Loflatil® [Loperamide, Simethicone]

Pharmacological properties

loflatil is a combination drug that combines two drugs: loperamide hydrochloride and Simethicone.

The mechanism of action of loperamide hydrochloride. Loperamide hydrochloride binds to opiate receptors on the intestinal wall. As a result, the release of acetylcholine and prostaglandins is inhibited, thereby reducing propulsive peristalsis and increasing the passage of contents through the digestive tract, as well as the ability of the intestinal wall to absorb liquid. Loperamide hydrochloride increases the tone of the anal sphincter, thereby reducing fecal incontinence and the urge to defecate.

The mechanism of action of Simethicone. Simethicone is a non-toxic inert surface-active compound, has anti-foaming properties and therefore alleviates the symptoms associated with diarrhea, including flatulence, abdominal discomfort, bloating and cramping.

Pharmacokinetics

For loperamide hydrochloride

Absorption: most of the loperamide taken by mouth is absorbed in the intestine, but as a result of the intensive metabolism of the first pass, the systemic bioavailability is only 0.3%.

Distribution: the results of studies on the distribution of loperamide in rats show a high affinity for the intestinal wall with preferential binding to the receptors of the longitudinal layer of the muscular membrane. The binding of loperamide to 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 conjugated and excreted with bile. Oxidative N-demethylation is the main metabolic pathway of loperamide, this process is mainly mediated by isoforms of CYP 3A4 and CYP 2C8. As a result of the very intense effect of the first passage through the liver, the concentrations of unchanged drug in the blood plasma remain very low.

Excretion: T_½ loperamide in humans is ≈11 hours with a range of 9-14 hours. Unchanged loperamide and its metabolites are excreted mainly with feces.

Pediatric Patient Population: No pharmacokinetic studies of the pediatric patient population have been performed. It is expected that the pharmacokinetic behavior of loperamide and drug interactions with loperamide will be similar to those observed in adults.

For Simethicone

Simethicone acts exclusively on the surface of gas bubbles and is not absorbed by the mucous membrane of the digestive tract. Simethicone is not absorbed by the mucous membrane of the digestive tract and, after oral administration, is excreted unchanged. Simethicone has no central effect.

Indications

Symptomatic treatment for acute diarrhea in adults and children over the age of 12 years, which is accompanied by abdominal discomfort, including bloating, spastic pain and flatulence.

Application

Adults the initial dose is 2 tablets once, in the future - 1 tablet after each bowel movement, but not more than 4 tablets per day. Duration of use - no more than 2 days.

Children over 12 years old. The initial dose is 1 tablet once, then 1 tablet after each bowel movement, but not more than 4 tablets per day. Duration of use - no more than 2 days.

Elderly patients. In the treatment of the elderly, dose adjustment is not required.

Impaired renal function. No dose adjustment is required for patients with impaired renal function.

Impaired liver function. Although there are no pharmacokinetic data on the effect of the drug in patients with impaired liver function, they should be prescribed Loflatil with caution because of a slowdown in the first-pass metabolism (seeSPECIAL INSTRUCTIONS).

Contraindications

Loflatil is contraindicated in patients with:

• hypersensitivity to loperamide, Simethicone or any of the components of the drug;
• acute dysentery, which is characterized by the presence of blood in the stool and fever;
• acute ulcerative colitis;
• pseudomembranous colitis associated with the use of broad-spectrum antibiotics;
• bacterial enterocolitis caused by microorganisms of the Salmonella, Shigella and Campylobacter family;
• intestinal obstruction or obstructive diseases of the digestive tract.

Loflatil 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 must immediately stop taking the drug if constipation, bloating, or intestinal obstruction develop.

Side effects

From the immune system: hypersensitivity reactions, anaphylactic reactions, including anaphylactic shock, anaphylactoid reactions.

On the part of the skin and subcutaneous tissue: skin rash, urticaria, pruritus, angioedema, bullous rash (including Stevens-Johnson syndrome), erythema multiforme, toxic epidermal necrolysis.

From the digestive tract: dry mouth, nausea, constipation, megacolon (including toxic megacolon), intestinal obstruction (including paralytic intestinal obstruction), abdominal pain, abdominal discomfort, vomiting, bloating, dyspepsia, flatulence.

From the nervous system: headache, dysgeusia (change in taste), drowsiness, dizziness, depression of consciousness, loss of consciousness, stupor, hypertonicity, impaired coordination.

From the urinary system: urinary retention.

From the side of the organ of vision: miosis.

General disorders: asthenia, fatigue.

special instructions

Treatment for diarrhea with loperamide and Simethicone is symptomatic. if it is possible to determine the etiology of the disease (or indicated that it needs to be done), specific treatment should be carried out whenever possible.

In patients with diarrhea, especially in children, weakened elderly patients, dehydration and an imbalance of electrolytes may occur. In such cases, the most important measure is the use of replacement therapy to replenish fluid and electrolytes.

The use of the drug does not replace the introduction of an appropriate amount of fluid and the restoration of electrolytes.

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

In acute diarrhea, when there is no clinical improvement within 48 hours, the use of the drug Loflatil should be discontinued and consult a doctor.

AIDS patients taking Loflatil 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 patients with AIDS, with infectious colitis of both viral and bacterial etiology in the treatment of loperamide.

Although there are no pharmacokinetic data for individuals with impaired liver function, such patients should be used with caution due to the slowing of the first-pass metabolism. This drug should be used with caution in patients with impaired liver function, since it can lead to a relative overdose, which can lead to toxic damage to the central nervous system.

Drugs that extend the transit time can lead to the development of toxic megacolon in patients of this group.

Despite the fact that loperamide is well metabolized and loperamide or its metabolites are excreted in the feces, it is usually not necessary to adjust the dose of Loflatil in patients with impaired renal function.

Since the drug contains lactose, it should not be used in patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

If the drug is taken to control attacks of diarrhea due to irritable bowel syndrome (IBS), which was previously diagnosed and there is no clinical improvement within 48 hours, it is necessary to stop using loperamide 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 treatment of acute episodes of diarrhea caused by IBS, Loflatil should be taken only when the doctor has previously diagnosed this disease.

In the following cases, the drug should not be used without prior consultation with the doctor, even if the patient knows that he has IBS:

• the patient is 40 years old and some time has passed since the last attack of IBS;
• the patient is 40 years old 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 case of new symptoms, worsening of symptoms, or if symptoms do not improve within 2 weeks, consult a doctor.

Use during pregnancy and lactation. It is not recommended to take this drug during pregnancy and lactation. In this regard, pregnant women and women who are breastfeeding should consult a doctor to receive appropriate treatment.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. During treatment, one should refrain from driving vehicles and working with other mechanisms.

Children. Do not use in children under the age of 12 years.

Interactions

Interactions associated with loperamide

Cases of interaction with drugs having similar pharmacological properties have been reported. Medicines that have a depressing effect on the central nervous system are not recommended for use simultaneously with the drug Loflatil in children.

Preclinical evidence suggests that loperamide is a substrate of P-glycoprotein. The simultaneous administration of loperamide (at a dose of 16 mg) simultaneously with P-glycoprotein inhibitors (quinidine, ritonavir) led to an increase in plasma levels of loperamide by 2–3 times. The clinical significance of this pharmacokinetic interaction with the use of loperamide in recommended doses is unknown.

The simultaneous use of loperamide (4 mg once) and itraconazole, a CYP 3A4 inhibitor and P-glycoprotein led to a three to four-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 four-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 five-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 pupilometry.

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

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

Simethicone-related interactions

Levothyroxine may bind to Simethicone. Absorption of levothyroxine in the intestine may be impaired while taking it with Simethicone.

Overdose

Symptoms: with an overdose (including overdose due to impaired liver function), CNS depression (stupor, impaired coordination of movements, drowsiness, myosis, increased muscle tone, respiratory depression) and paralytic intestinal obstruction, urinary retention are possible. in childhood, central nervous system suppression can occur more often.

Treatment. In case of overdose, the patient should immediately consult a doctor. If symptoms of an overdose occur, the patient should be administered as an antidote to naloxone. Since T_½ loperamide greater than T_½ naloxone (1-3 hours), additional administration of naloxone may be required. Around the clock monitoring of respiratory function. The patients condition must be carefully monitored for at least 48 hours to identify possible CNS depression.

Storage conditions

At a temperature not exceeding 25 ° C.