Lopedia

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOPE DIUM® (LOPEDIUM®)

Composition:

Active substance: loperamide hydrochloride;

1 capsule contains loperamide hydrochloride 2 mg;

Excipients: lactose monohydrate, maize starch, talc, magnesium stearate; capsule shell: gelatin, titanium dioxide (E 171), black iron oxide (E 172), yellow iron oxide (E 172), patent blue V (E 131).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules of grey – dark green color, size 3, containing a homogeneous white or almost white powder.

Pharmacotherapeutic group.

Agents inhibiting peristalsis. 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 contents through the gastrointestinal tract, 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: A large portion 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 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 to blood proteins 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 into bile. Oxidative N-demethylation is the main metabolic pathway of loperamide, mediated mainly by CYP3A4 and CYP2C8 isoenzymes. Due to the very extensive first-pass liver 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 patients: Pharmacokinetic studies of loperamide use 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 due to irritable bowel syndrome in adults aged 18 years and older, after initial diagnosis has been established by a physician.

Contraindications.

Hypersensitivity to loperamide hydrochloride or to any of the excipients of the medicinal product.

Children under 12 years of age.

• acute dysentery characterized by the presence of blood in stools and fever;
• acute ulcerative colitis or pseudomembranous colitis associated with the use of broad-spectrum antibiotics;
• bacterial enterocolitis caused by microorganisms of the genera Salmonella, Shigella, Campylobacter.

Lopedium® 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 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 in children.

Preclinical data have shown that loperamide is a substrate of P-glycoprotein. Concomitant administration of loperamide (single dose of 16 mg) with P-glycoprotein inhibitors (quinidine, ritonavir) results in a 2–3-fold increase in plasma loperamide levels. The clinical significance of this pharmacokinetic interaction when loperamide is used at recommended therapeutic doses (2 to 16 mg) is unknown.

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

Concomitant administration of loperamide (single dose of 16 mg) 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 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 drugs 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 the medicinal product does not replace the administration of an adequate amount of fluid or the restoration of electrolyte balance.

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.

Loperamide should 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 Lopedium® for diarrhoea should 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 both viral and bacterial origin treated with loperamide hydrochloride.

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

Pharmacokinetic data on the use of the drug in patients with impaired liver function are lacking; however, loperamide should be used with caution in such patients due to reduced first-pass metabolism, which may lead to relative overdosage and potentially cause central nervous system (CNS) toxicity.

The drug should be used with caution in patients experiencing an exacerbation of ulcerative colitis. 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 excreted in faeces together with its metabolites, dose adjustment is generally not required in patients with impaired renal function.

The product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Loperamide is not associated with significant cardiovascular complications within the therapeutic concentration range. However, at substantial overdoses (up to 47 times higher), loperamide has demonstrated cardiovascular complications in animal models in vivo and in vitro, including inhibition of potassium (hERG) and sodium currents, and arrhythmias.

Cardiac disturbances, including QT and QRS interval prolongation and torsade de pointes, have been reported following overdosage. Fatal outcomes have also been reported—see section "Overdose". Overdose may unmask pre-existing Brugada syndrome. Patients must not exceed the recommended dose or duration of treatment.

If the drug is used to control episodes of diarrhoea associated with irritable bowel syndrome previously diagnosed by a physician, and no clinical improvement is observed within 48 hours, 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, Lopedium® should only be taken if the condition has been previously diagnosed by a physician.

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

• patient aged 40 years or older and some time has passed since the last IBS episode;
• patient aged 40 years or older and current IBS symptoms differ from previous ones;
• 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, if symptoms worsen, or if symptoms do not improve within two weeks, medical advice should be sought.

Use during pregnancy or breastfeeding.

Use during pregnancy.

Despite the absence of data on teratogenic or embryotoxic properties of loperamide hydrochloride, the expected therapeutic benefit should be weighed against potential risks before initiating treatment with loperamide hydrochloride, especially during the first trimester of pregnancy. The use of this medicinal product during pregnancy is not recommended.

Use during breastfeeding.

Since a small amount of loperamide may pass into breast milk, the use of the drug during breastfeeding is not recommended.

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

Effects on ability to drive and use machines.

Fatigue, dizziness, or somnolence 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

Lopedium® 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 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 the physician. The maximum daily dose should not exceed 6 capsules (12 mg).

In acute diarrhea, if no clinical improvement is observed within 48 hours, Lopedium® 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.

Pharmacokinetic data on the effect of the drug in patients with hepatic impairment are lacking; however, 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 case of overdose (including relative overdose due to hepatic dysfunction), central nervous system (CNS) depression may occur (stupor, impaired coordination, drowsiness, miosis, increased muscle tone, respiratory depression, constipation, urinary retention, and a clinical picture resembling intestinal obstruction). Children and patients with hepatic dysfunction may be more sensitive to CNS effects.

Cardiac abnormalities have been observed in individuals with loperamide hydrochloride overdose, including QT and QRS interval prolongation, torsade de pointes, other serious ventricular arrhythmias, cardiac arrest, and syncope. Fatal outcomes have been reported. Overdose may unmask Brugada syndrome.

In individuals who intentionally ingested higher doses of loperamide (doses reported from 40 to 792 mg per day), cardiac arrest and syncope have been observed. Fatal cases have also been documented (see section "Special Warnings and Precautions for Use").

Treatment. In case of overdose, immediate medical attention is required. In the event of overdose symptoms, naloxone may be used as an antidote. Since 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.

Adverse reactions.

Nervous system disorders: headache, dizziness, somnolence, stupor, depression or loss of consciousness, hypertension, coordination disorders, tremor.

Gastrointestinal disorders: nausea, constipation, flatulence, abdominal pain, dry mouth, vomiting, dyspepsia, glossalgia, bloating, intestinal obstruction, including paralytic ileus; megacolon, including toxic megacolon, upper abdominal pain, acute pancreatitis in patients with history of cholecystectomy, acute pancreatitis.

Renal and urinary disorders: urinary retention.

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

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

Eye disorders: miosis.

General disorders: increased fatigue.

Shelf life. 5 years.

Storage conditions.

Store at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

6 or 10 capsules in a blister; 1 (6 × 1) or (10 × 1) blister in a cardboard box.

Availability. Over-the-counter.

Manufacturers.

1. Sandoz GmbH (bulk manufacturing, packaging, batch release).
2. Lek S.A. (packaging, batch release).
3. Sandoz S.r.l. (full-cycle manufacturing).

Manufacturer's address and location of operations.

1. Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.
2. Domaniewska Street 50C, Warsaw, 02-672, Poland.
3. Livezeni Street, No. 7A, 540472 Târgu Mureș, Mureș County, Romania.