo treat population) frequent with racecadotril during four days of treatment (mean number of episodes Primary outcome 3.9 vs 7.3), stool output was reduced by 25 per cent and normal stools were col - median duration of diarrhoea 1.75 days 2.81 days HR 2.04 (95% CI 1.85 – lected significantly sooner (36 vs 63 2.32) p<0.001 hours). 10 There was no consistent difference Selected secondary outcomes between racecadotril and loperamide in the incidence or duration of abdominal responders (% with diarrhoea 50.3% 25.8% RR 1.98 (95% CI 1.71 – symptoms, eg pain or distension. 6–10 for less than 48 hours) after 2.28) p value not stated adjusting for baseline NNT 4 Adverse effects dehydration and rotavirus Trials in children reported no difference in the frequency of adverse effects stool output in first 24 hours GMR 0.59 (95% CI 0.51 – between racecadotril and placebo. 4,5 In (inpatient studies only; ratio 0.74) p<0.001 adults, constipation was more frequent of mean stool output with loperamide (19–60 per cent) than racecadotril/placebo) racecadotril (8–16 per cent). 6–10 Racecadotril may be associated with number of diarrhoeic stools RR 0.63 (95% CI 0.51 – more itching (28 per cent vs none with until recovery (outpatient 0.74) p<0.001 loperamide) 9 and less nausea (10 vs 20 studies only; ratio of the mean per cent). 10 number of diarrhoeic stools racecadotril/placebo) References 1. Wingate D, et al. Aliment Pharmacol Ther Children experiencing adverse 11.6% 10.1% no significant difference 2001;15:773 –82. events (p value not stated) 2. Allen SJ, et al. Cochrane Database of Systematic Reviews 2010, Issue 11. Art. No.: HR = hazard ration; RR = relative risk; GMR = geometric mean ratio; NNT = number needed to treat CD003048. DOI: 10.1002/14651858. CD003048.pub3. Table 1. Summary of the 2011 meta-analysis that compared treatment with racecadotril plus ORS with 3. NICE. Diarrhoea and vomiting in children: ORS alone in children; after reference 4 Diarrhoea and vomiting caused by gastroen - teritis: diagnosis, assessment and manage - children. The dose is determined accord - vs 2.8 days with ORS) and almost dou - ment in children younger than 5 years. CG84. ing to bodyweight and taken three times bled the overall rate of recovery at 48 April 2009. daily: hours (50 vs 26 per cent with ORS solu - 4. Lehert P, et al. Dig Liver Dis 2011;43: • <9kg – one 10mg sachet tion). This gives a number needed to 707 –13. • 9–13kg – two 10mg sachets treat of four children treated with 5. NICE. Acute diarrhoea in children: • 13–27kg – one 30mg sachet racecadotril/ ORS rather than ORS racecadotril as an adjunct to oral rehydration . ESNM12. March 2013. • >27kg two 30mg sachets. alone for one additional child to recover 5 6. Roge J, et al. Scand J Gastroenterol It is contraindicated in children with in 48 hours. 1993;28:352 –4. hepatic or renal impairment. In outpatients, the number of diar - 7. Vetel JM, et al. Aliment Pharmacol Ther rhoea stools was reduced by 37 per cent 1999;13 Suppl 6:21 –6. Clinical trials and stool output was reduced in inpa - 8. Prado D. Scand J Gastroenterol 2002;37: Children tients by 41 per cent by racecadotril/ORS 656 –61. A meta-analysis of nine randomised trials compared with ORS alone. Results were 9. Wang HH, et al. World J Gastroenterol involving a total of 1384 children (median similar for infants (less than one year old) 2005;11:1540 –3. ages 11–32 months) compared treat - and toddlers. 10. Gallelli L, et al. Eur J Clin Pharmacol ment with racecadotril plus oral rehydra - 2010;66:137 –44. tion solution (ORS) with ORS alone (see Adults Table 1). 4 Outcomes were categorised by At least five trials comparing racecadotril Declaration of interests the degree of dehydration and the con - with loperamide have been published. 6–10 None to declare firmed presence of rotavirus. Four found no significant differences in Racecadotril/ORS reduced the stool frequency and/or the duration of Steve Chaplin is a pharmacist who duration of diarrhoea (median 1.7 days diarrhoea. 6–9 The fifth (n=61), carried out specialises in writing on therapeutics

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These enkephalins activate delta -opi - safety concerns. In most studies compar - Place in therapy oid receptors in the gastrointestinal tract ing racecadotril with loperamide the side- Acute diarrhoea can be debilitating and leading to reduced cyclic adenosine effect profile is better with racecadotril lead to significant dehydration. In its monophosphate (AMP) mucosal levels, (less abdominal distension, nausea and extremes electrolyte disturbances and resulting in a hyposecretion of water and reactive constipation reported). renal failure can also develop and compli - electrolytes in the intestinal lumen. 1 Race cadotril is not currently licensed cations can be potentially life threatening. for the symptomatic management of Most episodes of acute diarrhoea in the UK Suggested use chronic diarrhoea, and only a single study are mild and self-limiting. The cornerstone Unlike loperamide, which is not recom - to date in patients with retroviral disease of management is to exclude infectious mended for children under the age of four and associated diarrhoea has been per - and inflammatory aetiology and, where the years , racecadotril does have a licence formed. 2 underlying condition requires no specific for infants over the age of three months There is no definite evidence that treatment, to replace fluid losses and offer and for children . It should always be used racecadotril reduces the need for intra - treatments that alleviate loose stools. in conjunction with adequate fluid venous rehydration, leads to more rapid Racecadotril has recently been replacement. The maximum use should discharge from hospital or helps conserve licensed in the UK as a treatment for be limited to seven days in all age groups. healthcare resources. There is inadequate acute self-limiting diarrhoea. Thiorphan The evidence available suggests that evidence to support routine use of is the active metabolite of racecadotril adding racecadotril to ORS may reduce racecadotril among patients likely to be and acts as a peripheral enkephalinase stool output and duration of diarrhoea in encountered in UK primary care ; however, inhibitor, thus increasing the availability acute gastroenteritis. The safety profile it is an option that may be considered in of enkephalins. of the drug is good with no significant certain patients as a viable alternative to

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loperamide. Therefore, it could be provided also be used as first-line treatment. Data References to adult patients with suspected self-limit - from developing countries suggest cul - 1. Bergmann JF, et al. Aliment Pharmacy Ther ing diarrhoea to control symptoms where ture-negative diarrh oea and diarrhoea 1992;6:305 –13. there is a known intolerance to loperamide. proven to be secondary to rotavirus can 2. Baumer P, et al. Gastroenterology 199 5; Adults prone to traveller’s diarrhoea safely be treated with racecadotril with 10(4)Suppl: A778. and intolerant to loperamide could also significant symptomatic benefit. Declaration of interests be prescribed racecadotril as an alterna - It must be appreciated that the evi - None to declare. tive. A single study from Italy also sup - dence defining the role of racecadotril in ports its use in elderly patients , and the diarrhoea is somewhat inadequate and Dr Al-Hilou is gastroenterology SpR, Dr drug therefore remains an option for eld - most scenarios where benefits are likely to Patel is gastroenterology registrar and erly patients prone to abdominal pain and be significant are unlikely to be encountered Dr Wilkinson is consultant gastro- constipation secondary to loperamide. frequently in the UK primary care setting. No enterologist in the Department of For children between three months concerns regarding the safety profile of Gastroenterology, Guys and St Thomas’ and four years of age, racecadotril could racecadotril have been raised to date. NHS Foundation Trust

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