Hidrasec

Capsule: Each capsule contains 100 mg of racecadotril.
Granules for oral suspension: Each HIDRASEC 10 mg INFANTS contains racecadotril 10 mg for one unit dose sachet.
Each HIDRASEC 30 mg CHILDREN contain racecadotril 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: Gelatine, titanium dioxide (E171), yellow iron oxide (E172).
Granules for oral suspension: Sucrose, anhydrous colloidal silica, 30% polyacrylate dispersion, apricot flavor.

Pharmacotherapeutic group: Other antidiarrhoeals agent (intestinal antisecretory antidiarrhoeal agent). ATC code: A07XA04. (A: digestive system and metabolism).
Pharmacology: Pharmacodynamics: Racecadotril is a prodrug that must be hydrolysed to its active metabolite thiorphan, which is an inhibitor of enkephalinase, a cell membrane enzyme present in various tissues, including the intestinal epithelium.
This enzyme contributes to the hydrolysis of exogenous and endogenous peptides, such as enkephalins.
Racecadotril thus protects enkephalins from enzymatic degradation, thereby prolonging their action at enkephalinergic synapses in the small intestine and thus reducing hypersecretion.
Racecadotril is a pure intestinal antisecretory active substance. It decreases intestinal hypersecretion of water and electrolytes induced by cholera toxin or inflammation, with no effect on basal secretion. It exerts antidiarrhoeal activity of rapid onset without altering the intestinal transit time.
Capsule: Racecadotril does not trigger abdominal distension. During clinical trials, secondary constipation is observed at the same frequency in racecadotril and placebo groups.
In oral use, the activity of racecadotril remains peripheral without any effect on the central nervous system.
A randomized, crossover clinical study has shown that 100 mg racecadotril at the therapeutic dose (one capsule) or at a higher dose (4 capsules) does not induce QT/QTc prolongation in 56 healthy adult volunteers (unlike the effect observed with moxifloxacin, used as a positive control).
Granules for oral suspension: In two clinical studies performed in children, racecadotril reduced stool weight by 40% and 46%, respectively, within the first 48 hours.
A significant reduction in the duration of the diarrhoea and the need for rehydration was also observed.
A meta-analysis (9 randomised clinical trials, racecadotril versus placebo, in addition to oral rehydration solution) collected individual patient data from 1,384 boys and girls suffering from acute diarrhoea of varying severity, treated in an outpatient or hospitalized setting.
The mean age was 12 months (interquartile range: 6-39 months).
A total of 714 patients were less than 1 year and 670 patients were more than 1 year old. The mean weight ranged from 7.4 kg to 12.2 kg, depending on the study. The overall mean duration of diarrhoea after enrolment was 2.81 days in the placebo group and 1.75 days for racecadotril.
In oral use, the activity if racecadotril remains peripheral without any effect on the central nervous system.
A randomized, crossover clinical study has shown that 100 mg racecadotril at the therapeutic dose (one capsule) or at a higher dose (4 capsules) does not induce QT/QTc prolongation in 56 healthy adult volunteers (unlike the effect observed with moxifloxacin, used as a positive control).
Pharmacokinetics: Absorption: Following oral administration, racecadotril is rapidly absorbed. 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: Following oral administration of 14C-labelled racecadotril in healthy volunteers, the concentration of racecadotril was about 200 times higher in plasma than in blood cells and about 3 times higher in plasma than in the total blood volume. Racecadotril does not significantly bind to blood cells.
In plasma, the mean apparent volume of distribution of 66.4 L/kg demonstrates moderate distribution of 14C in other tissues.
Ninety percent of the active metabolite of racecadotril, thiorphan, (RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycine, is bound to plasma proteins, primarily albumin.
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.
For a 100 mg dose, the duration of plasma enkephalinase inhibition is about 8 hours.
Capsules: Peak plasma enkephalinase activity occurs approximately 2 hours post-dose, corresponding to 75% inhibition for the dose of 100 mg/kg.
Granules for oral suspension: The peak concentration is reached within approximately 2.5 hours, corresponding to 90% inhibition of enzymatic activity for the administered dose of 1.5 mg/kg.
Metabolism: The biological half-life of racecadotril, as determined by plasma enkephalinase inhibition, is 3 hours.
Racecadotril is rapidly hydrolysed to thiorphan (RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycine, its active metabolite, which is itself transformed into inactive metabolites S-methylthiorphan sulphoxide, S-methylthiorphan, 2-methanesulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which were all formed on greater than 10% systemic exposure to the parent compound.
Other minor metabolites have also been detected and quantified in urine and faecal matter.
Repeated administration of racecadotril does not induce accumulation within the body.
In vitro data show that racecadotril/thiorphan and its four major inactive metabolites have no significant action as inhibitors of the cytochrome CYP isoforms 3A4, 2D6, 2C9, 1A2 and 2C19.
In vitro data show that racecadotril/thiorphan and its four major inactive metabolites have no significant action as inducers of the cytochrome CYP isoforms (family 3A, 2A6, 2B6, 2C9/2C19, family 1A, 2E1) and enzymes that bind to glucuronyl transferase.
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).
In the paediatric population, the pharmacodynamic results are similar to those of the adult population, with C_max reached 2.5 hours post-dose. There is no accumulation after repeated doses every 8 hours for 7 days.
Excretion: Racecadotril is eliminated via its active and inactive metabolites. Elimination takes place mainly via the kidney (81.4%), and, to a lesser degree, via the faecal (around 8%). Excretion via the lungs is not significant (less than 1% of the dose).
Toxicology: Preclinical safety data: Four-week chronic toxicity studies performed in monkeys and dogs, useful for assessing the duration of treatment in humans, have not demonstrated any effect at dosages up to 1250 mg/kg/day and 200 mg/kg, corresponding to safety margins of 625 and 62 (compared to humans), respectively.
Racecadotril did not proved to be immunotoxic in mice treated for 1 month.
A longer duration of exposure (1 year) in monkeys showed generalised infections and reduced antibody responses to vaccinations (at a dose of 500 mg/kg/day) and no infection/immunosuppression at 120 mg/kg/day.
Similarly, in dogs treated at a dose of 200 mg/kg/day for 26 weeks, some infectious/immune reactions were detected. Their clinical significance is unknown: see Adverse Reactions.
No mutagenic or clastogenic effect of racecadotril was detected during standard tests in vivo and in vitro.
No carcinogenicity tests have been conducted, as treatment is short term.
Reproductive toxicity and development studies (pre-embryonic development and fertility, prenatal and postnatal development, embryo-foetal development studies) revealed no particular effect of racecadotril.
Other preclinical effects (such as severe, probably aplastic anaemia, increased diuresis, ketonuria, diarrhoea) were observed only at exposures well above the maximum human dose. Their clinical significance is not known.
A toxicity study conducted in juvenile rats showed no significant effect due to racecadotril at doses up to 160 mg/kg/day, corresponding to a dose 35 times higher than the recommended paediatric dose (e.g. 4.5 mg/kg/day).
Despite the immaturity of renal function in children less than 1 year old, higher exposure levels are not expected in this group.
Other safety pharmacology studies revealed no harmful effects on the central nervous system, the cardiovascular and respiratory functions.
In animals, racecadotril potentiates the effects of butylhyoscine on intestinal transit and the anticonvulsant effect of phenytoin.

Capsule: Symptomatic treatment of acute diarrhoea in adults.
Granules for oral suspension: As a supplement to oral rehydration, symptomatic treatment of acute diarrhoea in infants (from 1 month to 30 months) and in children (from 30 months to 14 years). The level of rehydration with oral or intravenous rehydration solution should be adjusted according to the severity of the diarrhoea and the age and characteristics of the child (concomitant diseases).

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 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: Posology: The usual daily dose is determined according to bodyweight on the basis of 1.5 mg/kg per dose, with one initial dose and then 3 doses spread over the day.
In practice: Number of sachet(s) per dose according to child's weight: Hidrasec Infants: See Table 1.

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Hidrasec Children: See Table 2.

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Treatment regimen: On the 1st day: One starting dose and then 3 doses spread throughout the day. Subsequent days: 3 doses spread throughout the day.
The powder should be swallowed as it is. It can also be added to food or poured into a glass of water or a feeding bottle, stirring well and ensuring that all the mixture is swallowed immediately.
On the basis of the dosage stated previously, the recommended daily dose is about 6 mg/kg, i.e. about 42 mg/kg for one week of treatment.
Method of administration: The powder can be poured either onto food or into a glass of water or feeding bottle; stirring well and ensuring that the whole of the mixture is swallowed immediately.
Treatment must be continued until the return of two normal stools, but should not exceed 7 days.
Specific populations: No studies have been conducted in children less than 3 months old.
No studies have been conducted in children with hepatic or renal insufficiency (see Precautions).

In the cases of overdose reported, patients did not present any adverse reactions.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

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.
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.
Granules for oral suspension: Treatment with Hidrasec is merely an adjuvant therapy in addition to oral rehydration and does not in any way substitute it. Rehydration must be systematic in infants/children with acute diarrhoea to prevent or treat dehydration and must be adapted in such a way as to compensate for fluid and electrolyte losses.
Treatment of acute diarrhea in children is primarily based on correcting fluid and electrolyte losses, by using oral rehydration solutions and re-establishing feeding patterns as soon as possible, depending on the child's age and dietary habits prior to diarrhoea.
In cases of severe or prolonged diarrhoea, significant vomiting or refusal of food, intravenous rehydration must be envisaged.
The presence of blood or pus in the stools with fever can be a sign of diarrhoea due to invasive germs or indicate the presence of other ongoing diseases. In the case of infectious diarrhoea with clinical signs suggestion an invasive phenomenon, use antibacterial agents with good systemic diffusion. Racecadotril has not been evaluated in antibiotic-related diarrhoea. Hence, racecadotril must not be used in these cases.
Due to potentially reduced bioavailability, racecadotril must not be administered in cases of prolonged or uncontrollable vomiting.
In cases of renal or hepatic insufficiency, Hidrasec must not be administered due to lack of data.
This medicinal product contains sucrose. Its use is not recommended in patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase/isomaltase deficiency.
Each sachet contains: Hidrasec Infants: 0.9665 g of sucrose; Hidrasec Children: 2.8995 g of sucrose.
If the quantity of sucrose (source of glucose or fructose) in the daily dose of this medicine exceeds 5 g per day, this must be taken into account in the daily allowance of patients on slow-sugar diet or with diabetes.
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.
Effects on ability to drive and use machines: Racecadotril has no or negligible influence on the ability to drive and use machines.

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.

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).
Capsule: Clinical studies conducted on acute diarrhoea have provided data in 2193 adult patients treated with racecadotril and 282 treated with placebo.
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: Clinical studies conducted on acute diarrhoea have provided safety-in-use data in 860 infants and children treated with racecadotril and 441 treated with placebo.
Skin and subcutaneous tissue disorders: Uncommon: rash, erythema.
Not known: urticaria, angioedema, oedema of the tongue, face, lip or eyelids, erythema multiforme, erythema nodosum, papular rash, pruritus, prurigo.
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. Website: http://www.drugoffice.gov.hk/eps/do/en/pharmaceutical_trade/adr_reporting.

Interaction of racecadotril with angiotensin-converting enzyme (ACE) inhibitors.
Associated not advised: Concomitant use of racecadotril and angiotensin-converting enzyme inhibitors (ACE such as captopril, enalapril, lisinopril, perindopril and ramipril) may increase the risk of angioedema (Quincke's oedema) (see Precautions).
The concomitant administration of racecadotril with loperamide or nifuroxazide does not alter the kinetics of racecadotril.

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

Capsule: Store the product below 30°C.
Granules for oral suspension: Store below 25°C.
Shelf life: 3 years.

Antidiarrheals

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

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