Racecadotril is an antisecretory drug that widely used in treating acute diarrhea in children as an adjunct to oral rehydration therapy. Acute diarrhea is one of the morbidity and mortality causes in children aged <5 years in developing countries.

Acute Diarrhea in Children
Acute Diarrhea in Children
Source: https://iycf.spring-nutrition.org/content/sick-baby-health-care-toddler-diarrhea-00-non-country-specific


Although most acute diarrhea cases in children are self-limiting, death can occur as a complication of dehydration. Dehydration can be prevented and treated by giving oral rehydration. However, providing oral rehydration sometimes has problems such as parental compliance and the presence of complications for nausea and vomiting.

It has been two decades that Racecadotril is used as an antidiarrheal drug. Racecadotril has potential as a symptomatic therapy for acute diarrhea in children, but the available scientific evidence shows different results regarding its efficacy.

Several studies have shown that racecadotril has good efficacy in reducing the risk of failure to rehydration and stool output during diarrhea. Also, It has effectiveness in accelerating healing time. But some studies show no significant difference with placebo.

Pharmacologically, racecadotril is included in the class of antisecretory drugs. Racecadotril is a prodrug which will be converted into the active form of thiorphan after hydrolyzed in blood plasma. Thiorphan interacts with the opioid neurotransmitter system in the digestive tract walls, acting as a selective enkephalinase inhibitor.

Enkephalinase is an enzyme that causes the degradation of enkephalin. Enkephalin is an endogenous opioid peptide secreted by the myenteric and submucosal nerves of the gastrointestinal tract. When the enkephalinase function is inhibited, the degradation of enkephalin will be reduced. Enkephalin prevents the secretion of water and electrolytes into the intestinal lumen, reducing fluid discharge during diarrhea and reducing the risk of dehydration.

Racecadotril is absorbed in the small intestine and excreted by the kidneys. In contrast to other antidiarrheal drugs, racecadotril has advantages:

  1. does not affect intestinal motility,
  2. does not slow down the digestive tract's transit time,
  3. and does not increase the risk of bacterial growth in the small intestine.

Racecadotril
Racecadotril 


Efficacy of Racecadotril for Acute Diarrhea in Children

The criteria for the effectiveness of antidiarrheal drugs for children, determined by the WHO, are the reduced duration of diarrhea and the volume of stool excreted with minimal side effects. In various clinical studies report that racecadotril added to oral rehydration therapy effective in reducing dehydration risk and the failure of rehydration by decreasing the stool volume excreted during diarrhea and accelerating the healing of diarrhea.

In 2018, A meta-analysis published summarized data from 58 clinical trials in 9 different countries. The analysis showed that racecadotril had more benefits than existing diarrhea therapies, both for outpatients and inpatients. Racecadotril accelerated the healing duration from 106.2 hours to 78.2 hours (mean reduction 28 hours; ρ <0.0001 in 24 clinical studies using this parameter). After 48 hours, stool output was significantly reduced by 53% in the racecadotril group compared to the placebo group.

A study by Pienaar et al. concluded similar results that racecadotril has good efficacy as an antidiarrheal drug for pediatric patients. Also, it can be used as an adjunct therapy apart from giving oral rehydration. Racecadotril decreased the duration of diarrhea with a mean difference of -53.48 hours compared to placebo or without any intervention. The total number of stools excreted in the racecadotril group was also significantly lower than in the placebo group, with a mean difference of -150 g / kg.

In contrast to the above two studies, a randomized controlled clinical trial in Kenya concluded that racecadotril did not significantly reduce the duration and severity of acute pediatric diarrhea symptoms compared to placebo. Racecadotril and placebo were added to the standard therapy for acute pediatric diarrhea in oral rehydration therapy and zinc administration. They also found that The length of hospitalization was not significantly different between the two study groups.

Health Costs

From a cost perspective, available scientific evidence suggests that adding racecadotril to the treatment of acute pediatric diarrhea can save treatment costs compared to oral rehydration alone (cost-effective). Racecadotril was also reported to reduce the need for intravenous rehydration therapy compared to the placebo group. The addition of racecadotril reduced treatment costs associated with acute diarrhea by up to 380 pounds compared to just giving oral rehydration. Treatment costs were reduced because repeated consultations and secondary care were lower in the racecadotril group.


Side Effects and Tolerance of Using Racecadotril for Acute Diarrhea in Children

The most common side effects of racecadotril were urticaria and vomiting. In Santos et al. 's study, there was one patient from the oral rehydration group + racecadotril who experienced an increase in serum transaminase, which required hospitalization. Other side effects of racecadotril include abdominal distension, abdominal pain, and constipation. However, these side effects were not significantly different from that of patients who received the placebo.

A meta-analysis that included data from 5 studies (total sample 949) showed no significant difference in racecadotril's side effects compared to placebo. In terms of safety for use, racecadotril is well tolerated by pediatric patients three months of age and over.

Avoid using racecadotril in patients with fructose intolerance, sucrase-isomaltase deficiency, and malabsorption syndrome. Why? Because the sachets contain sucrose content. Racecadotril should also not be given to patients with a history of allergy to racecadotril and children <1 month of age. There are not enough studies regarding the administration of racecadotril in patients with kidney or hepatic disorders.


Comparison with Other Antidiarrheal Drugs

Other antidiarrheal drugs such as adsorbents (attapulgite, kaolin, smectite), antimotility (loperamide), and Bismuth subsalicylate, have the potential to cause serious side effects in children, so their use is not recommended. The side effect of abdominal distension is a side effect that often occurs when using this group of drugs.

Providing loperamide is not recommended in children. Why? Because of its potential antimotility effects, which can cause constipation after acute diarrhea. On the other hand, racecadotril does not affect intestinal motility. Various studies have shown that the constipation incidence due to using loperamide is significantly higher than racecadotril. The other side effects incidence was also lower in the racecadotril group than in loperamide.

Use of Racecadotril in Various Countries

The use of racecadotril as a symptomatic therapy for diarrhea has been carried out in European countries since two decades ago. In the United Kingdom, racecadotril therapy has been approved as a symptomatic adjunct therapy for acute diarrhea in children (> 3 months) since 2012. The European Society of Paediatric Gastroenterology, Hepatology, and Nutrition also state that racecadotril can be used in treating acute diarrhea in children.

Apart from European countries, racecadotril has also been used in various South American and Asian countries. Usually, giving Racecadotril is if standard therapy for acute diarrhea (oral rehydration) does not provide significant clinical improvement.

Racecadotril for children is available in granule form for oral suspension in sachets of 10 mg and 30 mg dosages. Racecadotril in the granule dosage form can be mixed with food or dissolved in water and then given to children.

The dose of racecadotril for children is 1.5 mg/kg/dose and given three times a day. The administration is carried out at fixed intervals and does not follow diarrhea's frequency, like other antidiarrheal drugs. The treatment duration in various studies is five days or up to 2 times normal defecation in children. Maximum racecadotril treatment is given for seven days.

There are proposals to include racecadotril as part of the treatment of acute diarrhea in children because scientific evidence shows that the effectiveness in relieving diarrhea symptoms, reduces treatment costs, and has an excellent safety profile and tolerance in children> 3 months of age. However, to date, the WHO management guidelines do not recommend the administration of any antidiarrheal drugs for children <5 years of age.

In Malaysia, racecadotril has been recognized as a symptomatic adjunct therapy for acute diarrhea in children> 3 months of age. Complement primary oral rehydration therapy and other standard therapies for acute diarrhea if these standard therapies are not sufficient to improve the patient's clinical condition, or there is no specific therapy for the cause of diarrhea.

Conclusion
Various existing scientific evidence shows that racecadotril has a good efficacy and safety profile as an adjunct therapy for oral rehydration in pediatric diarrhea cases. However, the quality of this scientific evidence is low to moderate, and some studies do not show the efficacy of racecadotril in treating diarrhea in children. Therefore, further studies with a larger scale are still needed before recommend to use racecadotril routinely to manage diarrhea in children. Until now, the guidelines for managing children's diarrhea issued by WHO have not included racecadotril as a routine therapy for cases of childhood diarrhea.