Loperamide hydrochloride "oz"

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOPERAMIDE HYDROCHLORIDE "OZ"

Composition:

Active substance: loperamide;

One tablet contains 2 mg of loperamide hydrochloride;

Excipients: lactose monohydrate, corn starch, povidone, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: white tablets with a biconvex surface.

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 for defecation.

Pharmacokinetics.

Absorption: Following oral administration, most of the loperamide is absorbed from the gastrointestinal tract; however, due to extensive first-pass metabolism, systemic bioavailability is only approximately 0.3%.

Distribution: Data from studies on loperamide distribution in rats indicate high affinity for the intestinal wall, with predominant binding to receptors in the longitudinal muscle layer. Protein binding of loperamide is about 95%, primarily to albumin. Loperamide is known to be a substrate of P-glycoprotein.

Metabolism: Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated, and excreted via bile. Oxidative N-demethylation is the main metabolic pathway of loperamide, mediated primarily by CYP3A4 and CYP2C8 isoenzymes. Due to this 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 predominantly in feces.

Pediatric population: Pharmacokinetic studies of the drug 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 medicinal product is contraindicated:

• in patients with known hypersensitivity to loperamide hydrochloride or to any of the excipients;
• in children under 12 years of age;
• in patients with acute dysentery characterized by the presence of blood in stools and high fever;
• 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 hydrochloride should not be used when inhibition of peristalsis must be avoided, due to the risk of developing serious complications, including intestinal obstruction, megacolon, and toxic megacolon.

The medicinal product 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 loperamide in children.

Loperamide is known to be 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.

There are data showing that 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 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 effect.

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, particularly 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 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, 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 increased risk of toxic megacolon in AIDS patients with infectious colitis of either viral or bacterial origin during treatment with loperamide hydrochloride.

Although pharmacokinetic data in patients with hepatic impairment are lacking, this medicinal product should be used with caution in such patients due to reduced first-pass metabolism. This drug should be prescribed cautiously to patients with impaired liver function, as it may lead to relative overdose, potentially causing CNS toxicity.

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 has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

If a patient is taking the medicinal product to control episodes of diarrhoea associated with irritable bowel syndrome 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 treatment of acute episodes of diarrhoea associated with irritable bowel syndrome, the medicinal product should be used only 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 cases, even if you know you have irritable bowel syndrome (IBS):

• patient’s age is 40 years or older and there has been a period of time since the last IBS episode;
• patient’s age is 40 years or older and the current IBS symptoms are different;
• 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, symptoms worsen, or symptoms do not improve within two weeks, medical advice should be sought.

Cardiac adverse events such as QT and QRS interval prolongation, torsades de pointes tachycardia, have been reported in cases of overdose (see section "Overdose"). Fatal cases have also been reported. Overdose may unmask Brugada syndrome. Patients must not exceed the recommended dose or the recommended duration of treatment.

Use during pregnancy or breastfeeding.

It is not recommended to take this medicinal product during pregnancy. Therefore, pregnant women and women who are breastfeeding should be advised to consult their physician for appropriate treatment.

Ability to influence the speed of reactions while driving or operating machinery.

Increased fatigue, dizziness, or drowsiness may occur during treatment with loperamide hydrochloride, particularly in patients with diarrhoea. Therefore, caution is recommended when driving a vehicle or operating machinery.

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 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 stools 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, the medication 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 use of 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 product is indicated for use in children aged 12 years and older for symptomatic treatment of acute diarrhea.

Overdose

Symptoms. In case of overdose (including relative overdose due to impaired liver function), central nervous system depression may occur (stupor, impaired coordination, drowsiness, miosis, increased muscle tone, respiratory depression), urinary retention, and a clinical picture resembling intestinal obstruction.

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

Cardiac adverse events have been observed following overdose with loperamide hydrochloride, such as QT and QRS interval prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest, and loss of consciousness (see section "Special Warnings and Precautions for Use"). Fatal outcomes have also been reported. Overdose may unmask an 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 doses of naloxone may be required. 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 observed in clinical trials with a frequency of 1% or more:

Nervous system disorders: headache.

Gastrointestinal disorders: constipation, abdominal distension, nausea; frequency unknown — acute pancreatitis.

Adverse effects observed in clinical trials 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.

Post-marketing experience

The following adverse reactions have been reported spontaneously.

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

Nervous system disorders: coordination disorders, loss of consciousness, depressed consciousness, hypertonia, somnolence, stupor.

Eye disorders: miosis.

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

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

Renal and urinary disorders: urinary retention.

General disorders: increased fatigue.

Shelf life: 5 years.

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

Keep out of reach and sight of children.

Packaging: Tablets No. 10, No. 10×2, No. 10×3 in blisters in a carton; No. 10 in blisters.

Release category: Over-the-counter.

Manufacturer:

Limited Liability Company "Experimental Plant "GNCLS", or

Limited Liability Company "FARMEKS GROUP", or

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVTYA".

Manufacturer's address and place of business:

8 Vorobiova Street, Kharkiv, Kharkiv Region, Ukraine.

(Limited Liability Company "Experimental Plant "GNCLS")

100 Shevchenka Street, Boryspil, Kyiv Region, 08301, Ukraine.

(Limited Liability Company "FARMEKS GROUP")

22 Shevchenka Street, Kharkiv, Kharkiv Region, 61013, Ukraine.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVTYA")