Ursowal®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSOVAL® (URSOVAL®)

Composition:

Active substance: ursodeoxycholic acid;

1 capsule contains 250 mg of ursodeoxycholic acid;

Excipients: maize starch, pregelatinized maize starch, hydroxypropylcellulose, colloidal anhydrous silicon dioxide, magnesium stearate;

composition of the hard gelatin capsule: gelatin, titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules, cylindrical in shape with hemispherical ends. Capsule cap and body – white. The contents of the capsule – powder or granules of white or almost white color. The presence of small lumps or columns that disintegrate upon pressure is permissible.

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 diseases, lipotropic agents.

ATC Code A05B.

Pharmacological properties.

Pharmacodynamics.

A small amount of ursodeoxycholic acid is found naturally in human bile.

After oral administration, it reduces the cholesterol saturation of bile by inhibiting intestinal cholesterol absorption 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 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

Available clinical data report long-term use of ursodeoxycholic acid (for periods up to 10 years) in the treatment of children with hepatobiliary abnormalities associated with mucoviscidosis. Evidence suggests that ursodeoxycholic acid may reduce bile duct proliferation, halt the progression of histological changes, and even reverse hepatobiliary abnormalities, provided therapy is initiated at an early stage of mucoviscidosis. For optimal treatment efficacy, therapy with ursodeoxycholic acid should be started immediately after confirmation of the diagnosis of mucoviscidosis.

Pharmacokinetics.

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

Depending on the daily dose and the underlying disorder or liver condition, 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 may cause liver parenchyma damage in some animal species. In humans, only a small amount is absorbed, which is then sulfated in the liver, thereby detoxified, before being excreted in bile and subsequently in feces.

The biological half-life of ursodeoxycholic acid is 3.5–5.8 days.

Clinical characteristics.

Indications.

For dissolution of radiolucent cholesterol gallstones not exceeding 15 mm in diameter in patients with a functioning gallbladder, regardless of the presence of gallstone(s) in it.

For the treatment of biliary reflux gastritis.

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

Frequent episodes of hepatic colic.

Radiopaque calcified gallstones.

Impaired gallbladder contractility.

Failed portoenterostomy or absence of adequate bile flow in children with biliary atresia.

Interaction with other medicinal products and other forms of interaction.

Capsules Ursoval**®** 250 mg should not be used concomitantly with cholestyramine, colestipol, or antacid preparations containing aluminium hydroxide and/or smectite, as these agents bind ursodeoxycholic acid in the intestine, thereby interfering with its absorption and reducing efficacy. If administration of agents containing any of these substances is necessary, they should be taken at least 2 hours before or 2 hours after Ursoval**®** 250 mg capsules.

Capsules Ursoval**®** 250 mg 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, Ursoval**®** 250 mg capsules may reduce absorption of ciprofloxacin.

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

It has been demonstrated that ursodeoxycholic acid reduces the peak plasma concentration (Cmax) and area under the curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers. Careful monitoring is recommended when nifedipine and ursodeoxycholic acid are used concomitantly. An increase in nifedipine dosage may be required.

Furthermore, reduced therapeutic effect of dapsone has been reported.

These data, together with in vitro findings, suggest that ursodeoxycholic acid may potentially induce cytochrome P450 3A enzymes. However, in a well-designed interaction study with budesonide, a well-established cytochrome P450 3A substrate, such an effect was not observed.

Estrogenic hormones, as well as cholesterol-lowering agents such as clofibrate, may enhance hepatic cholesterol secretion and thus promote gallstone formation, which is an opposing effect to that of ursodeoxycholic acid used for their dissolution.

Special precautions for use

The administration of Ursoval® 250 mg capsules should be carried out under medical supervision.

During the first three months of treatment, liver function parameters (AST, ALT, and GGT) should be monitored every 4 weeks, and thereafter once every three months. This allows assessment of treatment response in patients with PBC and timely detection of potential liver function abnormalities, particularly in patients with advanced-stage PBC.

Use for dissolution of cholesterol gallstones

To evaluate treatment progress and to detect any signs of stone calcification in a timely manner, visualization of the gallbladder (oral cholecystography) with imaging of opacities in both upright and supine positions (under ultrasound monitoring) should be performed 6–10 months after initiation of therapy, depending on stone size.

Ursoval® 250 mg capsules should not be used if the gallbladder cannot be visualized on X-ray imaging, or in cases of stone calcification, impaired gallbladder contractility, or frequent biliary colics.

Women receiving Ursoval® 250 mg capsules for dissolution of gallstones should use an effective non-hormonal method of contraception, as hormonal contraceptives may increase the risk of gallstone formation.

Treatment of patients with advanced-stage PBC

Decompensation of liver cirrhosis has been reported very rarely, which may partially regress after discontinuation of therapy.

In patients with PBC, a transient worsening of symptoms may very rarely occur at the beginning of treatment, for example, pruritus may intensify. In such cases, the dose should be reduced to one Ursoval® 250 mg capsule per day; the dose may then be gradually increased as described in the section "Dosage and administration".

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

Use during pregnancy or breastfeeding

Animal studies have not shown any effect of ursodeoxycholic acid on fertility. There are no data available on the effect on fertility in humans.

Data on the use of ursodeoxycholic acid in pregnant women are insufficient. Animal studies indicate reproductive toxicity in early pregnancy. Ursoval® 250 mg capsules should not be used during pregnancy except in cases of urgent medical need. Women of childbearing potential should only take the medication if they are using reliable contraceptive methods.

It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Patients receiving Ursoval® 250 mg for dissolution of gallstones should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be ruled out before initiating treatment.

Based on several reported cases of use in breastfeeding women, the concentration of ursodeoxycholic acid in breast milk is extremely low; therefore, adverse effects in breastfed infants are not expected.

Ability to influence reaction rate while driving or operating machinery

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

Method of administration and dosage.

For patients with body weight less than 47 kg or who experience difficulty swallowing tablets, it is recommended to use ursodeoxycholic acid in another pharmaceutical form, for example, as a suspension.

For dissolution of cholesterol gallstones

Approximately 10 mg of ursodeoxycholic acid per kg of body weight (see Table 1).

Table 1

The capsules should be swallowed whole with water, once daily in the evening before bedtime.

The 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 not be continued.

The success of treatment should be monitored every 6 months by ultrasound or X-ray examination. Additional examinations should be performed to determine whether calcification of the stones has occurred over time. If calcification has occurred, treatment should be discontinued.

For the treatment of biliary reflux gastritis

1 capsule of Ursoval**®** 250 mg once daily with some liquid in the evening before bedtime.

For the treatment of bile reflux gastritis, Ursoval**®** 250 mg capsules are usually taken for 10–14 days. The duration of use depends on the patient's condition. The physician must decide on the treatment duration individually in each case.

For symptomatic treatment of primary biliary cholangitis (PBC)

The daily dose depends on body weight and ranges from 3 to 7 capsules (14 ± 2 mg of ursodeoxycholic acid/kg body weight).

During the first 3 months of treatment, Ursoval**®** 250 mg capsules should be taken throughout the day, dividing the daily dose into 3 doses. When liver function parameters improve, the daily dose may be taken once daily in the evening.

Table 2

The capsules should be swallowed whole with liquid. Regularity of intake must be maintained.

The use of Ursoval**®** 250 mg capsules in primary biliary cirrhosis may be indefinite.

In patients with primary biliary cirrhosis, a temporary worsening of clinical symptoms may rarely occur at the beginning of treatment, for example, itching may intensify. In such cases, therapy should be continued by taking 1 capsule of Ursoval**®** 250 mg daily, followed by gradual dose escalation (increasing the daily dose by 1 capsule weekly) until the prescribed dosage regimen is reached.

Use in children

For children with cystic fibrosis aged 6 to 18 years, the dosage is 20 mg/kg/day, divided into 2–3 doses, with subsequent dose increase up to 30 mg/kg/day if necessary.

Table 3

Children.

For dissolution of cholesterol gallstones, treatment of biliary reflux gastritis, and symptomatic treatment of PBC.

There are no fundamental age restrictions for the use of Ursoval**®** in children. However, if a child weighs less than 47 kg and/or has difficulty swallowing, ursodeoxycholic acid in suspension form is recommended.

For the treatment of hepatobiliary disorders in cystic fibrosis.

Administer to children aged 6 to 18 years.

Overdose.

In case of overdose, diarrhea may occur. Other symptoms of overdose are unlikely, as the absorption of ursodeoxycholic acid decreases with increasing dose, and therefore most of the administered amount is excreted in feces.

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

Specific interventions are not required. Consequences of diarrhea should be managed symptomatically, with restoration of fluid and electrolyte balance.

Additional information regarding special patient populations

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

Side effects

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

Very common: >1/10;
Common: >1/100 to <1/10;
Uncommon: >1/1000 to <1/100;
Rare: >1/10,000 to <1/1000;
Very rare: <1/10,000, including isolated cases.

Gastrointestinal disorders

In clinical studies, pasty stools or diarrhea have been commonly reported during treatment with ursodeoxycholic acid.

Very rarely, severe abdominal pain localized in the right hypochondrium has been observed during treatment of primary biliary cirrhosis.

Hepatobiliary disorders

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

During therapy for advanced stages of primary biliary cirrhosis, very rarely decompensation of liver cirrhosis may develop, which partially regressed after discontinuation of treatment.

Hypersensitivity reactions

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

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

Shelf life. 4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging. 10 capsules per blister, 5 or 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

"VALARTIN PHARMA" Limited Liability Company.

Manufacturer's address and location of business activity.

60 Hrushevskoho Street, Village Chayky, Kyiv-Sviatoshyn District, Kyiv Oblast, 08135, Ukraine.