Imodium® duo

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

Composition:

Active substances: loperamide hydrochloride, simethicone;

One tablet contains loperamide hydrochloride 2 mg and simethicone equivalent to 125 mg of polymethylsiloxane;

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, potassium acesulfame, artificial vanilla flavor (containing propylene glycol, maltodextrin and benzyl alcohol), sodium starch glycolate (type A), stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, capsule-shaped tablet with a vanilla odor. The tablet is marked with «IMO» on one side and a line between the numbers «2» and «125» on the other side.

Pharmacotherapeutic group. Antidiarrheal agents; drugs used in the treatment of infectious and inflammatory intestinal diseases. Antiperistaltic agents. Loperamide combinations. ATC code A07D A53.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Loperamide hydrochloride

Loperamide hydrochloride binds to opioid receptors in the intestinal wall, reducing propulsive peristalsis, increasing intestinal transit time, and enhancing absorption of water and electrolytes. Loperamide does not alter the physiological gut microflora. Loperamide increases the tone of the anal sphincter. The medicinal product IMODIUM® DUO has no central effects.

Simethicone

Simethicone is an inert surface-active agent with anti-foaming properties, which potentially alleviates gas-related symptoms associated with diarrhea.

Simethicone is a liquid dimethicone, activated with finely dispersed silicon dioxide to enhance the anti-foaming properties of silicone.

Pharmacokinetics

Absorption

A large portion of orally administered loperamide is absorbed in the intestine; however, due to extensive first-pass metabolism, systemic bioavailability is only approximately 0.3%. The simethicone component of the drug is not absorbed.

Distribution

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

Biotransformation

Loperamide is almost completely extracted by the liver, where it is primarily metabolized, conjugated, and excreted in bile. Oxidative N-demethylation is the main metabolic pathway of loperamide and is mediated predominantly 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, with a range of 9 to 14 hours. Loperamide and its metabolites are primarily excreted unchanged in feces.

Preclinical safety data

In studies of acute and chronic toxicity, loperamide did not show specific toxicity. Results of in vitro and in vivo studies indicate that loperamide is not genotoxic. In reproductive toxicity studies in rats administered very high doses (40 mg/kg/day – 20 times higher than the maximum human dose based on body surface area), loperamide impaired fertility and fetal survival, combined with maternal toxicity. Lower doses had no effect on maternal or fetal health and did not affect peri- and postnatal development.

Preclinical evaluation of loperamide in vitro and in vivo indicates absence of significant cardiac electrophysiological effects within the therapeutic concentration range and even at substantial exceedances of this range (up to 47-fold). However, at extremely high concentrations associated with overdose (see section "Overdose"), loperamide exhibits cardiac electrophysiological effects, including inhibition of potassium (hERG) and sodium currents, leading to arrhythmias.

Simethicone belongs to the class of linear polydimethylsiloxanes, which have been widely used for many years in general and medical practice and are considered biologically inert and non-toxic; therefore, they have not been subjected to specific toxicity studies in animals.

Clinical characteristics.

Indications.

Symptomatic treatment of acute diarrhoea in adults and adolescents aged 12 years and older, when acute diarrhoea is accompanied by gas-related abdominal discomfort, including bloating, cramps, and flatulence.

Contraindications.

IMODIUM® DUO is contraindicated:

• in patients with known hypersensitivity to loperamide hydrochloride, simethicone, or any of the excipients of the medicinal product, to prevent severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme;
• in children under 12 years of age;
• in patients with acute dysentery characterized by the presence of blood in stools and elevated body temperature;
• 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® DUO should not be used at all when inhibition of peristalsis must be avoided, due to the risk of significant 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 that depress the central nervous system (CNS) should not be used concomitantly with IMODIUM® DUO in children.

Preclinical studies have demonstrated that loperamide is a substrate of P-glycoprotein. Concomitant administration of loperamide (16 mg single dose) and quinidine or ritonavir, both P-glycoprotein inhibitors, resulted in a 2–3 fold increase in plasma loperamide concentrations. The clinical significance of this pharmacokinetic interaction with P-glycoprotein inhibitors at recommended doses of loperamide is unknown.

Concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3–4 fold increase in plasma loperamide concentrations. In the same study, gemfibrozil, an inhibitor of CYP2C8, increased loperamide concentrations by approximately 2-fold. Administration of the combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma loperamide concentrations and a 13-fold increase in total plasma exposure. These increases were 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 plasma loperamide concentrations. This increase was not associated with enhanced pharmacodynamic effects, as assessed by pupillometry.

Concomitant oral desmopressin treatment led to a 3-fold increase in plasma desmopressin concentrations, likely due to slowed 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.

Since simethicone is not absorbed from the gastrointestinal tract, significant interactions between simethicone and other medicinal products are not expected.

Interaction studies have been conducted only in adults.

Special precautions for use.

Treatment of diarrhoea is symptomatic. If the aetiology of the disease can be determined, specific therapy should be administered.

In patients with diarrhoea, especially 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 IMODIUM® DUO does not replace the administration of adequate fluid 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 sought.

Loperamide should not be used in situations where inhibition of peristalsis should be avoided due to the risk of serious consequences such as megacolon and toxic megacolon. Patients with acquired immunodeficiency syndrome (AIDS) who are taking IMODIUM® DUO 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 developing toxic megacolon in AIDS patients with infectious colitis of either viral or bacterial origin treated with loperamide hydrochloride.

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

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

The medicinal product 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 both loperamide and its metabolites are excreted in faeces, dosage adjustment is generally not required in patients with renal impairment.

Loperamide is not typically associated with significant cardiovascular complications when used within the therapeutic concentration range. However, substantial overdosing (up to 47 times higher) has been shown to cause cardiovascular complications, including inhibition of potassium (hERG) and sodium currents, and arrhythmias in both in vivo and in vitro animal models.

Cardiovascular complications, including QT prolongation and torsades de pointes, have been reported in association with overdose (see section "Overdose"). Patients must not exceed the recommended dose and/or the recommended duration of treatment.

If the medicinal product is used to control episodes of diarrhoea associated with irritable bowel syndrome (IBS) 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 consultation is also required if the nature of symptoms changes or recurrent diarrhoeal episodes persist for more than two weeks.

For the treatment of acute diarrhoeal episodes associated with IBS, IMODIUM® DUO should only be taken if the syndrome has been previously diagnosed by a physician.

The medicinal product should not be used without prior medical consultation in the following circumstances, even if you have a known history of IBS:

• age 40 years or older and a period of time has passed since the last IBS episode;
• age 40 years or older and current IBS symptoms are different 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, medical advice should be sought.

IMODIUM® DUO should be used with caution in patients with renal or hepatic impairment, during pregnancy, or in breastfeeding women due to the risk of accumulation and toxicity (metabolic acidosis).

Important information on excipients.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet and is therefore considered sodium-free.

IMODIUM® DUO contains benzyl alcohol, which may cause allergic reactions.

This medicinal product contains maltodextrin, which includes glucose. Patients with rare hereditary problems of glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of use in pregnant women has not been established, although studies in animals have not shown teratogenic or embryotoxic effects of loperamide or simethicone. IMODIUM® DUO should not be used during pregnancy, especially during the first trimester, unless clearly clinically justified.

Breastfeeding

A small amount of loperamide may pass into human breast milk. Therefore, the use of IMODIUM® DUO is not recommended during breastfeeding.

Fertility

Effects on human fertility have not been studied.

Ability to affect reaction speed when driving or operating machinery.

IMODIUM® DUO has no effect or only a negligible effect on the ability to drive or operate machinery. However, fatigue, dizziness, and drowsiness may occur during treatment with loperamide hydrochloride for conditions associated with diarrhoea (see section "Adverse reactions"). Therefore, caution is recommended when driving or operating machinery.

Dosage and Administration

Adults aged 18 years and older

Initially take 2 tablets, then 1 tablet after each loose bowel movement. Do not exceed 4 tablets per day for no more than 2 days.

Adolescents aged 12 to 18 years

Initially take 1 tablet, then 1 tablet after each loose bowel movement. Do not exceed 4 tablets per day for no more than 2 days.

Elderly patients

Dosage adjustment is not required for elderly patients.

Patients with renal impairment

Dosage adjustment is not required for patients with renal impairment.

Patients with hepatic impairment

Despite the lack of pharmacokinetic data in patients with hepatic insufficiency, IMODIUM® DUO should be used with caution in such patients due to reduced first-pass metabolism (see section "Special Warnings and Precautions for Use").

Administration method

Swallow tablets whole with water.

Children

This medication is intended for use in children aged 12 years and older.

Overdose

Symptoms

In case of overdose (including relative overdose due to hepatic impairment), central nervous system depression may occur (stupor, coordination disturbances, drowsiness, miosis, increased muscle tone, respiratory depression), dry mouth, abdominal discomfort, nausea and vomiting, constipation, urinary retention, and paralytic ileus. Children and patients with hepatic impairment may be more sensitive to CNS effects.

In patients who have taken an excessive dose of loperamide, cardiac adverse reactions have been observed, such as QT and QRS interval prolongation, torsades de pointes ventricular tachycardia, other serious ventricular arrhythmias, cardiac arrest, and syncope (see section "Special Warnings and Precautions for Use"). Fatal outcomes have also been reported. Overdose may unmask underlying Brugada syndrome.

Treatment

In case of overdose, initiate ECG monitoring immediately. If symptoms of overdose occur, naloxone may be administered as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated naloxone administration may be necessary. Patients should be closely monitored for at least 48 hours for possible CNS depression. Children may be more sensitive to CNS effects than adults.

Adverse Reactions

The safety of the combination of loperamide and simethicone was evaluated in 5 clinical studies involving 2040 patients. All studies with loperamide and simethicone in the form of chewable tablets were conducted in patients with acute diarrhea accompanied by gas-related discomfort. In four studies, loperamide and simethicone were compared with loperamide, simethicone, and placebo, and in one study two dosage forms of loperamide and simethicone were compared with placebo.

The most frequently reported adverse reactions (ARs) (i.e., with a frequency ≥ 1%) in clinical studies were (frequency in percentages): dysgeusia (2.6%) and nausea (1.6%).

The safety of loperamide hydrochloride was evaluated in 26 controlled and uncontrolled clinical studies in the treatment of acute diarrhea involving 2755 patients aged ≥ 12 years. The most frequently reported adverse reactions (> 1%) in these clinical studies were constipation (2.7%), flatulence (1.7%), headache (1.2%), and nausea (1.1%).

The safety of loperamide hydrochloride was also evaluated in 5 controlled and uncontrolled clinical studies in the treatment of chronic diarrhea involving 321 patients. The most frequently reported adverse reactions (> 1%) in these clinical studies were flatulence (2.8%), constipation (2.2%), dizziness (1.2%), and nausea (1.2%).

Children

The safety of loperamide hydrochloride was evaluated in 13 controlled and uncontrolled clinical studies in the treatment of acute diarrhea involving 607 patients aged from 10 days to 13 years. The only AR reported in ≥ 1% of patients receiving loperamide hydrochloride was vomiting.

The table below presents data on ARs reported during clinical studies or in the post-marketing period for the combination of loperamide and simethicone. Additionally, ARs reported during use of loperamide hydrochloride (one of the components of the medicinal product) are also included.

Frequency categories are based on data from clinical studies of the combination of loperamide and simethicone and loperamide hydrochloride separately, and are defined as follows: 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).

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

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

Eye disorders: rare – miosis^a.

Gastrointestinal disorders: common – nausea; uncommon – abdominal pain, abdominal discomfort^b, upper abdominal pain^b, vomiting, constipation, abdominal distension^c, dyspepsia^c, flatulence, dry mouth; rare – intestinal obstruction^a (including paralytic ileus), megacolon^a (including toxic megacolon^d).

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

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

General disorders: uncommon – asthenia; rare – fatigue^a.

^a This reaction was reported during the post-marketing period of loperamide hydrochloride. Since no distinction was made between chronic and acute conditions or between adults and children during the identification of ARs in the post-marketing period, the frequency is assessed based on data from all clinical studies of loperamide hydrochloride overall, including studies involving children aged ≤ 12 years (N = 3683).

^b This reaction was reported in clinical studies of loperamide hydrochloride. The frequency category was determined based on data from clinical studies of loperamide hydrochloride in acute diarrhea (N = 2755).

^c This reaction is known from post-marketing experience with loperamide and simethicone. The frequency category was determined based on data from clinical studies of the combination in acute diarrhea (N = 618). Dizziness and abdominal distension were also identified as ARs in a clinical study of loperamide hydrochloride.

^d See section "Special precautions for use".

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

This medicinal product does not require special storage conditions. Keep out of the reach of children.

Packaging.

6 tablets in a blister; 1 blister in a cardboard pack.

Prescription status. Over-the-counter.

Manufacturer.

JNTL Consumer Health (France) SAS / 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 Ostrizkykh Knyaziv St., Kyiv, 01010, Ukraine.

+38 (044) 498 0888

+38 (044) 498 7392