Imodium

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMODIUM® (IMODIUM®)

Composition:

Active substance: loperamide;

1 capsule contains 2 mg of loperamide hydrochloride;

Excipients: lactose monohydrate, corn starch, talc, magnesium stearate; capsule shell: iron oxide yellow (E 172), iron oxide black (E 172), titanium dioxide (E 171), indigocarmine (E 132), erythrosine (E 127), gelatin.

Pharmaceutical form. Capsules.

Main physico-chemical properties: size 4 capsules with green cap and dark grey body, containing white powder.

Pharmacotherapeutic group. Antidiarrheal agents; drugs used in the treatment of infectious and inflammatory intestinal diseases. Agents inhibiting peristalsis. Loperamide. 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, leading to a reduction in propulsive peristalsis and an increase in the transit time of contents through the gastrointestinal tract, as well as enhancing the intestinal wall's ability to absorb fluid and electrolytes. Loperamide hydrochloride increases the tone of the anal sphincter, thereby reducing fecal incontinence and the urge for defecation.

In a double-blind, randomized clinical study involving 56 patients with acute diarrhea who received loperamide, the onset of antidiarrheal effect was observed within one hour after a single 4 mg dose. Clinical comparisons with other antidiarrheal agents have confirmed the exceptionally rapid onset of action of loperamide.

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: 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. 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, mediated mainly 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 primarily in feces.

Pediatric patients: 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.

Preclinical data

Studies on loperamide treatment in acute and chronic conditions have not revealed specific toxicity. Results from in vivo and in vitro studies showed that loperamide is not genotoxic. In reproductive studies in female rats, administration of very high doses of loperamide (40 mg/kg/day, 20 times the maximum human use level [MHUL], adjusted for body surface area [mg/m²]) impaired fertility and fetal survival. Lower doses (≥10 mg/kg/day, 5 times the MHUL) showed no effect on maternal or fetal health and did not affect peri- and postnatal development.

Non-clinical assessments in vitro and in vivo indicate no significant cardiac complications when loperamide levels are within the therapeutic concentration range, as well as at significantly elevated levels (up to 47 times higher). However, at extremely high concentrations associated with overdose, loperamide exerts electrophysiological effects on the heart and demonstrates cardiac complications: inhibition of potassium (hERG) and sodium currents, and arrhythmias.

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.

Imodium® is contraindicated:

• in patients with known hypersensitivity to loperamide hydrochloride or to any of the excipients of the product;
• 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.

Imodium® should not be used when inhibition of peristalsis needs to be avoided, due to the risk of significant 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 Imodium® 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 levels. The clinical significance of this pharmacokinetic interaction with P-glycoprotein inhibitors 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, resulted in a 3- to 4-fold increase in loperamide plasma concentration. In the same study, gemfibrozil, an inhibitor of CYP2C8, increased loperamide exposure by approximately 2-fold. Combined administration of itraconazole and gemfibrozil led to 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 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 increased 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 with the medicinal product Imodium® is only symptomatic. If the aetiology of the disease can be determined, specific treatment should be administered whenever possible.

The most important measure in acute diarrhoea is prevention or correction of fluid and electrolyte loss. This is particularly important in children, debilitated patients, and elderly individuals with acute diarrhoea.

Use of this medicinal product does not replace the need for administration of adequate fluids and 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 should be sought.

Patients with acquired immunodeficiency syndrome (AIDS) who are taking Imodium® for diarrhoea must immediately discontinue treatment at 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 treated with loperamide hydrochloride.

Although pharmacokinetic data in patients with hepatic impairment are lacking, Imodium® 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.

If the product has been used to control episodes of diarrhoea associated with previously diagnosed irritable bowel syndrome (IBS), and no clinical improvement is observed within 48 hours, loperamide hydrochloride should be discontinued and a physician should be consulted. Medical advice should also be sought if the nature of symptoms changes or if recurrent episodes of diarrhoea persist for more than two weeks.

Cardiac complications, including QT prolongation, QRS complex prolongation, and torsades de pointes, have been reported in association with overdose. Some cases were fatal (see section "Overdose"). Overdose may unmask underlying Brugada syndrome. Patients must not exceed the recommended dose and/or the recommended duration of treatment.

Caution is required in patients with a history of drug abuse. Misuse and abuse of loperamide have been reported (see section "Overdose"). Loperamide is an opioid with low bioavailability and limited potential to cross the blood-brain barrier at therapeutic doses. However, dependence has been observed with opioids as a class.

For treatment of acute episodes of diarrhoea associated with irritable bowel syndrome, Imodium® should only be taken if this condition has been previously diagnosed by a physician.

The product 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;
• painful or difficult urination;
• fever;
• recent travel abroad.

If new symptoms develop, if symptoms worsen, or if symptoms do not improve within two weeks, a physician should be consulted.

Important information on excipients

This medicinal product contains 127 mg of lactose monohydrate per dose. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding

Use during pregnancy

The safety of use during pregnancy in humans has not been established, although animal studies have shown no evidence that loperamide hydrochloride has teratogenic or embryotoxic properties.

As with all medicinal products, use of Imodium® during pregnancy is not recommended, particularly during the first trimester of pregnancy.

Use during breastfeeding

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

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

Fertility

The effect on human fertility has not been evaluated.

Ability to affect reaction speed when driving or operating machinery

Loss of consciousness, depressed level of consciousness, increased fatigue, dizziness or drowsiness may occur during treatment with loperamide hydrochloride, particularly in association with diarrhoea syndrome. Therefore, caution is recommended when driving or operating machinery (see section "Adverse reactions").

Dosage and Administration

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 stool. The usual daily dose is 3–4 capsules (6–8 mg). The total daily dose 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 established by a physician

Initial dose is 2 capsules (4 mg); thereafter, 1 capsule (2 mg) should be taken after each subsequent loose stool or as otherwise directed by a physician. The maximum daily dose should not exceed 6 capsules (12 mg).

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, Imodium® should be administered with caution to such patients due to reduced first-pass metabolism (see section "Special precautions for use").

Administration method

For oral use. Capsules should be taken with liquid.

Children

The drug is indicated for 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, ataxia, drowsiness, miosis, muscle hypertonia, and respiratory depression), constipation, urinary retention, and intestinal obstruction. Children and patients with hepatic impairment may be more sensitive to CNS effects.

Cardiac complications have been reported in individuals who exceeded recommended doses of loperamide: QT interval and QRS complex prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest, and syncope (see section "Special precautions for use").

Fatal outcomes have also been reported. Overdose may unmask an underlying Brugada syndrome.

Treatment

In case of overdose, ECG monitoring should be initiated to detect QT interval prolongation. If CNS 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 required. The patient should remain under close observation for at least 48 hours to monitor for possible CNS depression.

Adverse Reactions.

Adults and children aged 12 years and older

The safety of loperamide hydrochloride was evaluated in 2755 adults and children 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. The most commonly reported adverse effects occurring at a frequency of ≥1%, as observed in these clinical studies, were constipation (2.7%), flatulence (1.7%), headache (1.2%), and nausea (1.1%).

The adverse reactions listed below were observed during clinical trials (acute diarrhea) and post-marketing use of the medicinal product.

The frequency of adverse reactions is categorized using the following conventional categories:

very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated based on available data).

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

Nervous system disorders:
common – headache; uncommon – dizziness, drowsiness; rare – loss of consciousness*, stupor, depression of consciousness*, hypertonia*, coordination disorder*.

Eye disorders:
rare – miosis*.

Gastrointestinal disorders:
common – constipation, abdominal distension, nausea; uncommon – abdominal pain and discomfort, dry mouth, upper abdominal pain, vomiting, dyspepsia*; rare – intestinal obstruction* (including paralytic ileus), megacolon (including toxic megacolon**), sensation of abdominal bloating; frequency not known – acute pancreatitis.

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

Renal and urinary disorders:
rare – urinary retention*.

General disorders:
rare – increased fatigue*.

*These adverse reactions are included based on post-marketing reports of loperamide hydrochloride use. Since post-marketing reports do not allow differentiation between adverse reactions in acute or chronic conditions, or between use in adults or children, the frequency of adverse reactions is estimated based on data from all clinical studies of loperamide hydrochloride, including studies in children under 12 years of age (N = 3683).

**See section "Special precautions for use".

Reporting of Adverse Reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging. 6 or 20 capsules in a blister; 1 blister per cardboard pack.

Prescription status. Over-the-counter (without prescription).

Manufacturer. JNTL Consumer Health (France) SAS.

Manufacturer's address.
Domaine de Maigremont, Val-de-Reuil, 27100, France.

Marketing Authorisation Holder.
McNeil Products Limited.

Address of Marketing Authorisation Holder.
50-100 Holmers Farm Way, High Wycombe, HP12 4EG, England.

Representative of the Marketing Authorisation Holder.
Johnson & Johnson Ukraine LLC.

Address of the Representative.
32/2 Ostrivskykh Knyaziv St., Kyiv, 01010, Ukraine.

+38 (044) 498 0888
+38 (044) 498 7392