Ursosan^® (Tablets, Capsules) Instructions for Use

ATC Code

A05AA02 (Ursodeoxycholic acid)

Active Substance

Ursodeoxycholic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hepatoprotective agent with choleretic and cholelitholytic action

Pharmacotherapeutic Group

Means for the treatment of diseases of the liver and biliary tract; agents for the treatment of diseases of the biliary tract; bile acids and their derivatives

Pharmacological Action

Hepatoprotector. It has choleretic, cholelitholytic, hypolipidemic, hypocholesterolemic, and immunomodulatory effects. Possessing high polar properties, Ursodeoxycholic acid (UDCA) is incorporated into the membrane of the hepatocyte, cholangiocyte, and gastrointestinal epithelial cell, stabilizes its structure and protects the cell from the damaging effects of toxic bile acid salts, thereby reducing their cytotoxic effect. It forms non-toxic mixed micelles with lipophilic (toxic) bile acids, which reduces the ability of gastric refluxate to damage cell membranes in cholestatic liver diseases, biliary reflux gastritis, and reflux esophagitis.

In cholestasis, UDCA activates Ca²⁺-dependent alpha-protease and stimulates exocytosis, reduces the concentration of toxic bile acids (chenodeoxycholic, lithocholic, deoxycholic, etc.), the concentrations of which are elevated in patients with chronic liver diseases. By reducing their concentration and stimulating bicarbonate-rich choleresis, UDCA effectively promotes the resolution of intrahepatic cholestasis. It competitively reduces the absorption of lipophilic bile acids in the intestine, increases their “fractional” turnover during enterohepatic circulation, induces choleresis, stimulates bile flow, and promotes the excretion of toxic bile acids through the intestine.

It reduces the cholesterol saturation of bile by inhibiting its absorption in the intestine, suppressing its synthesis in the liver, and reducing its secretion into bile; promotes the gradual dissolution of cholesterol gallstones, which is achieved mainly through the dispersion of cholesterol and the formation of liquid crystals; reduces the lithogenic index of bile, increases the concentration of bile acids in it. The result is the dissolution of cholesterol gallstones and the prevention of the formation of new stones.

It causes an increase in gastric and pancreatic secretion, enhances lipase activity, and has a hypoglycemic effect.

The immunomodulatory effect of UDCA is due to the suppression of the expression of histocompatibility antigens – HLA-1 – on hepatocyte membranes and HLA-2 – on cholangiocytes, normalization of the natural killer activity of lymphocytes, formation of interleukin-2, reduction in the number of eosinophils, suppression of immunocompetent immunoglobulins (Ig), primarily IgM; regulation of apoptosis of hepatocytes and gastrointestinal epithelial cells. It delays the progression of fibrosis.

Pharmacokinetics

Absorption and Distribution

UDCA is absorbed in the jejunum and upper parts of the ileum by passive diffusion (about 90%), and in the terminal parts of the ileum by active transport. The resorption rate is usually 60-80%.

After oral administration of 50 mg of UDCA, C_max at 30, 60, 90 min is 3.8 mmol/L, 5.5 mmol/L, and 3.7 mmol/L, respectively. The time to reach C_max is 1-3 hours. Plasma protein binding is high – up to 96-99%. It penetrates the placental barrier.

With systematic administration of the drug, UDCA becomes the main bile acid in the blood serum.

Metabolism and Excretion

It is metabolized in the liver (first-pass clearance through the liver is up to 60%) to taurine and glycine conjugates. The resulting conjugates are secreted into the bile. About 50-70% of the total dose of the drug is excreted in the bile. A small amount of UDCA not absorbed in the small intestine enters the large intestine, where it is broken down by bacteria (7-dehydroxylation); the resulting lithocholic acid is partially absorbed from the large intestine, sulfated in the liver, and quickly excreted in the bile as a sulfolithocholylglycine or sulfolithocholyltaurine conjugate.

Indications

• Uncomplicated cholelithiasis: biliary sludge; dissolution of cholesterol gallstones in a functioning gallbladder; prevention of recurrent stone formation after cholecystectomy;
• Chronic hepatitis of various origins (including toxic, drug-induced);
• Cholestatic liver diseases of various origins, including primary biliary cholangitis (in the absence of signs of decompensation), primary sclerosing cholangitis, cystic fibrosis (mucoviscidosis);
• Non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis;
• Alcoholic liver disease;
• Chronic viral hepatitis;
• Biliary dyskinesia;
• Biliary reflux gastritis and reflux esophagitis.

ICD codes

Dosage Regimen

Tablets, Capsules

Take orally, during or after meals, without chewing, with a sufficient amount of water.

For dissolution of cholesterol gallstones, the average daily dose is 10 mg/kg (up to 12-15 mg/kg). The daily dose is taken once at night. The course of treatment is 6-12 months or more until the stones are completely dissolved. If the gallstones do not decrease in size after 12 months of treatment, ursodeoxycholic acid should be discontinued.

For prevention of recurrent stone formation, it is recommended to use for several months after the dissolution of the stones.

For prevention of recurrent cholelithiasis after cholecystectomy, 250 mg is prescribed 2 times/day for several months.

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

For cholestatic liver diseases of various origins, including primary biliary cholangitis (in the absence of signs of decompensation), primary sclerosing cholangitis, cystic fibrosis (mucoviscidosis), the average daily dose is 12-15 mg/kg, if necessary – 20-30 mg/kg. During the first 3 months of treatment, the daily dose should be divided into 2-3 doses. In case of improvement in blood biochemical parameters, the daily dose is taken once at night. The duration of therapy is from 6 months to several years.

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

For biliary reflux gastritis and reflux esophagitis, the average daily dose is 250 mg once at night. The course of treatment is from 2 weeks to 6 months, if necessary – up to 2 years.

Adverse Reactions

Definition of frequency of adverse effects (number of cases/number of observations): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), frequency cannot be calculated from the available data.

From the digestive system: in clinical studies, diarrhea or pasty stools were frequently observed during treatment with ursodeoxycholic acid. In the treatment of primary biliary cholangitis, severe pain in the upper abdomen was very rarely noted.

From the liver and biliary tract: during treatment with ursodeoxycholic acid, calcification of gallstones was very rarely observed. In the treatment of primary biliary cholangitis at late stages, decompensation of liver cirrhosis was very rarely noted, which regressed after discontinuation of treatment.

From the skin and subcutaneous tissues: in very rare cases, urticaria may be observed.

Contraindications

• Hypersensitivity to ursodeoxycholic acid;
• X-ray positive (high calcium content) gallstones;
• Non-functioning gallbladder;
• Acute inflammatory diseases of the gallbladder and bile ducts;
• Liver cirrhosis in the stage of decompensation;
• Severe renal impairment;
• Severe hepatic impairment;
• Severe pancreatic impairment.

Ursodeoxycholic acid has no age restrictions for use, however, in children under 3 years of age, the use of the drug in this dosage form is not recommended.

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 or newborn (adequate strictly controlled studies of the use of ursodeoxycholic acid in pregnant women have not been conducted).

Women of reproductive age should take ursodeoxycholic acid with the simultaneous use of reliable contraceptive methods. Before starting treatment, pregnancy should be excluded.

Data on the excretion of ursodeoxycholic acid into breast milk are not available. If it is necessary to use ursodeoxycholic acid during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal impairment.

Pediatric Use

Ursodeoxycholic acid has no age restrictions for use, however, in children under 3 years of age, the use of the drug in this dosage form is not recommended.

Special Precautions

The use of ursodeoxycholic acid for the purpose of dissolving gallstones is possible under the following conditions: the stones must be cholesterol (X-ray negative), their size should not exceed 15-20 mm, the gallbladder must be functioning with preserved patency of the cystic and common bile duct, and filled with gallstones by no more than half.

With long-term use of ursodeoxycholic acid for the purpose of dissolving gallstones, a biochemical blood test to determine the activity of liver transaminases should be performed every 4 weeks during the first 3 months of treatment, and subsequently every 3 months. The effectiveness of treatment should be monitored every 6 months according to ultrasound data of the gallbladder and biliary tract.

After complete dissolution of the stones, it is recommended to continue the use of the drug for 3 months in order to promote the dissolution of the remnants of the stones, the size of which is too small for their detection, and to prevent the recurrence of stone formation.

Effect on ability to drive vehicles and operate machinery

The use of ursodeoxycholic acid does not affect the performance of potentially hazardous activities that require increased concentration and speed of psychomotor reactions (including the ability to drive a car, work with moving mechanisms).

Drug Interactions

Should not be used simultaneously with antacids containing aluminum, ion-exchange resins (cholestyramine, colestipol), as a decrease in the absorption of ursodeoxycholic acid is possible. If necessary, these drugs should be taken 2 hours before or 2 hours after taking UDCA.

Some drugs, such as estrogens, progestogens (oral contraceptives), neomycin, clofibrate, may increase cholelithiasis, thereby exerting an opposite effect to 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 plasma and, if necessary, adjustment of its dosage regimen.

In some cases, Ursodeoxycholic acid may reduce the absorption of ciprofloxacin.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.