Loxflatile®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOFLATIL® (LOFLATIL®)

Composition:

Active substances: loperamide hydrochloride, simethicone;

Each tablet contains loperamide hydrochloride 2 mg, simethicone 125 mg;

Excipients: microcrystalline cellulose, aluminum-magnesium silicate, lactose monohydrate, calcium hydrogen phosphate, colloidal anhydrous silicon dioxide, povidone K-30, stearic acid, sodium croscarmellose, Opadry II 85G52482 yellow coating: polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycols, lecithin, yellow iron oxide (E 172).

Pharmaceutical form. Coated tablets.

Main physicochemical properties: capsule-shaped coated tablets, yellow in color, with a break line on one side.

Pharmacotherapeutic group.

Antidiarrheal agents; drugs used in the treatment of infectious and inflammatory intestinal diseases. Antiperistaltic agents. Loperamide combinations. ATC code A07DA53.

Pharmacological properties.

Pharmacodynamics.

Loflatil® is a combination medicine containing two active substances: loperamide hydrochloride and simethicone.

Mechanism of action of loperamide hydrochloride.

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 fluids and electrolytes. Loperamide hydrochloride increases the tone of the anal sphincter, thus reducing fecal incontinence and defecation urges.

Mechanism of action of simethicone.

Simethicone is a non-toxic, inert surfactant with antifoaming properties, thereby alleviating symptoms associated with diarrhea, including meteorism, abdominal discomfort, bloating, and spasms. Simethicone is a liquid dimethicone activated with finely dispersed silicon dioxide to enhance the antifoaming properties of silicone.

Pharmacokinetics.

Loperamide hydrochloride.

Absorption: the majority of orally administered loperamide is absorbed from the intestine; however, due to extensive first-pass metabolism, systemic bioavailability is only approximately 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. Loperamide protein binding is about 95%, primarily 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 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 patients: population pharmacokinetic studies in pediatric patients have not been conducted. The pharmacokinetic behavior of loperamide and drug interactions with loperamide are expected to be similar to those observed in adults.

Simethicone.

Simethicone is physiologically and chemically inert; it is not absorbed and is excreted unchanged after passage through the gastrointestinal tract.

Clinical characteristics.

Indications.

Symptomatic treatment of acute diarrhea in adults and children aged 12 years and older, accompanied by abdominal discomfort, including bloating, cramping pain, and flatulence.

Contraindications.

Loflatil® is contraindicated:

• in patients with hypersensitivity to loperamide hydrochloride, simethicone, or any component of the medicinal product;
• 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;
• in patients with 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;
• in patients with intestinal obstruction or obstructive gastrointestinal disorders.

Loflatil® should not be used at all when inhibition of peristalsis must be avoided due to the risk of developing significant complications, including intestinal obstruction, megacolon, and toxic megacolon.

The drug should be discontinued immediately if constipation, abdominal distension, or intestinal obstruction develops.

Interaction with other medicinal products and other forms of interaction.

Interactions related to loperamide hydrochloride.

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 Loflatil® in children.

Preclinical data have shown that loperamide is a substrate of P-glycoprotein. 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 is unknown.

Concomitant administration of loperamide (4 mg as a single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, led to a 3–4-fold increase in loperamide plasma concentrations. In the same study, gemfibrozil, an inhibitor of CYP2C8, increased loperamide levels by approximately 2-fold. Combined administration of itraconazole and gemfibrozil resulted in a 4-fold increase in maximum loperamide plasma concentration and a 13-fold increase in total plasma exposure. This increase was 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 as a 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 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.

Interactions related to simethicone.

Levothyroxine may bind to simethicone. Intestinal absorption of levothyroxine may be impaired when administered concomitantly with simethicone.

Special precautions for use.

Treatment of diarrhea with loperamide hydrochloride and simethicone is symptomatic. If the etiology of the disease can be determined, specific therapy should be carried out whenever possible.

Dehydration and electrolyte imbalance

Dehydration and electrolyte imbalance may occur in patients with diarrhea, particularly in severe cases, as well as in children and debilitated elderly patients. In such cases, an important therapeutic measure is the administration of adequate fluids and restoration of electrolyte balance.

The use of this medicinal product does not replace the need for adequate fluid intake and electrolyte balance restoration.

Since persistent diarrhea may indicate potentially more serious conditions, this medicinal product should not be used for prolonged periods without investigating the cause of diarrhea.

In acute diarrhea, if no clinical improvement is observed within 48 hours, treatment with Loflatil® should be discontinued and medical advice should be sought.

Loperamide should not be used in situations where inhibition of peristalsis should be avoided due to the risk of serious complications such as megacolon and toxic megacolon.

Patients with acquired immunodeficiency syndrome (AIDS)

Patients with AIDS receiving Loflatil® for diarrhea should discontinue treatment immediately 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.

Patients with hepatic impairment

Pharmacokinetic data in patients with impaired liver function are lacking. Loflatil® should be used with caution in these patients due to reduced first-pass metabolism. This medicinal product should be prescribed cautiously to patients with hepatic impairment, as it may lead to relative overdose and potential CNS toxicity. Patients with severe hepatic impairment should receive Loflatil® under medical supervision. Medicinal products that prolong gastrointestinal transit time may lead to the development of toxic megacolon in patients in this group.

Patients with renal impairment

Since loperamide is extensively metabolized and metabolites or unchanged drug are excreted in feces, dosage adjustment of Loflatil® is generally not required in patients with renal impairment.

Overdose

Within the therapeutic concentration range, loperamide usually does not cause significant cardiovascular complications. However, significant overdose (approximately 47 times higher) has been associated with cardiovascular complications, including inhibition of potassium (hERG) and sodium channels, and arrhythmias in both in vivo and in vitro animal models.

Cardiac events, including QT interval prolongation, QRS complex widening, and torsades de pointes, have been reported in association with overdose. Some cases were fatal (see section "Overdose"). Overdose may unmask pre-existing Brugada syndrome. Patients should not exceed the recommended dose or duration of treatment.

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

Loflatil® should be used with caution in patients with renal or hepatic impairment due to the risk of accumulation and toxicity (metabolic acidosis).

Excipients

Since the medicinal product contains lactose, it should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

This medicinal product is not recommended during pregnancy or breastfeeding, including due to the risk of accumulation and toxicity (metabolic acidosis). Pregnant women and women who are breastfeeding should therefore be advised to consult their physician for appropriate treatment.

Effect on ability to drive and use machines.

During treatment with this medicinal product, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

Swallow tablets whole with water.

Adults.

Initial dose is 2 tablets as a single dose, followed by 1 tablet after each bowel movement, but not more than 4 tablets per day. Duration of use should not exceed 2 days.

Children aged 12 to 18 years.

Initial dose is 1 tablet as a single dose, followed by 1 tablet after each bowel movement, but not more than 4 tablets per day. Duration of use should not exceed 2 days.

Elderly patients.

Dosage adjustment is not required in elderly patients.

Renal impairment.

Dosage adjustment is not required in patients with renal impairment.

Hepatic impairment.

Although pharmacokinetic data on the use of the drug in patients with hepatic impairment are lacking, Loflatil® should be administered with caution in such patients due to reduced first-pass metabolism (see section "Special precautions").

Children.

Do not use in children under 12 years of age.

Overdose.

Symptoms.

In overdose (including overdose caused by hepatic impairment), central nervous system depression (stupor, impaired coordination, drowsiness, miosis, increased muscle tone, respiratory depression), dry mouth, abdominal discomfort, nausea, vomiting, constipation, urinary retention, and paralytic ileus may occur.

Children and patients with hepatic impairment may be more sensitive to CNS effects. CNS depression may occur more frequently in children.

In individuals exceeding recommended doses of loperamide, cardiac disturbances have been observed, such as QT and QRS interval prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest, and loss of consciousness.

In individuals who intentionally ingested high doses of loperamide (doses reported from 40 to 792 mg per day), cardiac arrest and syncope have been observed. Fatal cases have also been reported. Overdose may unmask Brugada syndrome.

Treatment.

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

In case of overdose, QT interval monitoring should be initiated.

If symptoms of overdose occur, naloxone should be administered as an antidote. Since the elimination half-life of loperamide is longer than that of naloxone (1 to 3 hours), repeated administration of naloxone may be required. Continuous respiratory monitoring is necessary. The patient should be closely observed for at least 48 hours to detect possible CNS depression.

Side effects

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), including isolated cases, and not known (frequency cannot be estimated from available data).

Immune system disorders:

Rare: hypersensitivity reactions, anaphylactic reactions, including anaphylactic shock, anaphylactoid reactions.

Skin and subcutaneous tissue disorders:

Uncommon: skin rash.

Rare: urticaria, pruritus, angioneurotic edema, facial swelling, tongue swelling, dyspnea, bullous eruptions (including Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis).

Gastrointestinal disorders:

Common: nausea.

Uncommon: dry mouth, constipation, abdominal pain, abdominal discomfort, vomiting, dyspepsia, flatulence.

Rare: megacolon (including toxic megacolon), intestinal obstruction (including paralytic ileus), sensation of abdominal distension.

Not known: acute pancreatitis.

Nervous system disorders:

Common: headache, dysgeusia (altered taste sensation).

Uncommon: somnolence, dizziness.

Rare: impaired consciousness, loss of consciousness, stupor, hypertonia, coordination disorders.

Renal and urinary disorders:

Rare: urinary retention.

Eye disorders:

Rare: miosis.

General disorders:

Uncommon: asthenia.

Rare: increased fatigue.

Reporting of suspected side effects.

Reporting suspected adverse reactions after marketing authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard pack.

10 tablets in a strip, 1 strip in a cardboard pack.

10 tablets in a blister, 1 blister in a cardboard pack, 10 packs in a cardboard box.

10 tablets in a strip, 1 strip in a cardboard pack, 10 packs in a cardboard box.

10 tablets in a blister, 10 blisters in a cardboard pack.

Release category.

Over-the-counter:

10 tablets in a blister, 1 blister in a cardboard pack.

10 tablets in a strip, 1 strip in a cardboard pack.

By prescription only:

10 tablets in a blister, 1 blister in a cardboard pack, 10 packs in a cardboard box.

10 tablets in a strip, 1 strip in a cardboard pack, 10 packs in a cardboard box.

10 tablets in a blister, 10 blisters in a cardboard pack.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of its operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.