Hidrasec

Capsule: Each capsule contains 100 mg of racecadotril.
Granules for oral suspension: Racecadotril 10 mg or 30 mg for one unit dose sachet.
Excipients/Inactive Ingredients: Capsule: Lactose monohydrate, pre-gelatinised maize starch, magnesium stearate, anhydrous colloidal silica.
Composition of the capsule shell: gelatin, titanium dioxide (E171), yellow iron oxide (E172).
Granules for oral suspension: Sucrose, anhydrous colloidal silica, 30% polyacrylate dispersion, apricot flavor.

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 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.
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 100 mg 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).
Granules for oral suspension: 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 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.
Distribution: After oral administration of 14C-labeled racecadotril in healthy volunteers, racecadotril concentration was more than 200-fold higher in plasma than in blood cells and 3-fold higher in plasma than in total 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.
Metabolism: The half-life of racecadotril, measured as plasma enkephalinase inhibition, is approximately 3 hours.
Racecadotril is rapidly hydrolysed to thiorphan (RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycine, the active metabolite, which is in turn transformed into inactive metabolites S-methylthiorphan sulphoxide, S-methylthiorphan, 2-methanesulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which all were formed at greater than 10% of parent drug systemic exposure.
Additional minor metabolites were also detected and quantified in urine and faeces.
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.
In the paediatric population, pharmacodynamic/pharmacokinetic results are similar to those of the adult population, reaching C_max 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 (81.4%), and to a much lesser extent via the faecal route (around 8%). The pulmonary route is not significant (less than 1% of the dose).
Capsule: Absorption: The activity on plasma enkephalinase appears from the thirtieth minutes onwards.
The bioavailability of racecadotril is not altered by food, but the peak activity is delayed by about one and a half hours.
Distribution: The pharmacokinetic properties of racecadotril are not altered during repeat-dose administration or in the elderly.
The intensity and duration of action of racecadotril are dose-related. Peak plasma enkephalinase activity occurs approximately 2 hours post-dose, corresponding to 75% inhibition for the dose of 100 mg/kg.
For a 100 mg dose, the duration of plasma enkephalinase inhibition is about 8 hours.
Metabolism: Repeated administration of racecadotril does not induce accumulation within the body.
Racecadotril does not alter the protein binding of highly protein-bound products, such as tolbutamide, warfarin, niflumic acid, digoxin or phenytoin.
In patients with hepatic insufficiency (cirrhosis, Child-Pugh B), the kinetic profile of the metabolite shows the same T_max and T_1/2 and lower C_max (-65%) and areas under the curve (-29%), compared to healthy subjects.
In patients with severe renal insufficiency (creatinine clearance between 11 and 39 mL/min), the kinetic profile of the metabolite shows a lower C_max (-49%) and larger areas under the curve (+15%) and T_1/2 compared to healthy volunteers (creatinine clearance >70 mL/min).
Granules for oral suspension: Absorption: The exposure at steady state is comparable with the exposure following a single dose.
Distribution: The duration and extent of the effect of racecadotril are dose-dependent. 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. The duration of plasma enkephalinase inhibition is approximately 8 hours.
Toxicology: Preclinical safety data: Chronic 4-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 corresponding to safety margins of 625 and 62 (vs human). Racecadotril was not immunotoxic in mice given racecadotril for up to 1 month. Longer exposure (1 year) in monkeys showed generalized infections and reduced antibody responses to vaccination at a 500 mg/kg/day dose and no infection/immune depression at 120 mg/kg/day. Similarly in the dog receiving 200 mg/kg/day for 26 weeks some infection/immune parameters were affected. The clinical relevance is unknown (see Adverse Reactions).
No mutagenic or clastogenic effect of racecadotril has been found in the standard in vitro and in vivo tests. Carcinogenicity testing has not been performed with racecadotril as the drug is provided for short-term treatment.
Reproductive and developmental toxicity (fertility and early embryonic development, prenatal and postnatal development including maternal function, embryo-foetal development 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).
Despite the immature renal function in children below 1 year of age, higher exposure levels are not expected in these individuals.
Other preclinical effects (e.g., severe, most likely aplastic anaemia, increased diuresis, ketonuria, diarrhoea) were observed only at exposures considered sufficiently in excess of maximum human exposure. Their clinical relevance is unknown.
Other safety pharmacology studies did not evidence any deleterious effects of racecadotril on the central nervous system, the cardiovascular and the respiratory functions.
In animals, racecadotril reinforced the effects of butylhyoscine upon bowel transit and on the anticonvulsive effects of phenytoin.

Capsule: Symptomatic treatment of acute diarrhoea in adults.
Granules for oral suspension: Complementary symptomatic treatment of acute diarrhoea in infants (older than 3 months) and in children together with oral rehydration and the usual support measures, when these measures alone are insufficient to control the clinical condition, and when causal treatment is not possible.
If causal treatment is possible, racecadotril can be administered as a complementary treatment.

Capsule: Oral route.
Adults: In the treatment of acute diarrhoea, the treatment should be initiated with a single 100 mg capsule given regardless of the time, further treatment is a single 100 mg capsule at the beginning of the three main meals.
The administration of Hidrasec 100 mg capsules does not exempt of rehydration therapy if necessary. The duration of treatment must not exceed seven days.
Specific populations: Paediatric population: Hidrasec 100 mg capsules must not be administered to infants and children.
Other pharmaceutical forms of Hidrasec suitable for the paediatric population are available.
Elderly: Dosage adjustment is not necessary in the elderly (see Pharmacology: Pharmacokinetics under Actions).
Caution is advised in patients with hepatic or renal impairment.
Granules for oral suspension: Hidrasec Infants 10 mg and Hidrasec Children 30 mg are administered via the oral route, together with oral rehydration (see Precautions).
Hidrasec Infants 10 mg is intended for children <13 kg. 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 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.
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.
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 Warnings).
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: In the cases of overdose reported, patients did not present any adverse reactions.
Granules for oral suspension: 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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Granules for oral suspension: This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or saccharase-isomaltase deficiency should not take this medicine.

Granules for oral suspension: Chronic diarrhoea has not been sufficiently studied with Hidrasec Infants.
In patients with diabetes, it should be taken into account that each sachet contains: 0.9665 g of sucrose (Hidrasec Infants) or 2.8995 g of sucrose (Hidrasec Children).
If the quantity of sucrose (source of glucose and fructose) present in the daily dose of Hidrasec Infants 10 mg or 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 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.
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/Angioneurotic Oedema have been reported in patients with racecadotril. This may occur at any time during therapy.
Angioedema of the face, extremities, lips, mucous membranes may occur.
Where there is angioedema associated with upper airway obstruction, such as tongue, glottis and/or larynx, emergency therapy should be administered promptly.
Racecadotril should be discontinued and the patient should be under close medical supervision with appropriate monitoring initiated and continued until complete and sustained resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to racecadotril therapy may be at increased risk of angioedema.
Concomitant use of racecadotril and ACE inhibitors may increase the risk of angioedema (see Interactions). Hence, a careful benefit-risk assessment is needed before initiating treatment with racecadotril in patients on ACE inhibitors.

Capsule: Hidrasec is not substitute for rehydration, if required.
Racecadotril must not be used if signs of acute dysenteric syndrome are present, such as bloody stools or fever.
Racecadotril has not been evaluated and must not be used in antibiotic-related diarrhoea.
There is insufficient data regarding chronic diarrhoea and this medicinal product.
Data are limited in patients with renal or hepatic insufficiency. Caution should therefore be exercised when treating these patients (see Pharmacology: Pharmacokinetics under Actions).
Bioavailability may be reduced in patients with prolonged vomiting.
This medicinal product contains lactose. Its use is not recommended in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases).
Skin reaction have been reported with the use of this medicinal product. In most cases, these reactions are mild and do not require any treatment. However, in certain situations, these reactions may be severe and life-threatening; the link with taking racecadotril cannot be ruled out entirely. If severe skin reaction appear, treatment with racecadotril must be discontinued immediately.
Cases of hypersensitivity and Quincke's oedema have been reported in patients treated with racecadotril. These events may occur at any time during treatment. Angioedema of the face, extremities, lips and mucosa may develop.
Emergency treatment must be administered immediately if angioedema is associated with obstruction of the upper airways involving the tongue, glottis and/or larynx, for instance.
Racecadotril must be discontinued and the patient subjected to strict medical monitoring with the introduction of appropriate follow-up until these symptoms have completely regressed in the long term.
Patients with a history of angioedema not associated with racecadotril treatment may be at increased risk of developing angioedema.
The concomitant used of racecadotril and angiotensin-converting enzyme (ACE) inhibitors may increase the risk of angioedema (see Interactions). Consequently, rigorous evaluation of the benefit/risk balance is required before introducing racecadotril treatment in patients receiving angiotensin-converting enzyme inhibitors.
Effects on ability to drive and use machines: Racecadotril has no or negligible influence on the ability to drive and use machines.
Granules for oral suspension: The administration of Hidrasec Infants or Hidrasec Children does not modify the usual rehydration regimens. 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.
In the event of serious or prolonged diarrhoea with important vomiting or a lack of appetite, intravenous rehydration should be considered.
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. Also, racecadotril has not been tested in antibiotic-associated diarrhoea. Therefore, racecadotril should not be administered under these conditions.
Chronic diarrhoea has not been sufficiently studied with Hidrasec Children.
Effects on ability to drive and use machines: Not relevant.
Racecadotril has no or negligible influence on the ability to drive and use machines.

Capsule: Fertility: No effect on fertility has been observed during fertility studies conducted in male and female rats.
Pregnancy: Animal studies have not shown any direct or indirect harmful effects with respect to reproductive toxicity. Clinical data on the use of racecadotril during pregnancy are very limited. As a precaution, it is therefore preferable to avoid the use of Hidrasec during pregnancy, regardless of trimester.
Breast-feeding: In the absence of data on the passage of racecadotril into breast milk and on account of its pharmacological properties and the immaturity of the neonatal digestive tract, Hidrasec should not be administered during breast-feeding.
Granules for oral suspension: Fertility: Fertility studies conducted with racecadotril on rats demonstrate no impact on fertility.
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, embryo-foetal development, childbirth/delivery 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 regarding racecadotril excretion in human milk, this medicinal product should not be administered to breastfeeding women.

Capsule: Clinical studies conducted on acute diarrhoea have provided data in 2193 adult patients treated with racecadotril and 282 treated with placebo.
The adverse reactions listed as follows have been observed more frequently with racecadotril than with placebo during clinical trials, or have been reported during marketing phase.
The frequency of adverse reactions has been defined according to 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).
Central nervous system disorders: Common: Headache.
Skin and subcutaneous tissue disorders: Uncommon: Rash, erythema.
Not known: Erythema multiforme, oedema of the tongue, face, lips or eyelids, angioedema (Quincke's oedema), urticaria, erythema nodosum, papular rash, pruritus, prurigo, toxidermia.
Granules for oral suspension: Data from clinical acute diarrhoea studies are available for 860 paediatric patients treated with racecadotril, and 441 treated with placebo.
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).
Infections and infestations: Uncommon: Tonsillitis.
Skin and subcutaneous tissue disorders (see Warnings): Uncommon: Rash, erythema.
Unknown: Erythema multiforme, tongue oedema, face oedema, lip oedema, eyelid oedema, angioedema, urticaria, erythema nodosum, rash papular, prurigo, pruritus.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report all suspected adverse reactions to Drug Office, Department of Health.

Capsule: Concomitant use of racecadotril and angiotensin-converting enzyme inhibitors (ACE such as captopril, enalapril, lisinopril, perindopril and ramipril) may increase the risk of Quincke's oedema (see Precautions).
The concomitant administration of racecadotril with loperamide or nifuroxazide does not alter the kinetics of racecadotril.
Granules for oral suspension: Concomitant use of racecadotril and ACE inhibitors (e.g. captopril, enalapril, lisinopril, perindopril, ramipril) may increase the risk of angioedema (see Warnings).
In humans, joint treatment with racecadotril and loperamide or nifuroxazide does not modify the kinetics of racecadotril.

Incompatibilities: Not applicable.
Capsule: Special precautions for disposal: No special requirements.

Capsule: Store the product below 30°C.
Shelf life: 3 years.

Antidiarrheals

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

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