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Pharmacotherapeutic group: Other antidiarrhoeals. ATC code: A07XA04.
Pharmacology: Pharmacodynamics: Racecadotril is a prodrug 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 hydrolysis of exogenous peptides and to the breakdown of endogenous peptides such as enkephalins. Consequently, Racecadotril protects endogenous enkephalins that are physiologically active at digestive tract level, prolonging their antisecretory effect.
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.
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.
Granules for oral suspension: 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 2.81 days 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).
Pharmacokinetics: Absorption: Following oral administration, racecadotril is rapidly absorbed. The initial time to plasma enkephaline inhibition is 30 minutes.
The bioavailability of racecadotril is not modified by food, but peak activity is delayed by about one hour and a half.
Distribution: In plasma, after oral administration of 14C-labeled racecadotril, measured exposure of radiocarbon was many orders of magnitude higher than in blood cells and 3-fold higher in plasma than whole blood. Thus, the drug did not bind to blood cells to any significant extent. Radiocarbon distribution in other body tissues was moderate, as indicated by the mean apparent volume of distribution in plasma of 66.4 kg. Ninety percent of the active metabolite of racecadotril (thiorphan=(RS)-N-(1-oxo-2- (mercaptomethyl)-3- phenylpropyl) glycine), is bound to plasma proteins, mainly to albumin.
The pharmacokinetic properties of racecadotril are not modified as a result of repeat dosing administration to elderly persons.
The duration and extent of the effect of racecadotril are dose dependent.
The duration of plasma enkephalinase inhibition is approximately 8 hours.
Granules for oral suspension: In children time to peak plasma enkephalinase inhibition is approximately 2 hours and corresponds to an inhibition of 90% with the dose of 1.5 mg/kg.
Capsules: In adults, time to peak plasma enkephalinase inhibition is approximately 2 hours and corresponds to 75% inhibition with the dose of 100 mg.
Metabolism: The half-life of racecadotril, measured as plasma enkephalinase inhibition, is approximately 3 hours.
Racecadotril is rapidly hydrolysed to thiorphan, the active metabolite, which is in turn transformed into inactive metabolites.
Repeated administration of racecadotril does not cause any accumulation in the body.
In vitro data indicate that racecadotril/thiorphan and the four major inactive metabolites do not inhibit the major CYP enzymes isoforms 3A4, 2D6, 2C9, 1A2 and 2C19 to an extent that would be clinically relevant.
In vitro data indicate that racecadotril/thiorphan and the four major inactive metabolites do not induce the CYP enzymes isoforms (3A family, 2A6, 2B6, 2C9/2C19, 1A family, 2E1) and UGTs conjugating enzymes to an extent that would be clinically relevant.
Racecadotril does not modify protein binding of active substances strongly bound to proteins, such as tolbutamide, warfarin, niflumic acid, digoxin or phenytoin.
In patients with liver failure [cirrhosis, grade B of the Child-Pugh classification], the kinetic profile of the active metabolite of racecadotril showed similar Tmax and T½ and lesser Cmax (-65%) and AUC (-29%) as compared to healthy subjects.
In patients with severe renal failure (creatinine clearance 11-39 ml/min), the kinetic profile of the active metabolite of racecadotril showed smaller Cmax (-49%) and greater AUC (+16%) and T½ as compared to healthy volunteers (creatinine clearance >70 ml/min).
In the paediatric population, pharmacokinetic results are similar to those of the adult population, reaching Cmax at 2 hours 30 min after administration. There is no accumulation after multiple dose administrated every 8 hours, for 7 days.
Excretion: Racecadotril is eliminated as active and inactive metabolites. Elimination is mainly via the renal route, and to a much lesser extent via the faecal route. The pulmonary route is not significant.
Toxicology: Preclinical safety data: Chronic exposure in monkeys at a dose of 500 mg/kg/day resulted in generalized infections and reduced antibody responses to vaccination but no infection/immune depression was observed at 120 mg/kg/day.
The clinical relevance of this finding is unknown.
Racecadotril was not immunotoxic in mice when given for up to 1 month.
Four-week toxicity studies in monkeys and dogs, relevant for the duration of treatment in human, do not point out any effect at doses up to 1250 mg/kg/day and 200 mg/kg, respectively.
Preclinical effects (e.g. severe, most likely aplastic anaemia, increased diuresis, ketonuria, diarrhoea) were observed only at exposures considered sufficiently in excess of the maximum human exposure.
The clinical relevance is unknown.
No mutagenic or clastogenic effect of racecadotril has been found in the standard in vitro and in vivo tests.
Reproductive and developmental toxicity studies have not revealed any special effects of racecadotril.
A toxicity study in juvenile rats has not revealed any significant effects of racecadotril up to a dose of 160 mg/kg/day which is 35 times higher than the usual paediatric regimen (i.e. 4.5 mg/kg/day).
In animals, racecadotril reinforced the effects of butylhyoscine upon bowel transit and on the anticonvulsive effects of phenytoin.
Granules for oral suspension: Despite the immature renal function in children below 1 year of age, higher exposure levels are not expected in these individuals.
