Loperamide

Pharmacological properties

loperamide binds to opiate receptors on the intestinal wall, reducing propulsive peristalsis, increasing the transit time of intestinal contents and improving the absorption of water and electrolytes. loperamide increases the tone of the anal sphincter, which helps to reduce fecal incontinence and the urge to defecate.

Pharmacokinetics Suction. Most of the loperamide after oral administration is absorbed in the intestine, but as a result of a significant first-pass metabolism, systemic bioavailability is only about 0.3%.

Distribution. Studies of the distribution of loperamide in rats demonstrate a high affinity for the intestinal wall with preferential binding to the receptors of the longitudinal muscle layer. The binding of loperamide to plasma proteins is 95%, mainly with albumin. Preclinical data showed that loperamide is a substrate of P-glycoprotein.

Metabolism. Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, bound and excreted with bile. Oxidative N-demethylation is the main metabolic pathway of loperamide and is mediated primarily by CYP 3A4 and CYP 2C8. As a result of this very intense first-pass effect, the concentration of unchanged drug in the blood plasma remains extremely low.

T_½ loperamide in humans is about 11 hours (range 9-14 hours). The allocation of unchanged loperamide and its metabolites occurs mainly with feces.

Indications

Symptomatic treatment of acute diarrhea in adults and children over 12 years of age. symptomatic treatment of acute episodes of diarrhea due to irritable bowel syndrome (SRC) in adults (over 18 years old) after the initial diagnosis by a doctor.

Application

Oral dispersible tablets should be placed on the tongue. the tablet will dissolve and will need to be swallowed along with saliva. a tablet dispersible in the oral cavity does not need to be washed down.

Acute diarrhea

Adults, elderly patients and children over 12 years old

The initial dose is 2 tablets (4 mg), then 1 tablet (2 mg) after each loose stool. The maximum daily dose should not exceed 6 tablets (12 mg). In acute diarrhea, if no clinical improvement is observed within 48 hours, the drug should be discontinued.

Symptomatic treatment of acute episodes of diarrhea due to IBS in adults (over 18 years of age) after the initial diagnosis by a doctor.

Adults (over 18 years old)

The initial dose is 2 tablets (4 mg), in the future - 1 tablet (2 mg) after each loose stool or according to the doctor’s preliminary recommendations. The maximum daily dose should not exceed 6 tablets (12 mg).

Elderly patients do not need dose adjustment.

Impaired renal function. Patients with impaired renal function do not require dose adjustment.

Impaired liver function. Although there is no data on the pharmacokinetics of patients with impaired liver function, such patients Imodium Express should be used with caution because of a slowdown in their first-pass metabolism (see SPECIAL INSTRUCTIONS).

Contraindications

Imodium express is contraindicated:

• patients with hypersensitivity to loperamide hydrochloride or to any of the components of the drug in order to avoid severe skin manifestations, including Stevens-Johnson syndrome, toxic epidermal necrolysis and polymorphic erythema;
• children under 12 years old;
• patients with acute dysentery, characterized by the presence of blood in the stool and fever;
• patients with acute ulcerative colitis or pseudomembranous colitis associated with the use of broad-spectrum antibiotics;
• patients with bacterial enterocolitis caused by microorganisms of the Salmonella, Shigella and Campylobacter families.

Imodium Express should not be used at all if it is necessary to avoid inhibition of peristalsis due to the possible risk of significant complications, including intestinal obstruction, megacolon and toxic megacolon.

You should immediately stop taking the drug if constipation, bloating or intestinal obstruction develops.

Side effects

Adults and children over 12 years old

Side effects in patients with acute diarrhea

Side effects that occur with a frequency of 1% or higher, reported in clinical trials.

Disorders of the nervous system: headache.

Digestive tract disorders: constipation, bloating, nausea.

Side effects that occur with a frequency of 1% in the above clinical studies.

Disorders of the nervous system: dizziness.

Digestive tract disorders: dry mouth, flatulence, pain and discomfort in the abdomen, vomiting, pain in the upper abdomen.

Disorders of the skin and subcutaneous tissue: rash.

Side effects in patients with acute diarrhea

Adverse reactions reported in ≥1% of patients treated with loperamide hydrochloride.

Digestive tract disorders: vomiting.

Side effects that occur with a frequency of 1%, which were reported in the above clinical studies.

Violations of the nervous system: drowsiness, dizziness, headache.

Digestive tract disorders: nausea, abdominal pain, constipation.

Disorders of the skin and subcutaneous tissue: rash.

Post-marketing experience.

Side effects reported spontaneously with a frequency of:

very often (≥1 / 10); often (≥1 / 100 - 1/10); infrequently (≥1 / 1000 - 1/100); rarely (≥1 / 10,000 - 1/1000); very rarely (1/10 000), including single messages.

Disorders from the immune system: very rarely - hypersensitivity reactions, anaphylactic reactions (including anaphylactic shock) and anaphylactoid reactions.

Violations of the nervous system: very rarely - impaired coordination, loss of consciousness, depression of consciousness, hypertonicity, drowsiness, stupor.

Violations of the organ of vision: very rarely - miosis.

Disorders from the gastrointestinal tract: very rarely - intestinal obstruction (including paralytic intestinal obstruction), megacolon (including toxic megacolon).

Disorders from the skin and its appendages: very rarely - angioedema, bullous rash, including Stevens-Johnson syndrome, erythema multiforme and toxic epidermal necrolysis, urticaria and pruritus.

Disorders from the kidneys and urinary system: very rarely - urinary retention.

General disorders: very rarely - increased fatigue.

special instructions

The treatment of diarrhea is symptomatic. if the etiology of the disease can be determined, then specific treatment should be carried out.

In patients with diarrhea, especially in children, debilitated patients and the elderly, dehydration and an imbalance of electrolytes may occur. In such cases, the most important measure is the use of replacement therapy to replenish fluids and electrolytes. The use of Imodium Express does not replace the introduction of an appropriate amount of fluid and the restoration of electrolytes.

Since persistent diarrhea can indicate potentially more serious conditions, the drug should not be used for a long time until the cause of diarrhea is established.

In case of acute diarrhea, if clinical improvement is not observed within 48 hours, the use of loperamide hydrochloride should be discontinued and seek medical advice.

It is forbidden to use loperamide in situations where suppression of peristalsis should be avoided due to the possible risk of serious consequences, such as megacolon and toxic megacolon. Patients with acquired immunodeficiency syndrome who are taking Imodium Express for diarrhea should immediately stop treatment when the first signs of bloating appear. There are separate reports of cases of intestinal obstruction with an increased risk of toxic megacolon in the treatment of loperamide hydrochloride in patients with AIDS, with infectious colitis of both viral and bacterial origin.

The abuse or misuse of loperamide as an opioid substitute has been described in individuals with opioid dependence.

Although pharmacokinetic data are not available for patients with impaired liver function, in such patients Imodium Express should be used with caution due to a slowdown in the metabolism of the first passage. Patients with impaired liver function should be closely monitored in order to timely detect signs of toxic damage to the central nervous system.

With caution, the drug should be used in patients with exacerbation of ulcerative colitis. Drugs that lengthen the travel time can lead to the development of toxic megacolon in patients of this group.

Since loperamide is well metabolized, it and its metabolites are excreted in the feces; usually, it is not necessary to adjust the dose of the drug to patients with impaired renal function.

Loperamide is not characterized by pronounced cardiological complications within the range of therapeutic concentrations. But with a significant excess of these values ​​(up to 47 times), loperamide shows cardiac complications: inhibition of potassium (hERG) and sodium fluxes and arrhythmias in animal models in vivo and in vitro.

Cardiac complications, including Q-T prolongation and torsades de pointes, have been reported in connection with an overdose (see OVERDOSAGE). Patients should not exceed the recommended dose and / or recommended duration of treatment.

If the drug is taken to control attacks of diarrhea due to IBS, which was previously diagnosed by a doctor, and there is no clinical improvement within 48 hours, stop using loperamide hydrochloride and consult a doctor. You should also consult a doctor if the nature of the symptoms has changed or repeated attacks of diarrhea last more than 2 weeks.

For the treatment of acute attacks of diarrhea due to IBS, Imodium Express should be taken only if the doctor has previously diagnosed this syndrome.

In the following cases, the drug should not be used without first consulting a doctor, even if you know that you have IBS:

• age 40 or more, and some time has passed since the last IBS attack;
• age 40 or more, and this time the symptoms of IBS are different;
• recent intestinal bleeding;
• severe constipation;
• nausea or vomiting
• loss of appetite or weight loss;
• difficulty or painful urination;
• fever;
• recent trip abroad.

In the event of new symptoms, worsening symptoms, or if the severity of symptoms has not decreased within 2 weeks, you should consult a doctor.

Peppermint flavoring contains sulfites, which can occasionally cause hypersensitivity reactions and bronchospasm.

Mannitol (E421) may have a mild laxative effect.

Aspartame (E951) is a phenylalanine derivative that is dangerous for patients with phenylketonuria.

Use during pregnancy and lactation. The safety of the drug during pregnancy has not been established, although in animal studies there were no signs of teratogenic or embryotoxic effects of loperamide hydrochloride.As with other drugs, the use of loperamide during pregnancy is not recommended, especially during the first trimester.

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

Pregnant and lactating women should be advised to consult a doctor for appropriate treatment.

Children. The drug is used in children over the age of 12 years for the symptomatic treatment of acute diarrhea.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Given the possibility of loss of consciousness, depression of consciousness, the occurrence of fatigue, dizziness or drowsiness with diarrhea, when using loperamide hydrochloride it is not recommended to drive a car or work with complex equipment.

Interactions

Cases of interaction with drugs having similar pharmacological properties have been reported. drugs that inhibit the central nervous system should not be used in children simultaneously with Imodium Express.

Preclinical data showed that loperamide is a substrate of P-glycoprotein. The simultaneous administration of loperamide (in a single dose of 16 mg) with drugs - inhibitors of R-glycoproteins (quinidine, ritonavir) led to an increase in the level of loperamide in blood plasma by 2-3 times. The clinical significance of this pharmacokinetic interaction with the use of loperamide in recommended doses (from 2 to 16 mg) is unknown.

The simultaneous use of loperamide (4 mg once) and itraconazole, an inhibitor of CYP 3A4 and P-glycoprotein, led to a 3-4-fold increase in plasma concentrations of loperamide. In the same study, the CYP 2C8 inhibitor gemfibrozil increased the content of loperamide by about 2 times. The combined use of itraconazole and gemfibrozil led to a 4-fold increase in the maximum plasma loperamide content and a 13-fold increase in the total plasma exposure. This increase was not related to the effect on the central nervous system, which was determined using psychomotor tests (i.e. subjective drowsiness and a test for replacing digital characters).

The simultaneous use of loperamide (16 mg once) and ketoconazole, an inhibitor of CYP 3A4 and P-glycoprotein, led to a 5-fold increase in the concentration of loperamide in blood plasma. This increase was not associated with an increase in the severity of pharmacodynamic effects, was determined using pupillometry.

Concomitant treatment with desmopressin for oral administration led to a 3-fold increase in the concentration of desmopressin in blood plasma, probably due to slower gastrointestinal motility.

It is expected that drugs with similar pharmacological properties can enhance the effect of loperamide, and drugs that accelerate the transit of food through the digestive tract can reduce its effect.

Overdose

Symptoms

In case of overdose (including relative overdose due to impaired liver function), CNS depression (stupor, impaired coordination, drowsiness, miosis, muscle hypertonicity and respiratory depression), constipation, urinary retention and intestinal obstruction are possible. Children and patients with impaired liver function may be more sensitive to effects on the central nervous system.

Individuals who exceeded doses of loperamide had an extended Q-T interval and / or severe ventricular arrhythmias, including torsades de pointes (such as pirouette), which are associated with abuse or misuse of loperamide.

Persons who knowingly used high doses of loperamide (doses of 40 to 792 mg / day were reported), cardiac arrest, fainting were observed. Lethal outcomes were also recorded. (See SPECIAL INSTRUCTIONS).

Treatment. In case of an overdose, ECG monitoring should begin. As an antidote, naloxone can be used.Since the duration of action of loperamide is longer than the duration of action of naloxone (1-3 hours), repeated administration of naloxone may be required. Therefore, careful monitoring of the condition of patients should be carried out at least in the first 48 hours in order to identify possible CNS depression.

Storage conditions

At a temperature of no higher than 25 ° C out of the reach of children.