Loperamide grindex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOOPERAMIDE GRINDEKS (LOPERAMIDE GRINDEKS)

Composition:

Active substance: loperamide;

1 hard capsule contains 2 mg of loperamide hydrochloride;

Excipients: lactose monohydrate; maize starch; magnesium stearate;

capsule:

body: patent blue V (E 131), ponceau 4R (E 124), titanium dioxide (E 171), gelatin;

cap: patent blue V (E 131), quinoline yellow (E 104), titanium dioxide (E 171), yellow iron oxide (E 172), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules. Body is pink, cap is dark green; contents – white powder.

Pharmacotherapeutic group. Antidiarrheal agents. Agents inhibiting peristalsis.

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, thereby reducing propulsive peristalsis and increasing the transit time of intestinal contents, 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: the majority 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 loperamide distribution in rats show high affinity for the intestinal wall, with predominant binding to receptors in the longitudinal muscle layer. Protein binding of loperamide, mainly to albumin, is about 95%. 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 in bile. Oxidative N-demethylation is the main metabolic pathway of loperamide, mediated predominantly 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 population: pharmacokinetic studies in pediatric patients have not been conducted. It is expected that the pharmacokinetics 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 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;
• acute dysentery characterized by the presence of blood in stools and elevated body temperature;
• acute ulcerative colitis or pseudomembranous colitis associated with the use of broad-spectrum antibiotics;
• bacterial enterocolitis caused by microorganisms of the genera Salmonella, Shigella, and Campylobacter.

The medicinal product should not be used when inhibition of peristalsis should 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 have been reported with medicinal products having similar pharmacological properties. Medicinal products with central nervous system (CNS) depressant effects should not be used concomitantly with Loperamide Grindex 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 loperamide plasma levels. The clinical significance of this pharmacokinetic interaction 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, led to a 3- to 4-fold increase in loperamide plasma concentrations.

In the same study, gemfibrozil, an inhibitor of CYP2C8, increased loperamide concentrations by approximately 2-fold. Combined administration of itraconazole and gemfibrozil resulted in a 4-fold increase in the 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 as assessed by psychomotor tests (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 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 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 and weakened elderly patients, dehydration and electrolyte imbalance may occur. In such cases, the most important measure is replacement therapy to replenish fluids and electrolytes.

Use of the drug does not replace administration of adequate fluid and restoration of electrolytes.

Since persistent diarrhoea may indicate potentially more serious conditions, the drug should not be used for prolonged periods before the cause of diarrhoea has been determined.

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 the drug for diarrhoea must immediately discontinue treatment upon 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 during treatment with loperamide hydrochloride.

Cases of cardiac events, including QT interval prolongation, QRS complex prolongation, and torsades de pointes, have been reported with loperamide doses exceeding the recommended dose. In some cases, fatal outcomes have been reported. Loperamide overdose may unmask underlying Brugada syndrome. Patients must not exceed the recommended dose and/or duration of treatment.

Although pharmacokinetic data in patients with impaired liver function are lacking, the drug 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.

Drugs that prolong gastrointestinal transit time may lead to the development of toxic megacolon in patients in this group.

Since loperamide is extensively metabolized and loperamide or its metabolites are excreted in faeces, dosage adjustment of loperamide is generally not required in patients with renal impairment.

The capsules contain the colouring agent Ponceau 4R (E 124), which may cause allergic reactions.

Capsules also contain lactose; therefore, the drug should not be administered to patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

If the drug is used to control episodes of diarrhoea caused by irritable bowel syndrome 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 advice should also be sought if the nature of symptoms changes or if recurrent episodes of diarrhoea persist for more than two weeks.

For treatment of acute episodes of diarrhoea associated with irritable bowel syndrome, the drug should be used only if a physician has previously diagnosed this condition.

The drug should not be used without prior consultation with a physician in the following cases, even if the patient is known to 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 this time the IBS symptoms are different;
• 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, symptoms worsen, or symptoms do not improve within two weeks, medical advice should be sought.

Use during pregnancy or breastfeeding.

This medicinal product is not recommended during pregnancy. Therefore, pregnant women and women who are breastfeeding should consult their physician to obtain appropriate treatment.

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

Increased fatigue, dizziness, or drowsiness may occur during diarrhoea syndrome while using loperamide hydrochloride. Therefore, caution is recommended when taking this drug while driving vehicles or operating machinery.

Method of Administration and Dosage

The product 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 orally, without chewing, 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 bowel movement (in case of 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 due to 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 stool 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, the medication should be discontinued and medical advice sought.

Elderly patients: dose adjustment is not required.

Patients with renal impairment: dose adjustment is not required.

Patients with hepatic impairment:

Although pharmacokinetic data on the drug’s effects in patients with impaired liver function are lacking, the drug should be administered with caution in such patients due to reduced first-pass metabolism (see section "Special Warnings and Precautions for Use").

Children:

The use of this drug is contraindicated in children under 12 years of age.

The drug may be used 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 depression may occur (stupor, coordination disturbances, drowsiness, miosis, muscular hypertonia, respiratory depression), urinary retention, and a clinical picture resembling intestinal obstruction.

Children may be more sensitive to the central nervous system effects.

When loperamide is used in doses exceeding the recommended amount, cardiac adverse effects have been observed, including QT and QRS complex prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest, and loss of consciousness. In some cases, fatal outcomes have been reported. Loperamide overdose may unmask underlying Brugada syndrome.

Treatment:

In case of overdose, the patient should immediately seek medical attention.

Antidote: naloxone. Since the duration of action of loperamide is longer than that of naloxone (1–3 hours), repeated administration of naloxone may be required. The patient should be closely monitored for at least 48 hours to detect possible CNS depression.

Side effects

Adverse reactions are classified by organ systems and frequency of occurrence: common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000).

Central nervous system: common – loss of consciousness, depressed consciousness, headache; uncommon – dizziness; very rare – coordination disorder, loss of consciousness, depressed consciousness, hypertonia, somnolence, stupor.

Gastrointestinal tract: common – constipation, flatulence, nausea; uncommon – dry mouth, abdominal pain and discomfort, vomiting, epigastric pain, dyspepsia; very rare – intestinal obstruction (including paralytic ileus), megacolon (including toxic megacolon); frequency unknown – acute pancreatitis.

Skin and subcutaneous tissue: uncommon – rash; very rare – angioneurotic edema, bullous rashes including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), pruritus, urticaria.

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

Eye disorders: very rare – miosis.

Renal and urinary disorders: very rare – urinary retention.

General disorders: very rare – increased fatigue.

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 capsules in a blister; 1 blister per cardboard box.

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

Manufacturer.

JSC "Grindeks".

Manufacturer's address and location of business activity.

53 Krustpils Street, Riga, LV-1057, Latvia.

Marketing authorization holder.

JSC "Grindeks".

Address of marketing authorization holder.

53 Krustpils Street, Riga, LV-1057, Latvia.

Tel./fax: +371 67083205 / +371 67083505.

E-mail: [email protected]