4.9 Overdose
No cases of overdose have been reported. In adults, single doses above 2 g, which is equivalent to 20 times the therapeutic dose, have been administered, and no harmful effects have been described.

5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antidiarrhoeals.

ATC code: A07XA04.

Racecadotril is a pro-drug that needs to be hydrolysed to its active metabolite thiorphan, which is an inhibitor of enkephalinase, a cell membrane peptidase enzyme located in various tissues, notably the epithelium of the small intestine.

This enzyme contributes both to the digestion of exogenous peptides and to the breakdown of endogenous peptides such as enkephalins.

Racecadotril protects enkephalins from enzymatic degradation thereby prolonging their action at enkephalinergic synapses in the small intestine and reducing hypersecretion.

Racecadotril is a pure intestinal antisecretory active substance. It decreases the intestinal hypersecretion of water and electrolytes induced by the cholera toxin or inflammation, and does not have effects on basal secretory activity. Racecadotril exerts rapid antidiarrhoeal action, without modifying the duration of intestinal transit.

In two clinical studies in children, racecadotril reduced by 40% and 46%, respectively, the stool weights in the first 48 hours. A significant reduction in the duration of the diarrhoea and the need for rehydration was also observed.

An individual patient data meta-analysis (9 randomised clinical trials racecadotril versus placebo, in addition to oral rehydration solution) collected individual patient data from 1384 boys and girls suffering from acute diarrhoea of miscellaneous severity and treated as in- or out-patients The median age was 12 months (interquartile range: 6 to 39 months). A total of 714 patients were < 1 year and 670 patients were ≥ 1 year old. Mean weight ranged from 7.4 kg to 12.2 kg across studies. The overall median diarrhoea duration after inclusion was 2.81days for placebo and 1.75 days for racecadotril. The proportion of recovered patients was higher in racecadotril groups compared with placebo [Hazard Ratio (HR): 2.04; 95%CI: 1.85 to 2.32; p < 0.001; Cox Proportional Hazards Regression]. Results were very similar for infants (<1 year) (HR: 2.01; 95%CI: 1.71 to 2.36; p < 0.001) and toddlers (>1 year) (HR: 2.16; 95%CI: 1.83 to 2.57; p < 0.001). For inpatient studies (n=637 patients), the ratio of mean stool output racecadotril/placebo was 0.59 (95%CI: 0.51 to 0.74); p < 0.001). For outpatient studies (n = 695 patients), the ratio of the mean number of diarrhoeic stools racecadotril/placebo was 0.63(95%CI: 0.47 to 0.85; p < 0.001).

Racecadotril does not produce abdominal distension. During its clinical development, racecadotril produced secondary constipation at a rate comparable to placebo. When administered via the oral route, its activity is exclusively peripheral, with no effects on the central nervous system.

A randomized crossover study demonstrated that racecadotril 100mg capsule at therapeutic dose (1 capsule) or at supratherapeutic dose (4 capsules) did not induce QT/QTc prolongation in 56 healthy volunteers (at the opposite of moxifloxacin, used as a positive control).

5.2 Pharmacokinetic properties
Absorption: following oral administration, racecadotril is rapidly absorbed.

The exposure at steady stat