Instructions Hydrasec granules for oral suspension 10 mg sachet No. 16
Composition
active ingredient: racecadotril;
1 sachet contains 10 mg of racecadotril or 30 mg of racecadotril;
excipients: sucrose, colloidal anhydrous silicon dioxide, polyacrylate dispersion, apricot flavoring.
Dosage form
Granules for oral suspension.
Main physicochemical properties: white powder with a characteristic apricot odor.
Pharmacotherapeutic group
Other antidiarrheal agents.
ATX code A07X A04.
Pharmacological properties
Pharmacodynamics
Racecadotril is a prodrug that requires hydrolysis to form the active metabolite thiorphan, which is an inhibitor of enkephalinase, a cell membrane peptidase found in various tissues, especially in the small intestinal epithelium. This enzyme promotes both the hydrolysis of exogenous and the cleavage of endogenous peptides such as enkephalins. Therefore, racecadotril protects endogenous enkephalins, which are physiologically active at the level of the digestive tract, prolonging their antisecretory function.
Racecadotril is an antisecretory agent that acts exclusively in the intestinal mucosa. It reduces intestinal hypersecretion of water and electrolytes caused by cholera toxins or inflammation, without affecting basal secretory activity. Racecadotril exhibits a rapid antidiarrheal effect without altering intestinal transit time.
Racecadotril does not cause bloating. In clinical trials, the incidence of secondary constipation with racecadotril was similar to that observed in the placebo group.
When administered orally, the drug exhibits exclusively peripheral activity, without affecting the central nervous system.
In two clinical trials in children, racecadotril reduced stool weight by 40% and 46%, respectively, in the first 48 hours. There was also a significant reduction in the duration of diarrhea and the need for rehydration.
In a meta-analysis of individual patient data (9 randomized clinical trials of racecadotril versus placebo in addition to oral rehydration solution), individual patient data (1384 boys and girls) with acute diarrhea of varying severity and treated inpatiently or outpatiently were collected. The median age was 12 months (interquartile range: 6 to 39 months). Of the total, 714 patients were <1 year of age and 670 patients were >1 year of age. The mean body weight ranged from 7.4 kg to 12.2 kg during the studies. The overall mean duration of diarrhea after inclusion was 2.81 days in the placebo group and 1.75 days in the racecadotril group. The percentage of patients who recovered was higher in the racecadotril groups compared to placebo [Hazard Ratio (HR): 2.04; 95% CI: 1.85 to 2.32; p<0.001; Cox Proportional Hazards Regression]. The results were very similar for infants (<1 year) (HR: 2.01; 95% CI: 1.71 to 2.36; p<0.001) and preschool children (>1 year) (HR: 2.16; 95% CI: 1.83 to 2.57; p<0.001). For inpatients (n=637), the ratio of mean stool weight in the racecadotril group to the mean stool weight in the placebo group was 0.59 (95% CI: 0.51 to 0.74; p<0.001). For outpatients (n=695), the ratio of the mean number of stools per diarrhea in the racecadotril group to the mean number of stools per diarrhea in the placebo group was 0.63 (95% CI: 0.47 to 0.85; p<0.001).
Pharmacokinetics
Absorption
Racecadotril is rapidly absorbed after oral administration. The initial time to inhibition of plasma enkephalinase is 30 minutes.
The bioavailability of racecadotril is not altered by food intake, but the time to peak activity is delayed by approximately one and a half hours.
Distribution
After an oral dose of 14C-labeled racecadotril, the measured concentration of the radioactive carbon isotope in plasma was many orders of magnitude higher than in blood cells and three times higher than in whole blood. Thus, the drug does not bind to blood cells to a significant extent. Distribution of the radioactive carbon isotope to other body tissues is modest, as evidenced by a 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 albumin. The pharmacokinetic properties of racecadotril are not altered by repeated dosing or by use in elderly patients.
The duration and extent of action of racecadotril are dose-dependent.
In children, the time to peak inhibition of plasma enkephalinase is approximately 2 hours and corresponds to 90% inhibition at a dose of 1.5 mg/kg. In adults, the time to peak inhibition of plasma enkephalinase is approximately 2 hours and corresponds to 75% inhibition at a dose of 100 mg.
The duration of inhibition of plasma enkephalinase is about 8 hours.
Metabolism
The biological half-life of racecadotril, based on the degree of inhibition of plasma enkephalinase, is approximately 3 hours.
Racecadotril is rapidly hydrolyzed to thiorphan, the active metabolite, which in turn is converted to inactive metabolites.
In vitro data indicate that racecadotril/thiorphane and the 4 major inactive metabolites do not inhibit the major CYP enzyme isoforms 3A4, 2D6, 2C9, 1A2 and 2C19 to a clinically relevant extent.
In vitro data indicate that racecadotril/thiorphan and the 4 major inactive metabolites do not induce CYP enzyme isoforms (class 3A, 2A6, 2B6, 2C9/2C19, class 1A, 2E1) and UHT conjugating enzymes to a clinically relevant extent.
Racecadotril does not affect the protein binding of active substances that are significantly protein bound, such as tolbutamide, warfarin, niflumic acid, digoxin or phenytoin.
In patients with hepatic impairment [cirrhosis, Child-Pugh B], the kinetic profile of the active metabolite of racecadotril was similar to that observed in healthy volunteers, but with lower Cmax (-65%) and AUC (-29%).
In patients with severe renal impairment (creatinine clearance 11-39 ml/min), the kinetic profile of the active metabolite of racecadotril was characterized by a lower Cmax (-49%) and a longer AUC (+16%) and T½ than in healthy volunteers (creatinine clearance >70 ml/min).
In children, pharmacokinetic parameters are similar to those in adults, reaching Cmax 2 hours 30 minutes after administration. No accumulation is observed after multiple doses every 8 hours for 7 days.
Breeding
Racecadotril is excreted in the form of both active and inactive metabolites. The drug is excreted mainly by the kidneys, to a much lesser extent - with feces. Pulmonary excretion is insignificant.
Indication
Adjunctive symptomatic treatment of acute diarrhea in infants (aged 3 months and older) and children in combination with oral rehydration and usual supportive measures, when these measures alone are insufficient to control the clinical condition and when etiotropic treatment is not possible.
If etiotropic treatment is possible, racecadotril can be used as an adjunctive therapy.
Contraindication
Hypersensitivity to the active substance or to any of the excipients.
Due to the presence of sucrose, Hydrasec is contraindicated in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.
Interaction with other medicinal products and other types of interactions
No interactions with other drugs have been recorded in humans to date.
Concomitant use of racecadotril with loperamide or nifuroxazide in humans does not alter the kinetics of racecadotril.
Application features
The use of the drug Hydrasec does not change the usual regimen for restoring water balance.
Rehydration is extremely important in the treatment of acute diarrhea in children. The type and method of rehydration should be based on the patient's age and weight, as well as the condition and severity of the condition, especially in cases of severe or prolonged diarrhea accompanied by significant vomiting or loss of appetite. It is also important to maintain regular feeding (including breastfeeding) and to ensure adequate fluid intake.
Bloody or purulent stools and fever may indicate either the presence of invasive bacteria as the cause of the diarrhea or another serious illness requiring etiotropic treatment (e.g. antibiotics) or further investigation. Therefore, racecadotril should not be used in such cases. Racecadotril may be used with antibiotics in acute bacterial diarrhea as an adjunct therapy.
The use of racecadotril in antibiotic-associated diarrhea and chronic diarrhea is not recommended due to insufficient data.
Diabetics should note that each sachet contains:
Hydrasec 10 mg: 0.966 g sucrose;
Hydrasec 30 mg: 2.899 g sucrose.
If the amount of sucrose (source of glucose and fructose) in the daily dose of Hydrasec exceeds 5 g per day, this should be taken into account in the daily sugar intake.
The drug should not be used in infants under 3 months of age, as clinical studies have not been conducted in this population.
The drug should not be used in children with any degree of renal or hepatic impairment due to limited information in this population.
Due to the possibility of reduced bioavailability, the drug should not be used in case of prolonged or uncontrolled vomiting.
Use during pregnancy or breastfeeding
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/fetal development, parturition or postnatal development. However, in the absence of specific clinical studies, racecadotril should not be used during pregnancy.
Breast-feeding.
Due to insufficient information on the excretion of Hydrasec into breast milk, it should not be used during breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
Racecadotril has no or negligible influence on the ability to drive and use machines.
Method of administration and doses
Hydrasec is administered orally together with oral rehydration therapy (see section "Special instructions").
Hydrasec 10 mg is used in children weighing up to 13 kg.
The recommended dose is calculated by body weight: 1.5 mg/kg per dose. This is 1-2 sachets of the appropriate dosage, taken 3 times a day at regular intervals.
Children weighing up to 9 kg: 1 sachet (10 mg) 3 times a day.
Children weighing 9 kg to 13 kg: 2 sachets (10 mg) 3 times a day.
Children weighing 13 kg to 27 kg: 1 sachet (30 mg) 3 times a day.
Children weighing 27 kg or more: 2 sachets (30 mg) 3 times a day.
In clinical studies involving children, the duration of treatment was 5 days.
Treatment should be continued until 2 cases of normal bowel movements are recorded.
The duration of treatment should not exceed 7 days.
Long-term treatment with racecadotril is not recommended.
Clinical studies have not been conducted in children under 3 months of age.
Special patient groups
Studies in infants or children with renal or hepatic insufficiency have not been conducted (see section "Special warnings and precautions for use").
The drug should be used with caution in patients with renal or hepatic insufficiency.
Hydrasec granules can be added to food, dissolved in a glass of water or in a feeding bottle, mixed well. The product should then be administered immediately.
Children.
Hydrasec, 10 mg granules, is used in infants and children aged 3 months to 2 years.
Hydrasec, 30 mg granules, is used for children from 2 years of age.
Overdose
No cases of overdose have been registered.
In adults, single doses of more than 2 g, i.e. 20 times the therapeutic dose, did not cause harmful effects.
Adverse reactions
The following are adverse drug reactions that were observed more frequently in the racecadotril group than in the placebo group or were reported in the post-marketing period. The adverse reactions were classified by frequency as: 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), unknown frequency (cannot be estimated from the available data).
Infections and infestations
Uncommon: tonsillitis.
Skin and subcutaneous tissue disorders
Uncommon: rash, erythema.
Unknown frequency: erythema multiforme, tongue swelling, face swelling, lip swelling, eyelid swelling, angioedema, urticaria, erythema nodosum, papular rash, pruritus, itching.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25°C. Keep out of the reach of children.
Packaging
16 sachets in a cardboard box.
Vacation category
Without a prescription.
Producer
Sofartex.
Location of the manufacturer and its business address
28500, Vernouillet, 21 rue du Pressoir, France/ 28500, Vernouillet, 21 rue du Pressoir, France.
Applicant
Abbott Laboratories GmbH.
Applicant's location
Freundallee 9A, 30173 Hannover, Germany.
