Hidrasec

Racecadotril.

Capsule: Each capsule contains 100 mg of racecadotril.
Excipients with known effects: Each capsule contains 41 mg lactose monohydrate.
Granules for oral suspension: Hidrasec Infants 10mg: Each sachet contains 10 mg of racecadotril.
Each sachet contains 0.966 g of sucrose.
Hidrasec Children 30mg: Each sachet contains 30 mg of racecadotril.
Each sachet contains 2.9 g of sucrose.
Excipients/Inactive Ingredients: Capsule: Powder: Lactose monohydrate, Pregelatinised starch (maize), Magnesium stearate, Colloidal anhydrous Silica.
Capsule: Yellow iron oxide (E172), Titanium dioxide (E171), Gelatin.
Granules for oral suspension: Sucrose, Anhydrous colloidal silica, polyacrylate dispersion 30 percent, Apricot aroma.

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.

Capsule: HIDRASEC is indicated for the symptomatic treatment of acute diarrhoea in adults when causal treatment is not possible.
If causal treatment is possible, racecadotril can be administered as a complementary treatment.
Granules for oral suspension: Complementary symptomatic treatment of acute diarrhoea in infants (older than 3 months) and children together with oral rehydration.
If causal treatment of acute diarrhoea is possible, racecadotril can be co-administered.

Capsule: For oral use.
Adults: One capsule initially regardless of the time of day. Then, one capsule three times daily preferably before the main meals. Treatment should be continued until two normal stools are recorded.
Treatment should not exceed 7 days.
Long-term treatment with racecadotril is not recommended.
Special populations: Children: There are specific formulations intended for infants, children and adolescents.
Older people: Dosage adjustment is not necessary in the older people (see Pharmacology: Pharmacokinetics under Actions).
Caution is advised in patients with hepatic or renal impairment.
Granules for oral suspension: HIDRASEC INFANTS and HIDRASEC CHILDREN are administered via the oral route, together with oral rehydration (see Precautions).
Hidrasec Infants is intended for children <13 kg: 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.
In infant less than 9 kg: one 10 mg sachet 3 times daily.
In infant from 9 kg to 13 kg: two 10 mg sachets 3 times daily.
Hidrasec Children 30 mg is intended for children ≥13 kg. 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.
In children from 13 kg to 27 kg: one 30 mg sachet 3 times daily.
In children of more than 27 kg: two 30 mg sachets 3 times daily.
The duration of treatment in the clinical trials with children was 5 days. Treatment should be continued until two normal stools are recorded. Treatment should not exceed 7 days. Long-term treatment with racecadotril is not recommended.
There are no clinical trials in infants under 3 months of age.
Special populations: There are no studies in infants or children with renal impairment or hepatic impairment (see Precautions).
Caution is advised in patients with hepatic or renal impairment.
The granules can be added to food, dispersed in a glass of water or in the feeding-bottle, mixing well and followed by immediate administration.

Capsule: 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.
Granules for oral suspension: 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.
Granules for oral suspension: Due to the presence of sucrose, HIDRASEC INFANTS 10mg and HIDRASEC CHILDREN 30mg is contraindicated in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or sucrose-isomaltase insufficiency.

Precautions for use: Administration of racecadotril does not modify the usual rehydration regimens.
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 causal (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.
Granules for oral suspension: 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.
In patients with diabetes, it should be taken into account that each sachet contains: HIDRASEC INFANTS 10mg: 0.966g of sucrose.
HIDRASEC CHILDREN 30mg: 2.899g of sucrose.
If the quantity of sucrose (source of glucose and fructose) present in the daily dose of HIDRASEC INFANT 10mg and HIDRASEC CHILDREN 30 mg 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 a 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.
Capsule: There are limited data in patients with renal or hepatic impairment. These patients should be treated with caution (see Pharmacology: Pharmacokinetics under Actions).
There is a possible reduced availability in patients with prolonged vomiting.
Warnings: 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 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.
Capsule: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.
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, fertility, embryofoetal development, parturition or postnatal development. However, since no specific clinical studies are available, Hidrasec should not be administered to pregnant women.
Lactation: Due to the lack of information regarding racecadotril secretion in human milk, this 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).
Skin and subcutaneous tissue disorders: Uncommon: rash, erythema. Unknown: erythema multiforme, tongue oedema, face oedema, lip oedema, eyelid oedema, angioedema, urticaria, erythema nodosum, rash papular, prurigo, pruritus.
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.
Capsule: Nervous system disorders: Common: headache.
Skin and subcutaneous tissue disorders: Unknown: toxic skin eruption.
Paediatric population:In infants or children treated with racecadotril the occurrence of tonsillitis has been reported as an uncommon adverse event. There are specific formulations for these age groups.
Granules for oral suspension: Infections and infestations: Uncommon: tonsillitis.

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, concomitant treatment with racecadotril and loperamide or nifuroxazide does not modify the kinetics of racecadotril.

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: No special requirements.

Capsule: This medicinal product does not require any special storage conditions. Do not store above 30°C.
Granules for oral suspension: Store below 30°C.
Shelf life: 3 years.

Antidiarrheals

A07XA04 - racecadotril ; Belongs to the class of other antidiarrheals.

C