LOPERAMIDE

INSTRUCTIONS for medical use of the medicinal product loperamide (loperamide)

Composition:

Active substance: loperamide;

1 tablet contains loperamide hydrochloride 0.002 g;

Excipients: lactose monohydrate, maize starch, magnesium stearate, stearic acid, povidone.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets from white to white with a yellowish tint.

Pharmacotherapeutic group. Antiperistaltic agents.

ATC code A07D A03.

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, thereby reducing fecal incontinence and the urge to defecate.

Pharmacokinetics.

Absorption: a large portion of orally administered loperamide is absorbed in the intestine, but due to extensive first-pass metabolism, systemic bioavailability is approximately 0.3%.

Distribution: studies on the distribution of loperamide in rats show high affinity for the intestinal wall, with predominant binding to receptors in the longitudinal muscle layer. Protein binding of loperamide is 95%, primarily to albumin. Preclinical data indicate that loperamide is a substrate for P-glycoprotein.

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

Elimination: the elimination half-life 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 populations have not been conducted. It is expected that the pharmacokinetics of loperamide and drug interactions with loperamide will 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.

Loperamide is contraindicated:

• in patients with hypersensitivity to loperamide hydrochloride or to any of the excipients;
• in patients with acute dysentery characterized by the presence of blood in stools and elevated body temperature;
• in patients with acute ulcerative colitis or pseudomembranous colitis associated with the use of broad-spectrum antibiotics;
• in patients with bacterial enterocolitis caused by microorganisms of the genera Salmonella, Shigella, and Campylobacter.

Loperamide should not be used at all when inhibition of peristalsis must 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 that depress the central nervous system (CNS) should not be used concomitantly with Loperamide in children.

Preclinical data indicate that 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 concentrations of loperamide. 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. In the same study, the CYP2C8 inhibitor gemfibrozil increased loperamide exposure by approximately 2-fold. Combined administration of itraconazole and gemfibrozil resulted in a 4-fold increase in the maximum plasma concentration of loperamide and a 13-fold increase in total plasma exposure. This increase was not associated with effects on the central nervous system (CNS), as assessed by psychomotor tests (i.e., subjective drowsiness and the 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 concentrations. This increase was not associated with an increase in pharmacodynamic effects, as assessed 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 in 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 need for adequate fluid intake and restoration of electrolytes.

Since persistent diarrhoea may indicate more serious conditions, this 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, treatment with loperamide hydrochloride should be discontinued and medical advice sought.

Patients with acquired immunodeficiency syndrome (AIDS) who are taking loperamide 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 toxic megacolon in AIDS patients with infectious colitis of both viral and bacterial origin during treatment with loperamide hydrochloride.

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

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 the unchanged substance or metabolites are excreted in faeces, dose adjustment of loperamide is generally not required in patients with impaired renal function.

As the product contains lactose, it should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Cardiac complications, including prolongation of the QT and QRS intervals, and torsade de pointes, have been reported in association with overdosage. Some cases were fatal (see section "Overdose"). Overdose may unmask an existing Brugada syndrome. Patients must not exceed the recommended dose and/or the recommended 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 advice should also be sought if the nature of symptoms changes or if recurrent episodes of diarrhoea persist for more than two weeks.

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

The product should not be used without prior consultation with a physician in the following cases, even if you know you have irritable bowel syndrome (IBS):

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

This medicinal product is not recommended during pregnancy. Pregnant women and those who are breastfeeding should consult their physician to obtain appropriate treatment.

Effect on ability to drive vehicles or operate machinery

Increased fatigue, dizziness, or somnolence may occur during treatment with loperamide hydrochloride. Therefore, caution is recommended when driving vehicles or operating machinery while taking this medicinal product.

Method of Administration and Dosage

Loperamide is not intended for the initial treatment of severe diarrhea accompanied by fluid and electrolyte depletion. In particular, in children, this loss should preferably be corrected by parenteral or oral replacement therapy.

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 loose bowel movement. 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 due to irritable bowel syndrome in adults (aged 18 years and older), after initial diagnosis has been established by a physician.

Initial dose is 2 tablets (4 mg); thereafter, take 1 tablet (2 mg) after each episode of loose stool or as previously directed by the physician. The maximum daily dose should not exceed 6 tablets (12 mg).

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

Use in elderly patients.

Dosage adjustment is not required for elderly patients.

Use in renal impairment.

Dosage adjustment is not required for patients with impaired renal function.

Use in hepatic impairment.

Although pharmacokinetic data on the use of loperamide in patients with impaired liver function are lacking, loperamide should be administered with caution in such patients due to reduced first-pass metabolism (see section "Special Warnings and Precautions for Use").

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 impaired liver function), central nervous system depression may occur (e.g., stupor, coordination disturbances, drowsiness, miosis, muscle hypertonia, respiratory depression), urinary retention, and a clinical picture resembling intestinal obstruction.

Children may be more sensitive to the central nervous system effects.

In patients who have exceeded the recommended loperamide dosage, QT and QRS interval prolongation, torsade de pointes, other serious ventricular arrhythmias, cardiac arrest, and syncope have been reported. Fatal outcomes have also been documented (see section "Special Warnings and Precautions for Use"). Overdose may unmask an underlying Brugada syndrome.

Treatment.

In case of overdose, immediate medical attention is required. 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 central nervous system depression.

Adverse Reactions

Adults and children aged 12 years and older.

Adverse effects in patients with acute diarrhea.

Adverse effects occurring with a frequency of 1% or more:

Nervous system disorders: headache.

Gastrointestinal disorders: constipation, abdominal distension, nausea.

Adverse effects occurring with a frequency of less than 1%:

Nervous system disorders: dizziness.

Gastrointestinal disorders: dry mouth, flatulence, abdominal pain and discomfort, vomiting, upper abdominal pain, dyspepsia.

Skin and subcutaneous tissue disorders: rash.

Adverse effects reported with "unknown" frequency:

Gastrointestinal disorders: acute pancreatitis.

Post-marketing experience.

The following adverse reactions have been reported spontaneously after product launch. Frequency categories are defined as follows:

very common (≥1/10);

common (≥1/100, <1/10);

uncommon (≥1/1000, <1/100);

rare (≥1/10,000, <1/1000);

very rare (<1/10,000), including isolated case reports.

Immune system disorders: very rare – hypersensitivity reactions, anaphylactic reactions (including anaphylactic shock), and anaphylactoid reactions.

Nervous system disorders: very rare – coordination disorders, loss of consciousness, depressed level of consciousness, hypertonia, somnolence, stupor.

Eye disorders: very rare – miosis.

Gastrointestinal disorders: very rare – intestinal obstruction (including paralytic ileus), megacolon (including toxic megacolon).

Skin and subcutaneous tissue disorders: very rare – angioneurotic edema, bullous rashes, including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis, urticaria, and pruritus.

Renal and urinary disorders: very rare – urinary retention.

General disorders: very rare – increased fatigue.

Shelf life. 5 years.

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

Keep out of reach and sight of children.

Packaging. 10 tablets per blister; 1, 2, 50, or 100 blisters per carton.

Prescription status. Over-the-counter – No. 10, No. 20. Prescription only – No. 500, No. 1000.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv". PJSC "Tekhnolog".

Manufacturer's address and location of operations:

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.

8 Stara Prorizna Street, Uman, Cherkasy Oblast, 20300, Ukraine.