Loperamide-zdorovya

INSTRUCTION for medical use of the medicinal product LOOPERAMIDE-ZDOROVYE (LOPERAMIDE-ZDOROVYE)

Composition:

Active substance: loperamide;

1 tablet contains loperamide hydrochloride 2 mg;

Excipients: lactose monohydrate, potato starch, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white colored tablets, flat cylindrical shape, with a bevel.

Pharmacotherapeutic group. Antiperistaltic agents. ATC code A07DA03.

Pharmacological properties.

Pharmacodynamics. Loperamide hydrochloride binds to opioid receptors in the intestinal wall. As a result, it inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing the transit time of intestinal contents, as well as enhancing the intestinal wall's ability to absorb fluid. Loperamide hydrochloride increases the tone of the anal sphincter, thus reducing fecal incontinence and the urge to defecate.

Pharmacokinetics.

Absorption: The majority of orally administered loperamide is absorbed from the intestine, but due to extensive first-pass metabolism, systemic bioavailability is only approximately 0.3%.

Distribution: In rats, loperamide has shown high affinity for the intestinal wall, with predominant binding to receptors in the longitudinal muscle layer. Protein binding of loperamide to blood proteins is 95%, mainly to albumin. Loperamide is a substrate for P-glycoprotein.

Metabolism: Loperamide is almost completely extracted by the liver, where it is primarily metabolized, conjugated, and excreted in bile. Oxidative N-demethylation is the main metabolic pathway of loperamide, mediated predominantly by CYP3A4 and CYP2C8 isoenzymes. Due to this extensive first-pass hepatic effect, plasma concentrations of unchanged drug remain very low.

Elimination: The half-life (T½) of loperamide in humans is approximately 11 hours, with a range of 9–14 hours. Excretion of unchanged loperamide and its metabolites occurs primarily via feces.

Pediatric population: Pharmacokinetic studies in pediatric patients have not been conducted. The pharmacokinetic behavior of loperamide and drug interactions with loperamide are expected to be similar to those observed in adults.

Clinical characteristics.

Indications. Symptomatic treatment of acute diarrhoea in adults and children aged 12 years and older.

Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome in adults aged 18 years and older, after initial diagnosis has been established by a physician.

Contraindications. The drug is contraindicated:

• in patients with known hypersensitivity to loperamide hydrochloride or to any component of the drug;
• in children under 12 years of age;
• in patients with acute dysentery characterized by the presence of blood in stools and elevated body temperature;
• in patients with acute ulcerative colitis or antibiotic-associated pseudomembranous colitis;
• in patients with bacterial enterocolitis caused by microorganisms of the genera Salmonella, Shigella, and Campylobacter.

The drug should not be used at all when inhibition of peristalsis should be avoided due to the risk of developing serious complications, including intestinal obstruction, megacolon, and toxic megacolon.

The drug must be discontinued immediately if constipation, abdominal distension, or intestinal obstruction develops.

Interaction with other medicinal products and other forms of interaction. Cases of interaction with medicinal products having similar pharmacological properties have been reported. Medicinal products with central nervous system (CNS) depressant effects should not be used concomitantly with the drug in children.

Loperamide is a substrate of P-glycoprotein. Concomitant administration of loperamide (at a dose of 16 mg) with P-glycoprotein inhibitors (quinidine, ritonavir) resulted in a 2- to 3-fold increase in plasma loperamide concentrations. The clinical significance of this pharmacokinetic interaction when loperamide is used at recommended doses is unknown.

Concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, led to a 3- to 4-fold increase in loperamide plasma concentrations. The CYP2C8 inhibitor gemfibrozil increased loperamide exposure by approximately 2-fold. Combined administration of itraconazole and gemfibrozil resulted in a 4-fold increase in maximum loperamide plasma concentration and a 13-fold increase in total plasma exposure. This increase was not associated with CNS effects as assessed by psychomotor tests (i.e., subjective drowsiness and digit-symbol substitution test).

Concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, led to a 5-fold increase in loperamide plasma concentration. This increase was not associated with increased pharmacodynamic effects as determined by pupillometry.

Concomitant treatment with orally administered desmopressin resulted in a 3-fold increase in desmopressin plasma concentration, likely due to slower gastrointestinal motility.

Medicinal products with similar pharmacological properties are expected to potentiate the effect of loperamide, while medicinal products that accelerate gastrointestinal transit may reduce its efficacy.

Special precautions for use.

Treatment of diarrhoea is symptomatic. If the aetiology of the disease can be determined (or if it is indicated that this should be done), specific treatment should be carried out whenever possible.

In patients with diarrhoea, especially children, debilitated patients, and elderly individuals, dehydration and electrolyte imbalance may occur. In such cases, the most important measure is replacement therapy to replenish fluids and electrolytes.

The use of this medicinal product does not replace the administration of adequate amounts of fluid and restoration of electrolytes.

Since persistent diarrhoea may indicate potentially more serious conditions, the medicinal product should not be used for prolonged periods until the cause of diarrhoea has been investigated.

In acute diarrhoea, if no clinical improvement is observed within 48 hours, administration of loperamide hydrochloride should be discontinued and medical advice sought.

Loperamide must not be used in situations where inhibition of peristalsis should be avoided due to the risk of serious complications such as megacolon and toxic megacolon.

Patients with acquired immunodeficiency syndrome (AIDS) who are taking the medicinal product for diarrhoea must discontinue treatment immediately upon the first signs of abdominal distension. There have been isolated reports of intestinal obstruction with an increased risk of developing toxic megacolon in AIDS patients with infectious colitis of either viral or bacterial origin treated with loperamide hydrochloride.

Abuse or misuse of loperamide as an opioid substitute has been reported in individuals with opioid dependence.

Although pharmacokinetic data in patients with hepatic impairment are lacking, the medicinal product should be used with caution in such patients due to reduced first-pass metabolism. This medicinal product should be prescribed with caution in patients with hepatic impairment, as it may lead to relative overdosage, potentially causing toxic effects on the central nervous system (CNS).

Medicinal products that prolong gastrointestinal transit time may lead to the development of toxic megacolon in patients in this group.

Since loperamide is extensively metabolized and loperamide or its metabolites are excreted in faeces, dose adjustment of loperamide is generally not required in patients with renal impairment.

If a patient is known to have intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Loperamide is not typically associated with significant cardiovascular complications within the therapeutic concentration range. However, when these levels are substantially exceeded (up to 47 times), loperamide has demonstrated cardiovascular complications in in vivo and in vitro animal models, including inhibition of potassium (hERG) and sodium currents, and arrhythmias.

Cases of cardiac events have been reported, including QT interval prolongation, QRS complex widening, and torsades de pointes, following ingestion of loperamide at doses exceeding the recommended dose. Fatal cases have also been reported. Patients must not exceed the recommended dose or duration of treatment.

If the medicinal product is used to control episodes of diarrhoea associated with irritable bowel syndrome (IBS) previously diagnosed by a physician, and no clinical improvement is observed within 48 hours, treatment with loperamide hydrochloride should be discontinued and medical advice sought. Medical consultation is also necessary if the symptom pattern changes or recurrent episodes of diarrhoea persist for more than two weeks.

For the treatment of acute episodes of diarrhoea associated with irritable bowel syndrome, the medicinal product should only be used if the condition has been previously diagnosed by a physician.

The medicinal product should not be used without prior consultation with a physician in the following circumstances, even if the patient is known to have irritable bowel syndrome (IBS):

• patient age is 40 years or older and some time has passed since the last IBS episode;
• patient age is 40 years or older and the current symptoms differ from previous IBS episodes;
• recent gastrointestinal bleeding;
• severe constipation;
• nausea or vomiting;
• loss of appetite or weight loss;
• difficult or painful urination;
• fever;
• recent travel abroad.

If new symptoms develop, existing symptoms worsen, or symptoms do not improve within two weeks, medical advice should be sought.

Use during pregnancy or breastfeeding.

Pregnancy. Despite the absence of data on teratogenic or embryotoxic effects of loperamide hydrochloride, the expected therapeutic benefit should be weighed against potential risks before initiating treatment with loperamide hydrochloride, particularly during the first trimester of pregnancy. This medicinal product is not recommended during pregnancy.

Breastfeeding. Since a small amount of loperamide may be excreted in breast milk, loperamide hydrochloride is not recommended during breastfeeding.

Therefore, pregnant women and women who are breastfeeding should be advised to consult their physician to obtain appropriate treatment.

Ability to affect reaction speed when driving or operating machinery. Increased fatigue, dizziness, or drowsiness may occur during treatment with loperamide hydrochloride, particularly in patients experiencing diarrhoea. Therefore, caution is recommended when driving or operating machinery while taking this medicinal product.

Method of Administration and Dosage.

The product is not intended for initial treatment of severe diarrhea associated with fluid and electrolyte loss. In particular, in children, this loss should preferably be compensated by replacement therapy administered parenterally or orally.

Tablets should be taken with liquid.

Symptomatic treatment of acute diarrhea in adults and children aged 12 years and older. Initial dose: 2 tablets (4 mg), followed by 1 tablet (2 mg) after each subsequent loose stool. The usual daily dose is 3–4 tablets (6–8 mg). The maximum daily dose in acute diarrhea should not exceed 6 tablets (12 mg).

Symptomatic treatment of acute episodes of diarrhea associated with irritable bowel syndrome in adults aged 18 years and older, after initial diagnosis has been established by a physician. Initial dose: 2 tablets (4 mg); thereafter, take 1 tablet (2 mg) after each episode of loose stools or as previously directed by a physician. The maximum daily dose should not exceed 6 tablets (12 mg).

In acute diarrhea, if no clinical improvement is observed within 48 hours, the drug should be discontinued.

Use in elderly patients. Dose adjustment is not required for elderly patients.

Use in renal impairment. Dose adjustment is not required for patients with impaired renal function.

Use in hepatic impairment. Although pharmacokinetic data on the drug in patients with hepatic impairment are lacking, the drug should be administered with caution in such patients due to reduced first-pass metabolism.

Children. The drug is indicated for use in children aged 12 years and older for symptomatic treatment of acute diarrhea.

Overdose.

Symptoms. In cases of overdose (including relative overdose due to hepatic impairment), central nervous system (CNS) depression may occur (stupor, coordination disturbances, drowsiness, miosis, muscular hypertonia, respiratory depression), constipation, urinary retention, and intestinal obstruction.

Children and patients with hepatic impairment may be more sensitive to CNS effects.

When loperamide is used in doses exceeding the recommended dose, cardiac adverse events have been observed, including QT and QRS interval prolongation, torsade de pointes, other serious ventricular arrhythmias, cardiac arrest, and loss of consciousness. Fatal cases have been reported in some instances.

In individuals who intentionally ingested high doses of loperamide (doses reported from 40 to 792 mg per day), cardiac arrest and syncope have been observed. Fatal outcomes have also been documented (see section "Special Warnings and Precautions for Use"). Overdose may unmask underlying Brugada syndrome.

Treatment. In case of overdose, the patient should seek immediate medical attention. If symptoms of overdose occur, naloxone may be used as an antidote. Because the duration of action of loperamide is longer than that of naloxone (1–3 hours), repeated administration of naloxone may be necessary. The patient should remain under close medical supervision for at least 48 hours to monitor for possible CNS depression.

Side effects.

Central nervous system: headache, dizziness, coordination disturbances, loss of consciousness, depressed consciousness, hypertonia, somnolence, stupor.

Gastrointestinal tract: constipation, abdominal distension, nausea, dry mouth, flatulence, abdominal pain and discomfort, vomiting, upper abdominal pain, intestinal obstruction (including paralytic intestinal obstruction), megacolon (including toxic megacolon), frequency unknown — acute pancreatitis.

Skin and subcutaneous tissue: rash, angioneurotic edema, bullous rashes including Stevens-Johnson syndrome, erythema multiforme and Lyell's syndrome, urticaria and pruritus.

Immune system: hypersensitivity reactions, anaphylactic reactions (including anaphylactic shock) and anaphylactoid reactions.

Eye disorders: miosis.

Renal and urinary system: urinary retention.

General disorders: increased fatigue.

Shelf life. 4 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Tablets, 10 pieces, 10×2 in blisters in a box.

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

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and location of business activity. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenko Street, 22.