Each capsule contains 100 mg racecadotril.
Excipients with known effect: Each capsule contains 41 mg lactose monohydrate.
HIDRASEC Paedriatric, 10 mg: Each sachet of HIDRASEC Paediatric contains 10 mg of racecadotril.
Each sachet HIDRASEC Paediatric contains 0.966 g of sucrose.
HIDRASEC Paedriatric, 30 mg: Each sachet of HIDRASEC Paediatric contains 30 mg of racecadotril.
Each sachet HIDRASEC Paediatric contains 2.899 g of sucrose.
Excipients/Inactive Ingredients: Hidrasec: Powder: Lactose, Pregelatinised starch (maize), Magnesium stearate, Colloidal anhydrous silica.
Capsule: Yellow iron oxide (E172), Titanium dioxide (E171), Gelatin.
Hidrasec Paediatric: Sucrose, Anhydrous Colloidal Silica, Polyacrylate Dispersion (30%), Apricot Flavouring.
Pharmacotherapeutic Group: Other antidiarrhoeals. ATC Code: A07XA04.
Pharmacology: Pharmacodynamics: Hidrasec/Hidrasec Paediatric: Racecadotril is a prodrug that needs to be hydrolysed to its active metabolite thiorphan, which is an inhibitor of enkephalinase, a cell membrane peptidase 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 intestinal hypersecretion of water and electrolytes induced by cholera toxin or inflammation, and dose not have effect on basal secretory activity. Racecadotril exerts rapid antidiarrhoeal action, without modifying the duration of intestinal transit.
Hidrasec Paediatric: 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 2.81 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 diarrheic stools racecadotril/placebo was 0.63 (95%CI: 0.47 to 0.85; p < 0.001).
Hidrasec/Hidrasec Paediatric: 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.
Pharmacokinetics: Absorption: Following oral administration, racecadotril is rapidly absorbed. The initial time to plasma enkephalinase 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 and oral dose of 14C-labeled racecadotril, measured exposure of radiocarbon was many orders of magnitude higher than in blood cell and 3-fold higher than in 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 or administration to elderly persons.
The duration and extent of the effect of racecadotril are dose-dependent.
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.
In adults time to peak plasma enkephalinase inhibition is approximately 2 hours and corresponds to 75% inhibition with a dose of 100 mg.
The duration of plasma enkephalinase inhibition is about 8 hours.
Metabolism: The biological half-life of racecadotril, measured as plasma enkephalinase inhibition, is 3 hours approximately.
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 a lower 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 a lower 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 doses 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. Elimination via 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 patients, do not point out any effect at doses up to 1250 mg/kg/day and 200 mg/kg/day, 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.
Hidrasec: Symptomatic treatment of acute diarrhoea in adults.
Hidrasec Paediatric: Adjunct therapy to oral or parenteral rehydration in the treatment of acute diarrhea in children and infant ≥3 month.
For oral use.
One capsule initially, regardless of the time of day. Then, one capsule three times daily, preferably before main meals. Treatment should be continued until two normal stools are recorded. Treatment should not exceed 7 days. Long-term treatment with rececadotril is not recommended.
If no improvement is seen after 3 days of treatment a doctor should be consulted.
Children: There are specific formulations intended for infants, children and adolescents.
Older people: Dosage adjustment is not necessary in older people.
HIDRASEC PAEDIATRIC SHOULD NOT BE GIVEN IN CONJUNCTION WITH ORAL REHYDRATION THERAPY IN INFANTS AND CHILDREN (see Precautions).
The recommended dose is determined according to body weight: 1.5 mg/kg per dose (corresponding to 1 to 2 sachets), three times daily at regular intervals.
The total daily dose should not exceed approximately 6 mg/kg.
The table as follows defines the usual dosage according to the weight and age of the infant or child. Use the weight of the child to calculate the dose. If this is not possible, use the age of the child. (See table.)
Click on icon to see table/diagram/image
In conjunction with Oral Rehydration Salts solution, treatment should be initiated with the recommended number of sachets regardless of the time. Further treatment should be given approximately 8 hourly until the cessation of diarrhoea.
If symptoms persist for more than 7 days then the patient should seek further medical advice.
Treatment should be continued until two normal stools are recorded.
Long-term treatment with racecadotril is not recommended.
There are no monitored clinical trials in infants under fewer than 3 months of age.
There are no studies in infants or children with renal impairment or hepatic impairment (see Precautions).
Directions for use: With water: Open the HIDRASEC Paediatric sachet by cutting across the top as marked.
Add the HIDRASEC Paediatric granules to a small amount of clean water. Stir the water and granules vigorously and give to the child to drink before the granules have had time to settle in the bottom of the cup or glass. If any granules remain in the bottom of the cup or glass after administration, add a little more water, stir and give to the child to drink, repeating until all the granules have been swallowed by the child.
Directly in the child's mouth: HIDRASEC Paediatric can also be given by sprinkling the contents of the sachets on the child's tongue.
With food: HIDRASEC Paediatric can also be given mixed in a small amount of food on a spoon.
Whatever the method of administration, it is important to ensure that all of the required dosage is taken by the child.
Hidrasec: So far sporadic cases of overdose without adverse events 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.
Hidrasec Paediatric: So far sporadic cases of overdose without adverse events have been reported in infants and children; ingested doses were up to 7 times the correct dose.
Hypersensitivity to the active substance or to any of the excipients.
Patients who have reported angioedema with angiotensin converting enzyme inhibitors (such as captopril, enalapril, lisinopril, perindopril, ramipril) should not take racecadotril.
Hidrasec Peaediatric: Due to the presence of sucrose, HIDRASEC Paediatric is contraindicated in patients with rare hereditary problems of fructose intolerance, glucose/galactose malabsorption syndrome or sucrase isomaltase insufficiency.
Hidrasec: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Hidrasec/Hidrasec Paediatric: Occurrence of skin reactions has been reported with the use of the product. These are in most cases mild and do not require treatment but in some cases they can be severe, even life-threatening. Association with racecadotril treatment cannot be fully excluded. When experiencing severe skin reactions, the treatment has to be stopped immediately.
Hypersensitivity/Angioedema have been reported in patients with racecadotril. This may occur at any time during therapy.
Patients with a history of angioedema unrelated to racecadotril therapy may be at increased risk of angioedema.
The administration of Hidrasec/Hidrasec Paediatric does not modify the usual rehydration regimens.
Hidrasec Paediatric: Rehydration is highly important in the management of acute diarrhoea in infants. The requirement for rehydration and route should be adapted to the age and weight of the patient and the stage and severity of the condition, specifically in case of serious or prolonged diarrhoea with significant vomiting or a lack of appetite. Additionally, it is important that regular feeding (incl. breastfeeding) is not interrupted and that adequate fluid intake is monitored.
Hidrasec/Hidrasec Paediatric: The presence of bloody or purulent stools and fever may indicate the presence of invasive bacteria as a reason for diarrhoea, or the presence of other severe disease, warranting casual (e.g. antibiotic) treatment or further investigation. Therefore, racecadotril should not be administered under these conditions. Racecadotril may be given concomitantly with antibiotics in case of acute diarrhoea with a bacterial cause as a complementary treatment.
Use of racecadotril in antibiotic-associated diarrhoea and chronic diarrhoea is not recommended due to insufficient data.
Hidrasec: There are limited data in patients with renal or hepatic impairment. These patients should be treated with caution (see Pharmacology: Pharmacokinetics under Actions).
These is a possible reduced availability in patients with prolonged vomiting.
Hidrasec Paediatric: In patients with diabetes, it should be taken into account that each sachet contains: HIDRASEC Paediatric 10 mg: 0.966 g of sucrose; HIDRASEC Paediatric 30 mg: 2.899 g of sucrose.
If the quantity of sucrose (source of glucose and fructose) present in the daily dose of HIDRASEC Paediatric exceeds 5 g a day, the latter should be taken into account in the daily sugar ration.
The product must not be administered to infants less than 3 months old, as there are no clinical trials in this population.
The product must not be administered to children with renal or liver impairment, whatever the degree of severity, due to lack of information on these patient populations.
Because of possible reduced bioavailability, the product must not be administered in cases of prolonged or uncontrolled vomiting.
Effects on ability to drive and use machines: Racecadotril has no or negligible influence on the ability to drive and use machines.
Pregnancy: There are no adequate data from the use of racecadotril in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. However, since no specific clinical studies are available, racecadotril should not be administered to pregnant women.
Lactation: Due to the lack of information on secretion of racecadotril in human milk, the product should not be administered to breastfeeding women.
The following adverse drug reactions listed as follows have occurred with racecadotril more often than with placebo or have been reported during post-marketing surveillance. The frequency of adverse reactions is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Hidrasec: Nervous system disorders:
Hidrasec Paediatric: Infections and infestations:
Skin and subcutaneous tissue disorders:
Uncommon: Rash, erythema.
Unknown: Erythema multiforme, tongue oedema, face oedema, lip oedema, eyelid oedema, angioedema, urticaria, erythema nodosum, papular rash, prurigo, pruritus, toxic skin eruption (Hidrasec only).
Hidrasec Paediatric: Paediatric population:
In infants or children treated with racecadotril the occurance of tonsilitis has been reported as an uncommon adverse event. There are specific formulations for these age groups.
Serious skin reactions (including angioedema) have been reported in patients on racecadotril therapy. The incidence of these reactions is unknown but if they occur, racecadotril therapy must be discontinued and appropriate alternative therapy instituted. Patients should be aware not to take racecadotril again in these cases.
Angiotensin converting enzyme inhibitors (such as captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril) are known to induce angioedema. This risk could be increased in presence of racecadotril.
In humans, the concomitant treatment with racecadotril and loperamide or nifuroxazide does not modify the kinetics of racecadotril.
Instructions for use/handling: Hidrasec: No special requirements.
Hidrasec Paediatric: No further information of relevance.
Incompatibilities: Not applicable.
Hidrasec: Do not store above 25°C.
Hidrasec Paediatric: Store below 30°C.
Shelf-Life: Hidrasec: 3 years.
Hidrasec Paediatric: 2 years.
A07XA04 - racecadotril ; Belongs to the class of other antidiarrheals.
Cap 100 mg (ivory coloured) x 10's. Powd for oral liquid (sachet) 10 mg (white powder with characteristic apricot smell) x 16's. 30 mg x 16's.