Organorik

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ORGANORIK® (ORGANORIK®)

Composition:

Active substance: racecadotril;

1 sachet contains 10 mg or 30 mg of racecadotril;

Excipients: sucrose, colloidal anhydrous silicon dioxide, povidone.

Medicinal form: Granules for oral suspension.

Main physicochemical characteristics: white or almost white granules, packed in thermally sealed aluminum sachets.

Pharmacotherapeutic group: Medicinal products affecting the digestive system and metabolism. Other antidiarrheal agents. Racecadotril. ATC code A07X A04.

Pharmacological properties.

Pharmacodynamics.

Racecadotril is a prodrug that requires hydrolysis to form the active metabolite thiorphan, which is an enkephalinase inhibitor. Enkephalinase is a peptidase located in cell membranes of various tissues, particularly in the epithelium of the small intestine. This enzyme promotes both hydrolysis of exogenous peptides and degradation of 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.

In two clinical trials in children, racecadotril reduced stool weight by 40% and 46%, respectively, during the first 48 hours. A significant reduction in the duration of diarrhea and the need for fluid replacement therapy was also observed.

In a meta-analysis of individual patient data (9 randomized clinical trials of racecadotril versus placebo, in addition to oral rehydration solution), individual data from 1384 boys and girls suffering from acute diarrhea of varying severity and treated either in hospital or on an outpatient basis were collected. The mean age was 12 months (interquartile range: 6 to 39 months). Of the total, 714 patients were under 1 year of age and 670 were aged 1 year or older. Mean body weight ranged from 7.4 kg to 12.2 kg across studies. The mean duration of diarrhea after study entry was 2.81 days in the placebo group and 1.75 days in the racecadotril group. The proportion of patients who recovered was higher in the racecadotril groups compared to placebo [risk ratio (RR): 2.04; 95% confidence interval (CI): 1.85 to 2.32; p < 0.001]. Results were very similar in infants (< 1 year) (RR: 2.01; 95% CI: 1.71 to 2.36; p < 0.001) and in preschool-aged children (1–3 years) (RR: 2.16; 95% CI: 1.83 to 2.57; p < 0.001). In hospitalized patients (n = 637), the ratio of mean stool weight in the racecadotril group to mean stool weight in the placebo group was 0.59 (95% CI: 0.51 to 0.74; p < 0.001). In outpatients (n = 695), the ratio of mean stool frequency in the racecadotril group to mean stool frequency 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 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 an oral dose of radiolabeled 14C-racecadotril, the concentration of radioactive carbon isotope measured in plasma was many orders of magnitude higher than in blood cells and three times higher than in total blood volume. Thus, the drug is largely not bound 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 kg. 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 administration 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 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 significantly inhibit the clinically relevant CYP enzyme isoforms 3A4, 2D6, 2C9, 1A2, and 2C19.

Additionally, in vitro data show that racecadotril/thiorphan and the four major inactive metabolites do not clinically significantly induce CYP enzyme isoforms 3A, 2A6, 2B6, 2C9/2C19, 1A, 2E1, or UGT (uridine-5-diphosphate glucuronosyltransferase) conjugating enzymes.

Racecadotril does not affect the 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 impairment (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 30 minutes after administration. No accumulation occurs after multiple doses every 8 hours for 7 days.

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

Clinical characteristics.

Indications.

For adjunctive symptomatic treatment of acute diarrhea in infants (from 3 months of age) and children, in combination with oral rehydration and standard supportive measures, when these measures alone are insufficient to control the clinical condition, and when etiological treatment is not possible.

If etiological treatment is possible, racecadotril may be used as an adjunctive therapy.

Contraindications.

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

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

Due to the presence of sucrose, Organorik® is contraindicated in patients with rare hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

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. This risk is increased in the presence of racecadotril.

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

Special precautions for use

The use of the medicinal product Organorik® does not alter the usual regimen for rehydration.

Restoration of fluid balance is extremely important in the treatment of acute diarrhea in children. When restoring fluid balance and choosing the appropriate rehydration method, the patient's age and body weight, as well as the stage and severity of the condition, must be taken into account—especially in cases of severe or prolonged diarrhea accompanied by significant vomiting or loss of appetite. It is also important to continue regular feeding (including breastfeeding) and to ensure adequate fluid intake.

Bloody or purulent stools and fever may indicate the presence of invasive bacteria as the cause of diarrhea or another serious illness requiring specific (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 adjunctive therapy.

The use of racecadotril in diarrhea induced by antibiotic treatment or in chronic diarrhea is not recommended due to insufficient data.

Patients with diabetes should be aware that each sachet contains:

Organorik®, 10 mg granules — 979.82 mg of sucrose;

Organorik®, 30 mg granules — 2939.45 mg of sucrose.

If the amount of sucrose (a source of glucose and fructose) in the daily dose of Organorik® exceeds 5 g per day, this should be taken into account when calculating daily sugar intake.

The product should not be used in infants under 3 months of age, as clinical studies have not been conducted in this population.

Racecadotril should not be administered to children with any degree of renal or hepatic impairment due to limited information in these patient populations.

Due to the potential for reduced bioavailability, the drug should not be used in cases of prolonged or uncontrolled vomiting.

Skin reactions have been reported during treatment with racecadotril. In most cases, these reactions are mild and do not require treatment. However, in some cases, they may be severe and even life-threatening. A causal relationship with racecadotril cannot be entirely ruled out. Treatment should be discontinued immediately if severe skin reactions occur.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with racecadotril treatment. These reactions may be life-threatening or fatal. Patients should be informed about the signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms suggestive of DRESS occur, racecadotril should be discontinued immediately, and alternative treatment options should be considered. Re-administration of racecadotril is contraindicated in patients who have experienced DRESS during prior treatment.

Hypersensitivity reactions, including angioedema, have been reported in patients treated with racecadotril. These conditions may occur at any time during treatment. Patients with a history of angioedema, even if not related to racecadotril, are at increased risk of developing angioedema.

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 data on the excretion of the medicinal product Evosec into breast milk, it 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

Organorik® should be administered orally together with oral rehydration solutions (see section "Special Instructions").

Organorik®, 10 mg granules, should be administered to children with body weight up to 13 kg.

Organorik®, 30 mg granules, should be administered to children with body weight of 13 kg and above.

The recommended dose is calculated according to body weight: 1.5 mg/kg per dose. This corresponds to 1–2 sachets of the appropriate strength, taken 3 times daily at regular intervals.

Children with body weight up to 9 kg — 1 sachet (10 mg) 3 times daily.

Children with body weight from 9 kg to 13 kg — 2 sachets (10 mg) 3 times daily.

Children with body weight from 13 kg to 27 kg — 1 sachet (30 mg) 3 times daily.

Children with body weight from 27 kg — 2 sachets (30 mg) 3 times daily.

In clinical trials involving children, the duration of treatment was 5 days.

Treatment should be continued until two episodes of normal bowel movements are observed.

The duration of treatment should not exceed 7 days.

Long-term treatment with racecadotril is not recommended.

Clinical studies in children under 3 months of age have not been conducted.

Special patient groups

Studies in infants or children with renal or hepatic impairment have not been conducted (see section "Special Instructions").

The medicinal product should not be administered to children with renal or hepatic impairment.

Organorik® granules may be added to food: dissolve them in a glass of water or in a feeding bottle, mixing well. The preparation should then be administered immediately.

Children

Organorik®, 10 mg granules, is indicated for infants and children aged from 3 months to 2 years.

Organorik®, 30 mg granules, is indicated for children aged 2 years and above.

Overdose

Isolated cases of overdose without occurrence of adverse reactions have been reported in infants and children. The ingested doses were up to 7 times higher than the recommended dose.

In adults, single doses exceeding 2 g, i.e. 20 times higher than the therapeutic dose, did not cause harmful effects.

Adverse Reactions

Serious skin reactions (SSRs), including drug-induced eosinophilia with systemic symptoms (DRESS), have been reported in association with racecadotril treatment (see section "Special Warnings and Precautions for Use").

The adverse reactions listed below were observed during clinical studies more frequently in the racecadotril group than in the placebo group, or were 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), frequency not known (cannot be estimated from available data).

Infections and infestations

Uncommon: tonsillitis.

Skin and subcutaneous tissue disorders

Uncommon: rash, erythema.

Frequency not known: polymorphic erythema, tongue swelling, facial swelling, lip swelling, eyelid swelling, angioneurotic edema, urticaria, nodular erythema, papular rash, prurigo, itching, drug-induced eosinophilia with systemic symptoms (DRESS), anaphylactic shock.

Severe skin reactions (including angioneurotic edema) have been reported in patients treated with racecadotril. The frequency of these reactions is unknown. However, if such reactions occur, treatment with racecadotril should be discontinued and appropriate alternative therapy initiated. Patients should be informed of the necessity to avoid re-administration of racecadotril in such cases.

Shelf life. 3 years.

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

Packaging. 16 sachets in a cardboard box.

Prescription status. Over-the-counter (non-prescription).

Manufacturer. Athena Drug Deliveries Pvt. Ltd.

Manufacturer's address and location of operations. Plot A1-A5, MIDC, Chemical Zone, Ambernath (West), Maharashtra, 421 501, India.