Ursosan forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSOSAN® FORTE (URSOSAN® FORTE)

Composition:

Active substance: ursodeoxycholic acid;

One film-coated tablet contains 500 mg of ursodeoxycholic acid;

Excipients: corn starch, pregelatinized corn starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, coating Opadry White 03B28796 (hypromellose 6, titanium dioxide (E 171), macrogol 400).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white or almost white, oblong-shaped, with a crosswise break line on one side and a crosswise notch on the other side, 17 mm in length.

Pharmacotherapeutic group.

Agents used in the treatment of liver and biliary tract disorders. Agents used in biliary pathology. ATC code A05AA02.

Agents used in liver disease, lipotropic agents.

ATC code A05B.

Pharmacological Properties

Pharmacodynamics

A small amount of ursodeoxycholic acid is naturally present in human bile. After oral administration, ursodeoxycholic acid reduces cholesterol saturation in bile by inhibiting intestinal absorption of cholesterol and decreasing cholesterol secretion into bile. Gradual dissolution of gallstones may occur due to dispersion of cholesterol and formation of liquid crystals.

According to current knowledge, the therapeutic effect of ursodeoxycholic acid in liver diseases and cholestasis is attributed to the relative replacement of lipophilic, detergent-like toxic bile acids with the hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of hepatocyte secretory function, and immunoregulatory processes.

Use in children

Mucoviscidosis (Cystic Fibrosis)

Clinical data are available on long-term use of ursodeoxycholic acid (for periods up to 10 years) in the treatment of children with hepatobiliary complications associated with cystic fibrosis. Evidence suggests that ursodeoxycholic acid may reduce proliferation in bile ducts, halt progression of histological changes, and even reverse hepatobiliary abnormalities if therapy is initiated at an early stage of cyst游戏副本idosis. For optimal treatment efficacy, ursodeoxycholic acid therapy should be started immediately after confirmation of the diagnosis of cystic fibrosis.

Pharmacokinetics

After oral administration, ursodeoxycholic acid is rapidly absorbed in the fasting state from the duodenum and upper part of the ileum via passive transport, and in the terminal ileum via active transport. The absorption rate is typically 60–80%. Following absorption, the bile acid undergoes almost complete conjugation in the liver with the amino acids glycine and taurine, and is then excreted into bile. First-pass hepatic clearance is up to 60%.

Depending on the daily dose and the underlying condition or liver status, the more hydrophilic ursodeoxycholic acid accumulates in bile. Concurrently, a relative reduction of other, more lipophilic bile acids is observed.

Under the influence of intestinal bacteria, partial degradation occurs to 7-ketolithocholic acid and lithocholic acid. Lithocholic acid is hepatotoxic and causes parenchymal liver damage in some animal species. In humans, only a small amount is absorbed, which is then sulfated in the liver and thus detoxified before being excreted in bile and subsequently in feces.

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

Clinical characteristics.

Indications.

For dissolution of radiolucent cholesterol gallstones no larger than 15 mm in patients with a functioning gallbladder, regardless of the presence of gallstone(s) within it.

For symptomatic treatment of primary biliary cirrhosis (PBC) in the absence of decompensated liver cirrhosis.

For the treatment of hepatobiliary disorders in cystic fibrosis in children aged 6 to 18 years.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Acute inflammation of the gallbladder or bile ducts.

Obstruction of the bile duct (obstruction of the common bile duct or cystic duct).

Frequent episodes of hepatic colic.

Radiopaque calcified gallstones.

Impaired contractility of the gallbladder.

Decompensated liver cirrhosis.

Failed outcome of portoenterostomy or absence of adequate biliary drainage in children with biliary atresia.

Interaction with other medicinal products and other forms of interaction.

Ursodeoxycholic acid should not be administered simultaneously with cholestyramine, colestipol, or antacid preparations containing aluminium hydroxide and/or smectite (aluminium oxide), as these agents bind ursodeoxycholic acid in the intestine, thereby interfering with its absorption and reducing efficacy. If treatment with any of these agents is necessary, they should be taken at least 2 hours before or 2 hours after administration of the medicinal product.

Ursodeoxycholic acid may enhance intestinal absorption of cyclosporine. In patients receiving cyclosporine, the physician should monitor blood levels of this substance and adjust the cyclosporine dose if necessary.

In individual cases, the medicinal product 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 with other statins is unknown. Ursodeoxycholic acid reduces the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for the calcium antagonist nitrendipine.

Careful monitoring is recommended when nitrendipine and ursodeoxycholic acid are used concomitantly. An increase in nitrendipine dosage may be necessary. In view of this, and due to reports of a single case of interaction with dapsone (reduced therapeutic effect) and in vitro studies, it can be concluded that ursodeoxycholic acid induces the cytochrome P450 3A enzyme, which metabolizes medicinal products. However, induction was not observed in a well-designed interaction study with budesonide, a known substrate of cytochrome P450 3A.

Estrogenic hormones and lipid-lowering agents such as clofibrate increase cholesterol secretion by the liver and thus may promote biliary lithiasis, counteracting the effect of ursodeoxycholic acid used for gallstone dissolution. Therefore, caution is advised when co-administering medicinal products metabolized by the P450 3A enzyme, and dose adjustments should be considered if necessary.

Special precautions for use

Ursosan® forte tablets should be taken under medical supervision.

During the first 3 months of therapy, the physician should monitor liver function parameters—AST (SGOT), ALT (SGPT), and γ-GT—every 4 weeks, and thereafter every 3 months. This allows assessment of the appropriate treatment response in patients with PBC, as well as timely detection of potential liver function abnormalities, particularly in patients with advanced-stage PBC.

Use for dissolution of cholesterol gallstones

After 6–10 months of treatment, oral cholecystography should be performed to evaluate the overall appearance of the stones and the filling of the gallbladder in both upright and supine positions (ultrasound examination). This is necessary to assess therapeutic progress and to detect possible calcification of gallstones in a timely manner.

The drug must not be administered to patients with a gallbladder that is not visualized by radiological methods, with calcified stones, impaired gallbladder contractility, or those experiencing frequent biliary colic attacks.

Female patients taking the drug for dissolution of gallstones should use an effective non-hormonal method of contraception, since hormonal contraceptives may promote gallstone formation (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or lactation").

Treatment of patients with advanced-stage PBC

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

In patients with PBC, worsening of symptoms at the beginning of treatment is very rare; for example, pruritus may intensify. In such cases, the dose should be reduced to half a tablet daily, and then gradually increased as described in the section "Dosage and administration".

If diarrhea develops, the dosage should be reduced; if diarrhea becomes persistent, treatment should be discontinued.

Use during pregnancy or lactation

Animal studies have not shown any effect of ursodeoxycholic acid on fertility. Data on the effect on human fertility are lacking.

Data on the use of ursodeoxycholic acid in pregnant women are insufficient. Animal studies indicate reproductive toxicity in early pregnancy. The drug should not be used during pregnancy unless clearly necessary. Women of childbearing potential should only take the drug if using reliable contraception.

It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Female patients receiving Ursosan® forte 500 mg film-coated tablets for dissolution of gallstones should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded before initiating treatment.

Based on several reported cases of use in breastfeeding women, the concentration of ursodeoxycholic acid in breast milk was found to be very low, so adverse effects in breastfed infants are not expected.

Ability to influence reaction speed when driving vehicles or operating machinery

No influence on the ability to drive vehicles or operate machinery has been observed.

Dosage and Administration

There are no age restrictions for the use of this medication.

For patients with body weight less than 47 kg or for those who have difficulty swallowing tablets, ursodeoxycholic acid in another pharmaceutical form may be used.

For dissolution of cholesterol gallstones

Approximately 0.10 mg of ursodeoxycholic acid per 1 kg of body weight per day (see Table 1)

Table 1

The tablets should be swallowed whole, without chewing, with a small amount of liquid, in the evening before bedtime.

The tablets should be taken regularly.

The time required to dissolve gallstones usually ranges from 6 to 24 months. If no reduction in gallstone size is observed after 12 months of treatment, therapy should not be continued.

Treatment success should be monitored every 6 months using ultrasound or X-ray imaging. Additional examinations should verify whether calcification of the stones has occurred over time. If calcification has occurred, treatment should be discontinued.

For symptomatic treatment of primary biliary cholangitis (PBC)

The daily dose depends on body weight and ranges from 1½ to 3½ tablets (14 ± 2 mg of ursodeoxycholic acid per kilogram of body weight), see Table 2.

During the first 3 months of treatment, the medication should be taken throughout the day, dividing the daily dose into several doses. Once liver function parameters have improved, the daily dose may be taken once daily in the evening.

Table 2

The tablets should be swallowed whole, without chewing, with liquid. The drug should be used regularly.

The use of the drug in primary biliary cirrhosis is possible over a prolonged period.

In patients with primary biliary cirrhosis, clinical symptoms may rarely worsen at the beginning of treatment; for example, pruritus may intensify. In such cases, therapy should be continued by taking half a tablet per day, followed by a gradual increase in dose (increasing the daily dose weekly by half a tablet of Ursofalk® forte until the recommended dosage regimen is reached).

Use in children

Children with cystic fibrosis aged 6 to 18 years

The dose is 20 mg/kg/day, divided into 2–3 doses, with subsequent dose escalation up to 30 mg/kg/day, if necessary.

Table 3

Children.

For dissolution of cholesterol gallstones and symptomatic treatment of PBC

There are no fundamental age restrictions for the use of Ursofalk® forte in children; however, in children with body weight below 47 kg and/or in children who have difficulties with swallowing, ursodeoxycholic acid in another pharmaceutical form is recommended.

For treatment of hepatobiliary disorders in cystic fibrosis

Administered to children aged 6 to 18 years.

Overdose.

Diarrhea may occur in case of overdose. Other symptoms of overdose are unlikely, since the absorption of ursodeoxycholic acid decreases with increasing dose; therefore, most of the administered dose is excreted in feces.

If diarrhea occurs, the dose should be reduced; if diarrhea persists, treatment should be discontinued.

Treatment is symptomatic and includes restoration of fluid and electrolyte balance.

Additional information regarding special patient groups

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

Adverse reactions.

The assessment of the frequency of adverse reactions is based on the following data:

Very common: more than 1 in 10 treated;

Common: more than 1 in 1,000 treated to 1 in 10 treated;

Uncommon: more than 1 in 1,000 treated to 1 in 100 treated;

Rare: more than 1 in 10,000 treated to 1 in 1,000 treated;

Very rare/unknown: 1 in 10,000 treated or less / cannot be estimated from available data.

Gastrointestinal disorders

During clinical trials, pasty stools or diarrhoea were frequently reported during treatment with ursodeoxycholic acid.

Very rarely, severe right upper abdominal pain has been observed during treatment of PBC.

Hepatobiliary disorders

Very rarely, calcification of gallstones may occur during treatment with ursodeoxycholic acid.

During therapy of advanced stages of PBC, decompensation of liver cirrhosis has been observed very rarely, which partially improves after discontinuation of treatment.

Hypersensitivity reactions

Very rarely, allergic reactions including rash and urticaria may occur.

Reporting of suspected adverse reactions

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

Shelf life. 4 years. Do not use after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 1, 2, 3, 5, 6, 9, or 10 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

PRO.MED.CS Prague, a.s.

Manufacturer's address and place of business.

Těchobuzská 377/1, Michle, Prague 4, 140 00, Czech Republic.