Livodexa^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

A05AA02 (Ursodeoxycholic acid)

Active Substance

Ursodeoxycholic acid (Rec.INN registered by WHO)

Dosage Forms

	Livodexa®	Film-coated tablets, 150 mg: 10, 50, 60, 90, 100 or 120 pcs.
		Film-coated tablets, 300 mg: 10, 50, 60, 90, 100 or 120 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets brownish-red in color, round, biconvex, with a score on one side; the core is white on the break.

Excipients: lactose – 43.5 mg, starch – 9 mg, microcrystalline cellulose – 22 mg, sodium carboxymethyl starch – 13 mg, sodium lauryl sulfate – 3 mg, magnesium stearate – 3 mg, colloidal silicon dioxide – 1.5 mg, purified talc – 6.4 mg, povidone K-30 – 10 mg.

Shell composition: hypromellose (E5 premium) – 4.8 mg, macrogol 6000 – 0.95 mg, titanium dioxide – 0.48 mg, yellow iron oxide – 0.08 mg, red iron oxide – 0.09 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Film-coated tablets brownish-red in color, round, biconvex, with a score on one side; the core is white on the break.

Excipients: lactose – 87 mg, starch – 18 mg, microcrystalline cellulose – 44 mg, sodium carboxymethyl starch – 26 mg, sodium lauryl sulfate – 6 mg, magnesium stearate – 6 mg, colloidal silicon dioxide – 3 mg, purified talc – 12.8 mg, povidone K-30 – 20 mg.

Shell composition: hypromellose (E5 premium) – 9.6 mg, macrogol 6000 – 1.9 mg, titanium dioxide – 0.96 mg, yellow iron oxide – 0.16 mg, red iron oxide – 0.18 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Hepatoprotective agent with choleretic and cholelitholytic action

Pharmacotherapeutic Group

Hepatoprotective agent

Pharmacological Action

Hepatoprotector. It also has choleretic, cholelitholytic, hypolipidemic, hypocholesterolemic and immunomodulatory effects. It stabilizes the membranes of hepatocytes and cholangiocytes and has a direct cytoprotective effect. As a result of the drug’s effect on the gastrointestinal circulation of bile acids, the content of hydrophobic (potentially toxic) acids decreases. By reducing the absorption of cholesterol in the intestine and other biochemical effects, it has a hypocholesterolemic effect. It suppresses cell death caused by toxic bile acids.

Having high polar properties, Ursodeoxycholic acid forms non-toxic mixed micelles with apolar (toxic) bile acids, which reduces the ability of gastric refluxate to damage cell membranes in biliary reflux gastritis and reflux esophagitis. In addition, Ursodeoxycholic acid forms double molecules capable of being incorporated into cell membranes, stabilizing them and making them insensitive to the action of cytotoxic micelles. It reduces the saturation of bile with cholesterol by inhibiting its absorption in the intestine, suppressing synthesis in the liver and reducing secretion into bile; increases the solubility of cholesterol in bile, forming liquid crystals with it; reduces the lithogenic index of bile. The result is the dissolution of cholesterol gallstones (a consequence of the change in the cholesterol/bile acids ratio in bile) and the prevention of the formation of new stones (a result of the decrease in cholesterol content in bile). It induces choleresis rich in bicarbonates, which leads to an increase in bile passage and stimulates the excretion of toxic bile acids through the intestine.

The immunomodulatory effect is due to the inhibition of HLA antigen expression (HLA – human leucocyte antigens – histocompatibility antigens) on the membranes of hepatocytes and cholangiocytes, normalization of the natural killer activity of lymphocytes. It significantly delays the progression of fibrosis in patients with primary biliary cirrhosis, cystic fibrosis and alcoholic steatohepatitis, and reduces the risk of developing esophageal varices.

Pharmacokinetics

Absorption and Distribution

Ursodeoxycholic acid is absorbed from the jejunum by passive diffusion, and from the ileum by active transport. The plasma concentration when taken orally at 500 mg is achieved after 30, 60, 90 minutes – 3.8 mmol/l, 5.5 mmol/l, 3.7 mmol/l, respectively.

The distribution of ursodeoxycholic acid is characterized by a high degree of binding to plasma proteins, which can be 96-99%. It penetrates the placental barrier.

Metabolism and Excretion

As a result of the presystemic elimination of ursodeoxycholic acid, taurine and glycine conjugates are formed, which are secreted into bile. About 50-70% of the total administered dose of ursodeoxycholic acid is excreted in bile.

The remaining part of the unabsorbed fraction of ursodeoxycholic acid enters the large intestine, where it undergoes bacterial breakdown (7-dehydroxylation) to form lithocholic acid. Lithocholic acid is partially absorbed from the intestine, biotransformed in the liver into sulfolithocholylglycine and sulfolithocholyltaurine conjugates and excreted.

Indications

• Primary biliary cirrhosis without signs of decompensation (symptomatic therapy);
• Dissolution of small and medium-sized cholesterol stones in a functioning gallbladder;
• Biliary reflux gastritis and reflux esophagitis;
• Chronic hepatitis of various origins;
• Alcoholic liver disease;
• Non-alcoholic steatohepatitis;
• Primary sclerosing cholangitis;
• Cystic fibrosis (mucoviscidosis);
• Biliary dyskinesia;

ICD codes

Dosage Regimen

The tablets are taken orally, without chewing, with a sufficient amount of water. The tablet can be divided in half.

For dissolution of cholesterol gallstones the average daily dose of Livodexa^® is 10 mg/kg (up to 12-15 mg/kg). The drug is taken in the evening, before going to bed. The course of treatment is 6-12 months.

For prevention of recurrent stone formation it is recommended to take the drug for several more months after the stones have dissolved.

Symptomatic therapy of primary biliary cirrhosis: average daily dose – 10-15 mg/kg (if necessary – up to 20 mg/kg) from 6 months to several years. The drug is taken with food, with a sufficient amount of fluid.

For biliary reflux gastritis and reflux esophagitis the dose is 10 mg/kg/day – once/day before bedtime. The course of treatment is from 10-14 days to 6 months, if necessary – up to 2 years.

For chronic hepatitis of various origins (toxic, drug-induced, etc.), primary non-alcoholic steatohepatitis, alcoholic liver disease the average daily dose is 10-15 mg/kg of body weight in 2-3 doses. The duration of therapy is 6-12 months or more.

For primary sclerosing cholangitis, cystic fibrosis (mucoviscidosis) the average daily dose is 12-15 mg/kg (if necessary – up to 20-30 mg/kg/day) in 2-3 doses. The duration of therapy is from 6 months to several years.

For biliary dyskinesia the average daily dose is 10 mg/kg in 2 doses for 2 weeks to 2 months. If necessary, the course of treatment is recommended to be repeated.

For children over 3 years old ursodeoxycholic acid is prescribed individually, at the rate of 10-20 mg/kg/day.

Calculation of the daily number of Livodexa^® 150 mg tablets depending on the patient’s body weight and the recommended drug dose per 1 kg of body weight

Calculation of the daily number of Livodexa^® 300 mg tablets depending on the patient’s body weight and the recommended drug dose per 1 kg of body weight

Adverse Reactions

From the digestive system: calcification of gallstones, increased activity of liver transaminases, diarrhea, nausea, abdominal pain; when treating primary biliary cirrhosis, transient decompensation of liver cirrhosis may be observed, which resolves after discontinuation of the drug.

Contraindications

• X-ray positive (high calcium content) gallstones;
• Non-functioning gallbladder;
• Acute inflammatory diseases of the gallbladder, bile ducts and intestines;
• Liver cirrhosis in the stage of decompensation;
• Severe impairment of kidney, liver, pancreas function;
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• Children under 3 years of age;
• Increased individual sensitivity to the components of the drug.

With caution the drug should be used in children aged 3 to 4 years, because difficulty in swallowing tablets is possible, although Ursodeoxycholic acid has no age restrictions in use.

Use in Pregnancy and Lactation

The use of ursodeoxycholic acid during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus (adequate strictly controlled studies of the use of ursodeoxycholic acid in pregnant women have not been conducted).

Data on the excretion of ursodeoxycholic acid in breast milk are currently unavailable. If it is necessary to use ursodeoxycholic acid during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Used according to indications. Contraindication: liver cirrhosis in the stage of decompensation, severe liver dysfunction.

Use in Renal Impairment

Contraindication: severe renal failure

Pediatric Use

Contraindication: children under 3 years of age.

With caution the drug should be used in children aged 3 to 4 years, because difficulty in swallowing tablets is possible, although Ursodeoxycholic acid has no age restrictions in use.

Special Precautions

For successful dissolution, the stones must be purely cholesterol, no larger than 15-20 mm, the gallbladder must be filled with stones by no more than half, and the bile ducts must fully retain their function.

When prescribed for the dissolution of gallstones, it is necessary to monitor the activity of liver transaminases and ALP, GGT, and bilirubin concentration. If the indicators remain elevated, the drug should be discontinued.

Cholecystography should be performed every 4 weeks during the first 3 months of treatment, then every 3 months. Treatment effectiveness control should be performed every 6 months during ultrasound examination during the first year of therapy. After complete dissolution of the stones, it is recommended to continue use for at least 3 months in order to promote the dissolution of stone residues that are too small to be detected.

If partial dissolution of the stones does not occur within 6-12 months after the start of therapy, it is unlikely that the treatment will be effective.

Detection of a non-visualized gallbladder during treatment is evidence that complete dissolution of the stones has not occurred, and treatment should be discontinued.

If gallstones calcify, the contractility of the gallbladder is impaired, or frequent attacks of biliary colic occur, treatment should be discontinued.

Effect on the ability to drive vehicles and mechanisms

There are no data on the effect of ursodeoxycholic acid on the ability to drive vehicles and work with mechanisms.

Overdose

Cases of overdose of ursodeoxycholic acid are not known.

Drug Interactions

The drug should not be used simultaneously with antacids containing aluminum and ion-exchange resins, as these drugs may impair the absorption of ursodeoxycholic acid.

With simultaneous use, hypolipidemic drugs, estrogens, neomycin or gestagens (oral contraceptives) increase the saturation of bile with cholesterol and may reduce the ability of ursodeoxycholic acid to dissolve cholesterol gallstones.

Ursodeoxycholic acid may increase the absorption of cyclosporine from the intestine, which requires monitoring of the concentration of cyclosporine in the blood, and if necessary, adjustment of its dosage regimen.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.