Stopperan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STOPERAN (STOPERAN®)

Composition:

Active substance: loperamide;

1 capsule contains 2 mg of loperamide hydrochloride;

Excipients: lactose monohydrate, maize starch, talc, magnesium stearate;
Capsule shell: gelatin, quinoline yellow (E 104), erythrosine (E 127), patent blue V (E 131), titanium dioxide (E 171).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules with a grey body and a blue cap.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Loperamide hydrochloride binds to opioid receptors in the intestinal wall. As a result, the release of acetylcholine and prostaglandins is reduced, leading to decreased propulsive peristalsis and increased transit time of intestinal contents, as well as enhanced fluid absorption by the intestinal wall. Loperamide hydrochloride increases the tone of the anal sphincter, thereby reducing fecal incontinence and defecation urges.

Pharmacokinetics.

Absorption. The majority of orally administered loperamide is absorbed from the intestine; however, due to extensive first-pass metabolism, systemic bioavailability is 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%, mainly 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 primarily by CYP3A4 and CYP2C8 isoenzymes. Due to this extensive first-pass effect in the liver, 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 predominantly in feces.

Pediatric population. Pharmacokinetic studies in pediatric patients have not been conducted. It is expected that the pharmacokinetic behavior of loperamide and drug interactions with loperamide will 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 (IBS) in adult patients after initial diagnosis has been established by a physician.

Contraindications.

• Known 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 high fever.
• Acute ulcerative colitis or antibiotic-associated pseudomembranous colitis.
• Bacterial enterocolitis caused by microorganisms of the genera Salmonella, Shigella, Campylobacter.

Stopan 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 use of the medicinal product must be discontinued immediately if constipation, abdominal distension, or intestinal obstruction develops.

The medicinal product should not be administered to patients with rare hereditary forms of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

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 Stopan in children.

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 when loperamide is used at recommended doses (from 2 mg to 16 mg) 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 concentration. In the same study, the CYP2C8 inhibitor gemfibrozil increased loperamide levels 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 CNS effects 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, 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 administration 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 enhance 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 Stoperan is purely symptomatic. If the underlying cause of the disease can be identified (or if it is indicated that this should be done), specific treatment should be administered whenever possible.

The most important measure in acute diarrhoea is prevention or correction of fluid and electrolyte loss. Dehydration and electrolyte imbalance may develop in patients with acute diarrhoea, particularly in children, debilitated patients, and elderly individuals. In such cases, replacement therapy to restore fluids and electrolytes is essential.

Use of this medicinal product does not replace the need for adequate fluid intake and electrolyte replenishment.

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.

Patients with acquired immunodeficiency syndrome (AIDS) who are taking Stoperan 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 either viral or bacterial origin during treatment with loperamide hydrochloride.

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

This medicinal product should be prescribed with caution in patients with impaired liver function, as reduced first-pass metabolism may lead to relative overdosage, potentially causing central nervous system (CNS) toxicity.

Medicinal products that prolong gastrointestinal transit time may lead to the development of toxic megacolon in patients in this group. Loperamide is contraindicated in situations where inhibition of peristalsis should be avoided due to the risk of serious complications such as megacolon and toxic megacolon.

Loperamide is not typically associated with significant cardiac complications within the therapeutic concentration range. However, when these levels are substantially exceeded (up to 47 times), loperamide has demonstrated cardiac complications, including inhibition of potassium (hERG) and sodium currents, and arrhythmias in both in vivo and in vitro animal models.

Cardiac complications, including QT prolongation and torsades de pointes, have been reported in association with overdose. Fatal cases have also been documented. Overdose may unmask underlying Brugada syndrome. Patients must not exceed the recommended dose or duration of treatment.

Since loperamide is extensively metabolized and both loperamide and its metabolites are excreted in faeces, dose adjustment of loperamide is generally not required in patients with impaired renal function.

As the product contains lactose, it should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

If the 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 necessary if the symptom pattern changes or recurrent diarrhoeal episodes persist for more than two weeks.

For the treatment of acute episodes of IBS-related diarrhoea, Stoperan should only be used if the condition has been previously diagnosed by a physician.

The product should not be used without prior medical consultation in the following cases, even if IBS has been previously diagnosed:

• patient age 40 years or older and some time has passed since the last IBS episode;
• patient age 40 years or older and current IBS symptoms differ from previous episodes;
• 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, medical advice should be sought.

Use during pregnancy or breastfeeding

Pregnancy

The safety of using this medicinal product during pregnancy in humans has not been established. However, animal studies have shown no evidence of teratogenic or embryotoxic effects of loperamide hydrochloride.

As with all medicinal products, Stoperan is not recommended during pregnancy, particularly during the first trimester.

Breastfeeding

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

Therefore, pregnant women and women 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 in patients with diarrhoea syndrome during treatment with loperamide hydrochloride. Therefore, caution is advised when driving or operating machinery while taking this medicinal product.

Dosage and Administration

Stoporan is not intended for initial treatment of severe diarrhea accompanied by fluid and electrolyte loss. In particular, in children, this loss should preferably be compensated by replacement therapy administered parenterally or orally.

The 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). Thereafter, 1 capsule (2 mg) after each subsequent loose stool. 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 IBS in adults aged 18 years and older, after initial diagnosis has been established by a physician

Initial dose: 2 capsules (4 mg). Thereafter, 1 capsule (2 mg) should be taken after each episode of loose stools or according to prior physician recommendations. The maximum daily dose should not exceed 6 capsules (12 mg).

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

Use in elderly patients

Dose adjustment is not required for elderly patients.

Use in renal impairment

Dose adjustment is not required for patients with renal impairment.

Use in hepatic impairment

Although pharmacokinetic data on the drug’s effects in patients with hepatic impairment are lacking, Stoporan should be used with caution in such patients due to reduced first-pass metabolism.

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 impaired liver function), central nervous system (CNS) depression may occur (e.g., stupor, coordination disturbances, drowsiness, miosis, muscle rigidity, respiratory depression), as well as constipation, urinary retention, and a clinical picture resembling intestinal obstruction. Children and adult patients with hepatic impairment are more sensitive to CNS effects due to incomplete blood-brain barrier function.

In patients who have exceeded recommended loperamide doses, QT and QRS interval prolongation on electrocardiogram, other serious ventricular arrhythmias including torsades de pointes, cardiac arrest, and syncope have been reported. Fatal outcomes have also been documented.

Abuse, misuse, and/or intentional overdose with excessively high doses of loperamide may lead to Brugada syndrome.

Treatment

In case of overdose, immediate medical attention is required. QT interval monitoring should be initiated promptly. If CNS symptoms of overdose occur, naloxone may be used as an antidote. Because the duration of action of loperamide is longer than that of naloxone (1–3 hours), repeated doses of naloxone may be necessary. To detect possible CNS depression, the patient should remain under close medical supervision for at least 48 hours. Symptomatic treatment should also be administered (e.g., gastric lavage, activated charcoal).

Adverse Reactions.

Adults and children aged 12 years and older

Adverse reactions in patients with acute diarrhea

Adverse effects reported to occur at a frequency of 1% or higher in patients treated with loperamide hydrochloride and in patients receiving placebo: constipation, nausea, headache.

Adverse effects reported more frequently in patients receiving placebo compared to those treated with loperamide hydrochloride, occurring at a frequency of 1% or higher: dry mouth, flatulence, abdominal cramps and colic, abdominal pain and discomfort, vomiting, dyspepsia, dizziness, rash.

Adverse reactions in patients with chronic diarrhea

Adverse reactions occurring at a frequency of 1% or higher reported to commonly occur in patients treated with loperamide hydrochloride and in patients receiving placebo: constipation and dizziness.

Adverse effects occurring at a frequency of 1% or higher reported more frequently in patients receiving placebo compared to those treated with loperamide hydrochloride: dizziness, nausea, vomiting, headache, bloating sensation, stomach pain, abdominal cramps and colic.

Adverse effects observed in 76 controlled and uncontrolled studies in patients with acute or chronic diarrhea, occurring at a frequency of 1% or higher in patients across all studies: nausea, constipation, and abdominal cramps.

Post-marketing experience

The following adverse effects of loperamide have been reported spontaneously (listed by frequency of occurrence):

very common (≥1/10);
common (≥1/100, <1/10);
uncommon (≥1/1000, <1/100);
rare (≥1/10000, <1/1000);
very rare (<1/10000).

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

Nervous system disorders: common – headache; uncommon – dizziness, somnolence; rare – coordination disorders^a, loss of consciousness^a, depression of consciousness^a, arterial hypertension^a, stupor.

Eye disorders: rare – miosis^a.

Gastrointestinal disorders: common – constipation, abdominal distension, nausea; uncommon – abdominal pain and discomfort, dry mouth, upper abdominal pain, vomiting, dyspepsia; rare – intestinal obstruction^a (including paralytic ileus), megacolon (including toxic megacolon^b), sensation of abdominal bloating; unknown – acute pancreatitis.

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

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

General disorders: very 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 of adverse reactions by acute or chronic conditions, or by adult versus pediatric use, the frequency of adverse reactions is estimated based on data from all clinical trials of loperamide hydrochloride, including studies in children under 12 years of age (N = 3683).

^b See section "Special precautions for use".

Among adverse events reported during clinical trials and post-marketing surveillance, the most commonly observed symptoms were those typical of diarrheal syndrome (abdominal pain/discomfort, nausea, vomiting, dry mouth, increased fatigue, somnolence, dizziness, constipation, and flatulence). Therefore, it is very difficult to distinguish these symptoms from adverse drug reactions.

Non-clinical in vitro and in vivo evaluations of loperamide indicate absence of significant cardiac complications within the therapeutic concentration range, as well as at significantly higher concentrations (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.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

4 or 8 capsules in a blister pack, 1 blister pack in a cardboard box.

Authorization category. Over-the-counter (without prescription).

Manufacturer.

TOV US Farmatsiya / US Pharmacia Sp. z o.o.

Manufacturer's address.

Ziebicka St. 40, 50-507 Wroclaw, Poland / Ul. Ziebicka 40, 50-507 Wroclaw, Poland.

Marketing Authorization Holder.

Unilab, LP.

Address of the Marketing Authorization Holder and/or its representative.

966 Hungerford Drive, Suite 3B, Rockville, MD 20850, USA.