Loperamide hydrochloride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOPERAMIDE HYDROCHLORIDE (LOPERAMIDI HYDROCHLORIDUM)

Composition:

Active substance: loperamide;

1 capsule contains loperamide hydrochloride 2 mg;

Excipients: lactose monohydrate, magnesium stearate.

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules with dark red body and black cap or with white body and yellow, green or blue cap, with hemispherical ends; capsule contents – almost white powder.

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

Distribution: studies on loperamide distribution in rats show high affinity for the intestinal wall, with predominant binding to receptors in the longitudinal muscle layer. Loperamide protein binding 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 primarily metabolized, conjugated, and excreted via bile. Oxidative N-demethylation is the main metabolic pathway of loperamide, a process mainly mediated 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 in 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, after initial diagnosis has been established by a physician.

Contraindications.

Loperamide hydrochloride is contraindicated:

• in patients with known hypersensitivity to loperamide hydrochloride or to any of the excipients of the product;
• in patients with acute dysentery characterized by the presence of blood in stools and high fever;
• 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.

Loperamide hydrochloride should not be used at all when inhibition of peristalsis must be avoided due to the potential 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 loperamide hydrochloride 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 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. In the same study, gemfibrozil, an inhibitor of CYP2C8, 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 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, resulted in a 5-fold increase in loperamide plasma concentration. This increase was not associated with an increase in pharmacodynamic effects, as assessed by pupillometry.

Concomitant treatment with orally administered desmopressin resulted in a threefold 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 people, dehydration and electrolyte imbalance may occur. In such cases, the most important measure is the use of replacement therapy to restore fluids and electrolytes.

The use of this medicinal product does not replace the administration of an adequate amount of fluid or the 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 the 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 hydrochloride 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 treated with loperamide hydrochloride.

Although pharmacokinetic data in patients with hepatic impairment are lacking, loperamide hydrochloride should be used with caution in such patients due to reduced first-pass metabolism. This medicinal product should be prescribed cautiously to patients with impaired liver function, 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, dosage adjustment of loperamide is generally not required in patients with impaired renal function.

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

If the product is taken to control episodes of diarrhoea caused by 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 last longer than two weeks.

For the treatment of acute episodes of diarrhoea associated with irritable bowel syndrome, loperamide hydrochloride 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 age 40 years or older and some time has passed since the last IBS episode;
• patient age 40 years or older and the current symptoms differ from previous IBS episodes;
• recent gastrointestinal bleeding;
• constipation;
• nausea or vomiting;
• loss of appetite or weight loss;
• difficult or painful urination;
• fever;
• recent travel abroad.

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

Cardiac disorders such as QT and QRS interval prolongation and torsades de pointes tachycardia have been reported in cases of overdose (see section "Overdose"). In some cases, fatal outcomes have been reported. Overdose may unmask an existing Brugada syndrome. Patients must not exceed the recommended dose or the recommended duration of treatment.

Use during pregnancy or breastfeeding

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

Effect on ability to drive and use machines

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

Method of Administration and Dosage

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

Capsules should be taken with liquid.

Symptomatic treatment of acute diarrhea in adults and children aged 12 years and older

Initial dose: 2 capsules (4 mg), followed by 1 capsule (2 mg) after each subsequent loose bowel movement. The usual daily dose is 3–4 capsules (6–8 mg). The maximum daily dose in acute diarrhea should not exceed 6 capsules (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 capsules (4 mg); thereafter, take 1 capsule (2 mg) after each episode of loose stools or as previously directed by a physician. The maximum daily dose should not exceed 6 capsules (12 mg).

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

Use in elderly patients

Dosage adjustment is not required for elderly patients.

Use in patients with renal impairment

Dosage adjustment is not required for patients with renal impairment.

Use in patients with hepatic impairment

Although pharmacokinetic data on the drug in patients with hepatic impairment are lacking, loperamide hydrochloride 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 hepatic impairment), central nervous system depression may occur (stupor, coordination disturbances, drowsiness, miosis, muscular hypertonia, respiratory depression), urinary retention, and a clinical picture resembling intestinal obstruction.

Cardiac adverse events such as QT and QRS interval prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest, and syncope have been reported in patients who overdosed on loperamide hydrochloride (see section "Special Warnings and Precautions for Use"). Fatal outcomes have also been reported. Overdose may unmask underlying Brugada syndrome.

Children may be more sensitive to the central nervous system effects due to the incomplete development of the blood-brain barrier.

Treatment

In case of overdose, immediate medical attention is required. If symptoms of overdose occur, naloxone may be used as an antidote. Since the duration of action of loperamide hydrochloride is longer than that of naloxone (1–3 hours), repeated administration of naloxone may be necessary. The patient should be closely monitored for at least 48 hours to detect possible central nervous system depression.

Adverse Reactions

Adults and children aged 12 years and older

Adverse effects in patients with acute diarrhea

The safety of loperamide hydrochloride was evaluated in 2755 patients aged 12 years and older who participated in 26 controlled and uncontrolled clinical studies on the use of loperamide hydrochloride for the treatment of acute diarrhea. Adverse effects occurring at a frequency of 1% or higher reported in these clinical studies:

Nervous system disorders: headache.

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

Adverse effects occurring at a frequency of less than 1% in the above-mentioned clinical studies:

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 effects have been observed based on spontaneous reporting (listed by frequency of occurrence):

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

Nervous system side effects: very rare – coordination disorders, loss of consciousness, suppression of consciousness, hypertonia, somnolence, stupor.

Eye disorders: very rare – miosis.

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

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

Renal and urinary side effects: very rare – urinary retention.

General disorders: very rare – increased fatigue.

Shelf life. 3 years.

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

Keep out of reach of children.

Packaging.

10 capsules in a blister; 1 or 2 blisters in a cardboard box;

10 capsules in a blister.

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

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and place of business.

41, Kulikovska Street, Kharkiv, Kharkiv region, 61002, Ukraine.