Imodium express

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMODIUM® EXPRESS (IMODIUM® EXPRESS)

Composition:

Active substance: loperamide hydrochloride;

1 tablet contains 2 mg of loperamide hydrochloride;

Excipients: gelatin, mannite (E 421), aspartame (E 951), peppermint flavour (contains traces of sulphites), sodium bicarbonate.

Pharmaceutical form.

Orodispersible tablets.

Main physico-chemical properties: round, lyophilized tablets, white to almost white in colour.

Pharmacotherapeutic group.

Antidiarrheal agents; drugs used in the treatment of infectious and inflammatory intestinal diseases. Peristalsis inhibitors. Loperamide. ATC code A07D A03.

Pharmacological properties.

Pharmacodynamics.

Loperamide binds to opioid receptors in the intestinal wall, reducing propulsive peristalsis, increasing intestinal transit time, and improving absorption of water and electrolytes. Loperamide increases the tone of the anal sphincter, which helps reduce 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. After oral administration, most of loperamide is absorbed in the intestine, but due to extensive first-pass metabolism, systemic bioavailability is only approximately 0.3%.

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

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

Elimination. The elimination half-life of loperamide in humans is approximately 11 hours (range 9–14 hours). Excretion of unchanged loperamide and its metabolites occurs predominantly in feces.

Preclinical data.

Studies on loperamide treatment in acute and chronic conditions revealed no specific toxicity. Results of 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, which is 20 times the maximum human dose on a body surface area basis [mg/m²]) resulted in impaired fertility and fetal survival. Lower doses (≥10 mg/kg/day, which is 5 times the maximum human dose) 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 absence of significant cardiac complications when loperamide concentrations are within the therapeutic range, as well as with substantial exceedance of these levels (up to 47 times). 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® Express 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 Salmonella, Shigella, and Campylobacter species.

Imodium® Express should not be used at all when inhibition of peristalsis must be avoided due to the potential risk of serious complications, including intestinal obstruction, megacolon, and toxic megacolon.

The use of 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 that depress the central nervous system (CNS) should not be used concomitantly with Imodium® Express 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) 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 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 loperamide 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 the 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 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, specific therapy should be initiated.

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

Use of Imodium® Express does not replace the need for adequate fluid intake and electrolyte replacement.

Since persistent diarrhoea may indicate potentially more serious conditions, the medicinal product should not be used for prolonged periods until the underlying cause of diarrhoea has been investigated.

In acute diarrhoea, if clinical improvement is not observed within 48 hours, treatment with loperamide hydrochloride should be discontinued and medical advice sought.

Patients with acquired immunodeficiency syndrome (AIDS) who take Imodium® Express for diarrhoea should 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 both viral and bacterial origin treated with loperamide hydrochloride.

Although pharmacokinetic data in patients with hepatic impairment are lacking, Imodium® Express should be used with caution in such patients due to reduced first-pass metabolism. Patients with impaired liver function should be closely monitored for early signs of CNS toxicity.

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 a physician consulted. A physician should also be consulted 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 (see section "Overdose"). Some cases have been fatal. Overdose may unmask underlying Brugada syndrome. Patients must not exceed the recommended dose or duration of treatment.

Caution is necessary 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 is observed with opioids as a class.

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

The following situations require prior consultation with a physician before using the drug, even if you know you have irritable bowel syndrome (IBS):

• age 40 years or older and a period has passed since the last IBS episode;
• age 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, existing symptoms worsen, or symptoms do not improve within two weeks, a physician should be consulted.

Important information on excipients

Peppermint flavour contains sulfites, which may rarely cause hypersensitivity reactions and bronchospasm. Reactions similar to allergic rhinitis, urticaria, and anaphylaxis may occur.

Mannitol (E 421) may have a mild laxative effect.

Aspartame (E 951) is a phenylalanine derivative and poses a risk for patients with phenylketonuria.

Use during pregnancy or breastfeeding

Pregnancy

The safety of using the drug during pregnancy has not been established, although animal studies have not shown teratogenic or embryotoxic effects of loperamide hydrochloride. As with other medicinal products, loperamide use during pregnancy is not recommended, especially during the first trimester.

Breastfeeding period

A small amount of loperamide may appear in breast milk. Therefore, loperamide is not recommended during breastfeeding.

Pregnant women and those who are breastfeeding should be advised to consult a physician for appropriate treatment.

Fertility

The effect on human fertility has not been evaluated.

Ability to affect reaction speed when driving vehicles or operating machinery.

Due to the possible occurrence of loss of consciousness, impaired consciousness, fatigue, dizziness, or drowsiness in diarrhoea syndrome, driving vehicles or operating complex machinery is not recommended during treatment with loperamide hydrochloride (see section "Adverse reactions").

Method of Administration and Dosage

Place the orally disintegrating tablet on the tongue. The tablet will dissolve and should be swallowed together with saliva. There is no need to take water with the orally disintegrating tablet.

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

Initial dose: 2 tablets (4 mg). Thereafter, 1 tablet (2 mg) after each loose stool. The usual daily dose is 3–4 tablets (6–8 mg). The maximum daily dose should not exceed 6 tablets (12 mg). In cases of acute diarrhea, if there is no clinical improvement within 48 hours, the medication should be discontinued.

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.

Adults (aged 18 years and older):

Initial dose: 2 tablets (4 mg). Thereafter, 1 tablet (2 mg) after each loose stool or as otherwise directed by the physician. The maximum daily dose should not exceed 6 tablets (12 mg).

Elderly patients

Dose adjustment is not required for elderly patients.

Renal impairment

Dose adjustment is not required for patients with renal impairment.

Hepatic impairment

Although pharmacokinetic data in patients with hepatic impairment are lacking, Imodium® Express should be used with caution in such patients due to reduced first-pass metabolism (see section "Special Warnings and Precautions").

Method of administration

For oral use. Allow the tablet to dissolve on the tongue and then swallow the medication.

Children

This medicinal product 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 (CNS) depression may occur (e.g., stupor, impaired coordination, drowsiness, miosis, muscular hypertonia, and respiratory depression), as well as constipation, urinary retention, and intestinal obstruction. Children and patients with hepatic impairment may be more sensitive to CNS effects.

Cardiac complications have been observed in individuals who have exceeded recommended doses of loperamide, including QT interval prolongation, QRS complex widening, torsades de pointes (twisting of the points), other serious ventricular arrhythmias, cardiac arrest, and syncope (see section "Special Warnings and Precautions"). Fatal outcomes have also been reported. Overdose may unmask underlying Brugada syndrome.

Treatment

In case of overdose, initiate ECG monitoring 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 is longer than that of naloxone (1–3 hours), repeated administration of naloxone may be necessary. Therefore, patients should be carefully monitored for at least the first 48 hours to detect 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 who participated in 26 controlled and uncontrolled clinical trials of loperamide hydrochloride for the treatment of acute diarrhea.

The most commonly reported (i.e., ≥1% of cases) adverse reactions (ADRs) in clinical trials of loperamide hydrochloride for acute diarrhea were: constipation (2.7%), flatulence (1.7%), headache (1.2%), and nausea (1.1%).

Listed below are adverse reactions reported during clinical trials (acute diarrhea) or following marketing of loperamide hydrochloride.

Adverse effects reported spontaneously, categorized by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated based on available data).

Immune system disorders: Rare – hypersensitivity reactions^a, anaphylactic reactions (including anaphylactic shock)^a, and anaphylactoid reactions^a.

Nervous system disorders: Common – headache; uncommon – dizziness, somnolence^a; rare – loss of consciousness^a, stupor, depression of consciousness^a, hypertonia^a, coordination disorder^a.

Eye disorders: Rare – miosis^a.

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

Skin and subcutaneous tissue disorders: Uncommon – rash; rare – angioedema, bullous eruptions^a (including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis), urticaria^a, pruritus.

Renal and urinary disorders: Rare – urinary retention^a.

General disorders: Rare – increased fatigue^a.

^a These adverse reactions are included based on post-marketing reports of loperamide hydrochloride use. Since post-marketing reports do not allow differentiation between reactions occurring in acute or chronic conditions, or between use in adults or children, the frequency of adverse reactions was assessed based on data from all clinical trials of loperamide hydrochloride, including studies involving children aged ≤12 years (N = 3683).

^b See section "Special precautions for use".

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare 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: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

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

Packaging. 6 tablets in a blister pack, 1 blister pack in a cardboard box.

Category of supply. Over-the-counter (without prescription).

Manufacturer.

Manufacturing, primary packaging, and finished product quality control:

Catalent UK Swindon Zydis Limited

Secondary packaging, finished product quality control, batch release:

JNTL Consumer Health (France) SAS

Manufacturer's location and address of its operating site.

Manufacturing, primary packaging, and finished product quality control:

Frankland Road, Blagrove, Swindon, Wiltshire, SN5 8RU, United Kingdom

Secondary packaging, finished product quality control, batch release:

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

Local Representative of the Marketing Authorisation Holder:

Johnson & Johnson Ukraine LLC

Address of the local representative:

32/2 Ostrizkykh Knyaziv Street, Kyiv, 01010, Ukraine

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