HYDRASEC

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HİDRASEC® (HIDRASEC®)

Composition:

Active substance: racecadotril;

1 capsule contains 100 mg of racecadotril;

Excipients: lactose monohydrate, pregelatinized corn starch, magnesium stearate, colloidal anhydrous silicon dioxide, iron oxide yellow (E 172), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: hard gelatin capsules No. 2, with ivory-colored caps and bodies, containing a white powder with a strong sulfur odor.

Pharmacotherapeutic group. Agents acting on the digestive system and metabolism. Other antidiarrheals. Racecadotril. ATC code A07XA04.

Pharmacological properties.

Pharmacodynamics.

Racecadotril is a prodrug requiring hydrolysis to form the active metabolite thiorphan, which is an enkephalinase inhibitor, a peptidase located in cell membranes of various tissues, particularly in the epithelium of the small intestine. This enzyme promotes the hydrolysis of both exogenous and endogenous peptides, such as enkephalins. Thus, racecadotril protects endogenous enkephalins—physiologically active in the gastrointestinal tract—by prolonging their antisecretory effect.

Racecadotril is an antisecretory agent acting exclusively on the intestinal mucosa. It reduces intestinal hypersecretion of water and electrolytes induced by cholera toxins or inflammation, without affecting basal secretory activity. Racecadotril exerts a rapid antidiarrheal effect without altering intestinal transit time.

Racecadotril does not cause abdominal distension. In clinical studies, the incidence of secondary constipation during racecadotril treatment was similar to that observed in the placebo group.

After oral administration, the drug exhibits exclusively peripheral activity and does not affect the central nervous system.

Pharmacokinetics.

Absorption.

Racecadotril is rapidly absorbed after oral administration. The time to onset of plasma enkephalinase inhibition is 30 minutes.

The bioavailability of racecadotril is not altered by food intake, although the time to reach maximum activity is delayed by approximately one and a half hours.

Distribution.

After oral administration of radiolabeled 14C-racecadotril, the measured concentration of radioactive carbon isotope in plasma was many orders of magnitude higher than in blood cells and three times higher than in total blood volume. Thus, the drug largely does not bind to blood cells. Distribution of the radioactive carbon isotope to other body tissues is moderate, as indicated by the mean apparent volume of distribution in plasma of 66.4 L. Ninety percent of the active metabolite of racecadotril, thiorphan ((RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl)glycine), is bound to plasma proteins, predominantly to albumin.

The pharmacokinetic properties of racecadotril are not altered upon repeated dosing or in elderly patients.

The duration and extent of racecadotril’s effect are dose-dependent.

In children, the time to peak plasma enkephalinase inhibition is approximately 2 hours, corresponding to 90% inhibition at a dose of 1.5 mg/kg. In adults, the time to peak plasma enkephalinase inhibition is also approximately 2 hours, corresponding to 75% inhibition at a dose of 100 mg.

The duration of plasma enkephalinase inhibition is approximately 8 hours.

Metabolism.

The biological half-life of racecadotril, based on the degree of plasma enkephalinase inhibition, is approximately 3 hours.

Racecadotril is rapidly hydrolyzed to thiorphan, the active metabolite, which is subsequently converted into inactive metabolites.

Repeated administration of racecadotril does not lead to compound accumulation in the body.

In vitro data indicate that racecadotril/thiorphan and four major inactive metabolites do not inhibit the main CYP enzyme isoforms 3A4, 2D6, 2C9, 1A2, and 2C19 to a clinically significant extent.

In vitro data indicate that racecadotril/thiorphan and four major inactive metabolites do not stimulate CYP enzyme isoforms (class 3A, 2A6, 2B6, 2C9/2C19, class 1A, 2E1) or conjugating enzymes UDP-GT (uridine-5-diphosphate glucuronosyltransferase) to a clinically significant extent.

Racecadotril does not affect protein binding of active substances for which such binding is significant, such as tolbutamide, warfarin, niflumic acid, digoxin, or phenytoin.

In patients with hepatic insufficiency [cirrhosis, Child-Pugh class B], the pharmacokinetic profile of the active metabolite of racecadotril showed Tmax and T½ values similar to those in healthy volunteers, but lower Cmax (-65%) and AUC (-29%).

In patients with severe renal insufficiency (creatinine clearance 11–39 mL/min), the pharmacokinetic profile of the active metabolite of racecadotril showed lower Cmax (-49%), higher AUC (+16%), and prolonged T½ compared to healthy volunteers (creatinine clearance >70 mL/min).

In children, pharmacokinetic parameters are similar to those in adults, with Cmax reached 2 hours and 30 minutes after administration. No accumulation was observed after multiple doses administered every 8 hours over 7 days.

Excretion.

Racecadotril is excreted in the form of both active and inactive metabolites. The drug is primarily eliminated via the kidneys, to a much lesser extent in feces. Pulmonary excretion is negligible.

Clinical characteristics.

Indications.

Hydrasec is indicated for symptomatic treatment of acute diarrhea in adults when etiotropic therapy is not possible.

When etiotropic treatment of acute diarrhea is used, racecadotril can be administered as an additional therapy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Racecadotril should not be used in patients who have experienced angioedema during treatment with angiotensin-converting enzyme (ACE) inhibitors (such as captopril, enalapril, lisinopril, perindopril, ramipril).

Interaction with other medicinal products and other forms of interaction.

Angiotensin-converting enzyme inhibitors (such as captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril) may cause angioedema. In the presence of racecadotril, this risk may be increased.

Concomitant administration of racecadotril with loperamide or nitroxoline in humans does not alter the pharmacokinetics of racecadotril.

Special precautions for use.

Precautionary measures during use

Administration of Hydrasec does not alter the usual regimen for restoring fluid balance.

Bloody or purulent stools and fever may indicate either the presence of invasive bacteria as a cause of diarrhea or another serious disease requiring etiological treatment (e.g., with antibiotics) or further investigation. Therefore, racecadotril should not be used in such cases. Racecadotril may be used concomitantly with antibiotics in cases of acute bacterial diarrhea as an additional therapy.

Use of the drug in diarrhea caused by antibiotic treatment or in chronic diarrhea is not recommended due to insufficient data.

Data on the use of the drug in patients with renal or hepatic impairment are limited. Administration of racecadotril to such patients requires caution (see section "Pharmacokinetics").

In cases of prolonged vomiting, the absorption and hence the effectiveness of racecadotril may be reduced.

Warnings

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Skin reactions have been reported during treatment with this drug. In most cases, these reactions are of moderate severity and do not require treatment. However, in some cases, they may be severe and even life-threatening. A causal relationship with racecadotril cannot be completely ruled out. If severe skin reactions occur, treatment must be discontinued immediately.

Hypersensitivity reactions/angioedema have been reported in patients receiving racecadotril. These conditions may occur at any time during treatment. Patients with a history of angioedema unrelated to racecadotril may have an increased risk of developing angioedema.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), have been reported in association with racecadotril treatment, which may be life-threatening or fatal. Patients should be informed about the signs and symptoms and closely monitored for skin reactions. If signs or symptoms suggestive of DRESS syndrome appear, racecadotril must be discontinued immediately, and alternative treatment options should be considered. Re-administration of racecadotril is absolutely contraindicated in patients who have developed DRESS syndrome during previous treatment with racecadotril.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of racecadotril in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryofetal development, delivery, or postnatal development. However, since specific clinical studies have not been conducted, racecadotril should not be used during pregnancy.

Breastfeeding.

Due to insufficient information on the excretion of Hydrasec in breast milk, the drug should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Racecadotril has no effect or has a negligible effect on the ability to drive or operate machinery.

Dosage and Administration

For oral use.

Adults

The initial dose is 1 capsule as a single dose, regardless of time of day. Subsequently, after the initial dose, take 1 capsule three times daily (every 8 hours) for the following days, preferably before main meals. Treatment should continue until two episodes of normal bowel movements have been observed.

The duration of treatment should not exceed 7 consecutive days.

Prolonged treatment with racecadotril is not recommended.

If there is no improvement in condition after 3 days of treatment, consult a physician.

Special patient groups

Children. Specific pharmaceutical forms are available for infants, children, and adolescents.

Elderly patients. Dose adjustment is not required in elderly patients (see section "Pharmacokinetics").

Use with caution in patients with hepatic or renal impairment.

Children.

For children, the medicinal product Hydrasec in granules for oral suspension should be used.

Overdose.

Isolated cases of overdose have been reported without occurrence of adverse reactions. In adults, single doses exceeding 2 g, i.e. 20 times higher than the therapeutic dose, did not cause harmful effects.

Adverse Reactions

Listed below are adverse reactions to the medicinal product observed more frequently in the racecadotril group compared to the placebo group, or reported during the post-marketing period. Adverse reactions are categorized by frequency as follows: 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), and frequency not known (cannot be estimated from the available data).

Serious skin adverse reactions (SSARs), including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), have been reported in association with racecadotril treatment (see section "Special precautions for use").

Disorders of the nervous system

Common: headache.

Disorders of the skin and subcutaneous tissue

Uncommon: rash, erythema.

Frequency not known: polymorphic erythema, tongue swelling, facial swelling, lip swelling, eyelid swelling, angioedema, urticaria, nodular erythema, papular rash, prurigo, itching, toxic skin eruption, drug-induced eosinophilia with systemic symptoms (DRESS syndrome).

Immune system disorders

Frequency not known: anaphylactic shock.

Children

Tonsillitis has been reported as an uncommon adverse reaction in children treated with racecadotril. The medicinal product is available in a special dosage form for this age group.

Serious skin reactions (including angioedema) have been reported in patients treated with racecadotril. The frequency of these reactions is unknown; however, if they occur, treatment with racecadotril should be discontinued and appropriate alternative therapy initiated. In such cases, patients should be informed of the necessity to avoid re-administration of racecadotril.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging. 10 capsules per blister pack. 1 blister pack in a cardboard box.

Availability. Over-the-counter (without prescription).

Manufacturer. Sophartex, France.

Manufacturer's address. 21 rue du Pressoir, 28500 Vernouillet, France.