Ursolizin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSOLISIN (URSOLISIN)

Composition:

Active ingredient: ursodesoxycholic acid;

1 capsule contains 300 mg of ursodesoxycholic acid;

Excipients: maize starch, sodium starch glycolate, amorphous anhydrous silicon dioxide, magnesium stearate, gelatin, titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules, white in color, containing a white powder (formation of agglomerates may occur during storage).

Pharmacotherapeutic group. Agents used in liver and biliary tract disorders. Agents used in biliary pathology.

ATC code A05A A02.

Pharmacological properties.

Pharmacodynamics.

The active substance of the drug, ursodeoxycholic acid, is a bile acid that is physiologically present in human bile in the form of cholic or chenodeoxycholic acid. After oral administration, ursodeoxycholic acid reduces cholesterol saturation in bile, prevents its intestinal absorption, and decreases cholesterol secretion into bile. The dissolution of gallstones is believed to occur due to cholesterol dispersion and formation of liquid crystals.

The effect of ursodeoxycholic acid in liver diseases and cholestasis is considered to be due to the relative replacement of lipophilic, detergent-like toxic bile acids with hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, as well as improvement of hepatocyte secretory function and immunoregulatory processes.

Pharmacokinetics.

After oral administration, ursodeoxycholic acid is rapidly absorbed in the jejunum and upper ileum via passive transport, and in the terminal ileum via active transport. Following absorption, ursodeoxycholic acid undergoes almost complete conjugation with glycine and taurine in the liver, and is then excreted in bile. The first-pass hepatic clearance is approximately 60%.

Under the influence of intestinal bacteria, partial degradation of ursodeoxycholic acid occurs, forming 7-ketolithocholic acid and lithocholic acid. Lithocholic acid is hepatotoxic and causes liver parenchyma damage in some animal species. In humans, only a small amount is absorbed, which is sulfated in the liver and thus detoxified, followed by excretion in bile and feces.

The biological half-life of ursodeoxycholic acid ranges from 3.5 to 5.8 days.

Clinical characteristics.

Indications.

• Dissolution of radiolucent cholesterol gallstones up to 15 mm in diameter in patients with a functioning gallbladder, regardless of the presence of gallstone(s) in it;
• treatment of biliary reflux gastritis;
• symptomatic treatment of primary biliary cholangitis (PBC) in the absence of decompensated liver cirrhosis.

Contraindications.

• Hypersensitivity to bile acids or to any component of the medicinal product;
• acute inflammation of the gallbladder or bile ducts;
• biliary tract obstruction (obstruction of the common bile duct or cystic duct);
• frequent episodes of biliary colic;
• radiopaque calcified gallstones;
• impaired contractility of the gallbladder.

Interaction with other medicinal products and other forms of interaction.

The medicinal product must not be administered concomitantly with cholestyramine, colestipol, or antacid preparations containing aluminium hydroxide and/or aluminium oxide (smectite), as these agents bind ursodeoxycholic acid in the intestine, thereby delaying its absorption and reducing efficacy. If treatment with any of the above-mentioned agents is required, they should be taken at least 2 hours before or after ursodeoxycholic acid.

Preparations containing ursodeoxycholic acid may enhance intestinal absorption of cyclosporine. Therefore, in patients receiving cyclosporine, blood levels of this substance should be monitored and the cyclosporine dose adjusted if necessary.

In individual cases, ursodeoxycholic acid may reduce absorption of ciprofloxacin.

In a clinical study involving healthy volunteers, concomitant administration of ursodeoxycholic acid (500 mg/day) and rosuvastatin (20 mg/day) resulted in a slight increase in rosuvastatin plasma levels. The clinical significance of this interaction, as well as similar interactions with other statins, is unknown.

It has been shown that ursodeoxycholic acid reduces maximum plasma concentrations (Cmax) and area under the curve (AUC) values for the calcium antagonist nitrendipine. Concomitant use of nitrendipine and ursodeoxycholic acid should therefore be carefully monitored.

In addition, an interaction with dapsone has been reported, leading to reduced therapeutic effect of the latter.

These data, together with in vitro study results, suggest a potential induction of cytochrome P450 3A isoenzymes by ursodeoxycholic acid. However, controlled clinical studies have shown that ursodeoxycholic acid does not have a significant inducing effect on cytochrome P450 3A isoenzymes.

Estrogens and cholesterol-lowering agents such as clofibrate may promote gallstone formation and thus reduce the efficacy of ursodeoxycholic acid when used for gallstone dissolution.

Special precautions for use

The drug should be administered under medical supervision.

During the first 3 months of treatment, liver function parameters (AST, ALT, and gamma-GT) should be monitored every 4 weeks, and every 3 months during continued therapy. This allows not only identification of patients with primary biliary cholangitis (PBC) who respond to treatment with the drug, but also early diagnosis of possible liver damage, especially in patients with advanced-stage primary biliary cholangitis.

Solubilization of cholesterol gallstones

To assess the therapeutic effect and timely detect calcification of gallstones, imaging of the overall appearance of the gallbladder (oral cholecystography) and possible duct obstruction in upright and supine positions (ultrasound examination) should be performed 6–10 months after initiation of treatment, depending on stone size.

The drug must not be used if the gallbladder cannot be visualized or in cases of stone calcification, impaired gallbladder contractility, or frequent biliary colic.

Women taking UrsoLysin for dissolution of gallstones should use effective non-hormonal contraceptive measures, as hormonal contraceptives may promote gallstone formation.

Treatment of advanced-stage primary biliary cholangitis

Very rare cases of hepatic cirrhosis decompensation have been observed, which partially regressed after discontinuation of treatment.

In isolated cases, symptoms of the disease (e.g., pruritus) may worsen at the beginning of treatment in patients with PBC. In such cases, the dose of ursodeoxycholic acid should be reduced and then gradually increased again, as described in the section "Dosage and administration".

If diarrhea develops, the dose should be reduced; in case of persistent diarrhea, treatment should be discontinued.

Use during pregnancy or breastfeeding

Animal studies have shown no effect of ursodeoxycholic acid on fertility. Data on the effect of ursodeoxycholic acid on human fertility are lacking.

There are insufficient data on the use of ursodeoxycholic acid during pregnancy. Ursodeoxycholic acid preparations should not be used during pregnancy unless clearly necessary.

Women of childbearing potential should only be prescribed the drug if reliable contraceptive methods are used: non-hormonal contraceptives or low-estrogen hormonal contraceptives are recommended. However, patients receiving ursodeoxycholic acid for gallstone dissolution should use only effective non-hormonal contraceptive methods, as hormonal contraceptives may promote gallstone formation. Pregnancy must be excluded before initiating treatment.

According to several documented cases in breastfeeding women, levels of ursodeoxycholic acid in breast milk are very low; therefore, adverse reactions in breastfed infants are unlikely.

Effect on the ability to drive and use machines

No effect of the drug on the patient's ability to drive or operate machinery has been observed.

Dosage and Administration

The product should be used under medical supervision. For patients weighing less than 47 kg or who have difficulty swallowing capsules, an alternative dosage form, such as a suspension, is recommended.

For dissolution of cholesterol gallstones

The recommended dose is 10 mg of ursodeoxycholic acid/kg body weight. Capsules should be swallowed whole with water, once daily in the evening before bedtime. Capsules should be taken regularly.

The time required for dissolution of gallstones usually ranges from 6 to 24 months. If no reduction in gallstone size is observed after 12 months of treatment, therapy should be discontinued.

Treatment efficacy should be monitored every 6 months by ultrasound or radiographic examination. Additional examinations should be performed to determine whether gallstones have become calcified over time. If calcification occurs, treatment should be discontinued.

For treatment of bile acid reflux gastritis

The dosage and duration of treatment should be determined individually by the physician. Usually, 1 capsule once daily in the evening before bedtime for 10–14 days is recommended.

For symptomatic treatment of primary biliary cirrhosis (PBC)

The daily dose depends on body weight and is 14 ± 2 mg of ursodeoxycholic acid/kg body weight.

During the first 3 months of treatment, the daily dose should be divided into 3 doses taken throughout the day. Once liver function parameters have improved, the daily dose may be taken as a single dose in the evening.

Capsules should be swallowed whole with liquid. Regular administration must be maintained.

The use of the drug in primary biliary cirrhosis may be indefinite.

In patients with primary biliary cirrhosis, clinical symptoms may occasionally worsen at the beginning of treatment; for example, pruritus may intensify. If this occurs, therapy should be continued at a dose of 1 capsule per day. After the symptoms of worsening have subsided, the dose should be gradually increased (by increasing the daily dose by 1 capsule weekly) until the prescribed dosage is reached.

Children.

There are no fundamental restrictions on the use of ursodeoxycholic acid drugs in children; however, capsules should not be used in children with body weight below 47 kg. If a child weighs less than 47 kg and/or has difficulty swallowing, ursodeoxycholic acid medication in another pharmaceutical form (e.g., suspension) is recommended.

Overdose.

Diarrhea may occur in case of overdose. Generally, other overdose symptoms are unlikely, since with increasing doses, the absorption of ursodeoxycholic acid decreases and the majority of the administered dose is excreted in feces.

If diarrhea develops, the dose of the drug should be reduced; in case of persistent diarrhea, therapy should be discontinued.

Specific interventions are not required; the consequences of diarrhea should be treated symptomatically, with restoration of fluid and electrolyte balance.

Additional information regarding specific patient groups

Long-term high-dose therapy with ursodeoxycholic acid (28–30 mg/kg/day) in patients with primary sclerosing cholangitis (use not registered indication) has been associated with a higher frequency of serious adverse reactions.

Adverse Reactions.

Gastrointestinal disorders

During treatment with ursodeoxycholic acid, cases of pasty stools or diarrhea have been reported.

During treatment of primary biliary cirrhosis, cases of severe abdominal pain localized in the right hypochondrium have been observed.

Hepatobiliary disorders

During treatment with ursodeoxycholic acid, cases of calcification of gallstones may occur.

During therapy for advanced stages of primary biliary cirrhosis, cases of hepatic decompensation have been observed, which partially regressed after discontinuation of treatment.

Immune system disorders

Hypersensitivity reactions, including rash and urticaria.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

20 capsules in a blister, 1 blister in a cardboard box;

25 capsules in a blister, 4 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer. ABC Farmaceutici S.p.A.

Manufacturer's address.

Via Cantone Moretti, 29, Ivrea 10015, Italy.