Ursoker®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSOCARE®

Composition:

Active substance: ursodeoxycholic acid;

1 capsule contains 250 mg of ursodeoxycholic acid;

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

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

250 mg capsules: hard gelatin capsules, size “0”, with body and cap both white in color.

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 naturally present in human bile.

After oral administration, it reduces the cholesterol saturation of bile by inhibiting intestinal cholesterol absorption and decreasing cholesterol secretion into bile. Cholesterol dispersion and formation of liquid crystals may gradually dissolve gallstones.

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 hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of hepatocyte secretory function, and immunoregulatory processes.

Use in children

Mucoviscidosis (Cystic Fibrosis)

Clinical reports provide data 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 bile duct proliferation, halt the progression of histological changes, and even reverse hepatobiliary abnormalities, provided therapy is initiated at an early stage of cystic fibrosis. For optimal treatment efficacy, ursodeoxycholic acid therapy should begin immediately after confirmation of the diagnosis of cystic fibrosis.

Pharmacokinetics

After oral administration, ursodeoxycholic acid is rapidly absorbed in the fasting state, primarily in the upper jejunum via passive transport and in the terminal ileum via active transport. The absorption rate typically ranges from 60% to 80%. Following absorption, the bile acid undergoes nearly complete conjugation in the liver with the amino acids glycine and taurine, and is subsequently excreted in bile. The 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 in 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 can 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, prior to 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 up to 15 mm in diameter in patients with a functioning gallbladder, regardless of the presence of gallstone(s) in it.
• For treatment of biliary reflux gastritis.
• For symptomatic treatment of primary biliary cirrhosis (PBC) in the absence of decompensated liver cirrhosis.
• For treatment of hepatobiliary disorders in cystic fibrosis in children aged 6 to 18 years.

Contraindications.

• Hypersensitivity to the active substance, bile acids, or to any of the other excipients 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 gallbladder contractility.
• Failed portoenterostomy or absence of adequate biliary drainage in children with biliary atresia.

Interaction with other medicinal products and other forms of interactions.

Ursoker® capsules must not be used concomitantly 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 administration of agents containing any of these substances is necessary, they should be taken at least 2 hours before or 2 hours after Ursoker®.

Ursoker® capsules 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, ursodeoxycholic acid 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. Dose adjustment of nifedipine may be required.

Additionally, reduced therapeutic effect of dapsone has been reported.

These findings, together with data from in vitro studies, 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, no such effect was observed.

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

Special precautions for use

Administration of the medicinal product Ursoker® should be carried out under medical supervision.

During the first three months of treatment, liver function parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT)] should be monitored every 4 weeks, and thereafter once every three months. This allows assessment of 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

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

Ursoker® capsules should not be used if the gallbladder cannot be visualized on X-ray images, or in cases of gallstone calcification, impaired gallbladder contractility, or frequent biliary colic.

Women taking Ursoker® 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 primary biliary cholangitis (PBC)

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

In patients with PBC, worsening of symptoms at the beginning of treatment (e.g. increased pruritus) may very rarely occur. In such cases, the dose of Ursoker® capsules should be reduced to one capsule per day; the dose may then be gradually increased as described in the section "Posology and method of 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. Data on effects 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. Ursoker® capsules should not be used during pregnancy except in cases of urgent medical need. Women of childbearing potential should only take the medicinal product if they are using reliable contraceptive methods.

It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Patients receiving Ursoker® capsules for gallstone dissolution should use effective non-hormonal contraception, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded before initiating treatment.

Available data from several reported cases in breastfeeding mothers show that the concentration of ursodeoxycholic acid in breast milk is extremely low; therefore, adverse effects in breastfed infants are not expected.

Ability to influence reaction speed when driving or operating machinery

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

Dosage and Administration

For patients with body weight less than 47 kg or who have difficulty swallowing Ursocher® capsules, ursodeoxycholic acid in the form of a suspension is recommended.

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 must be taken regularly.

The time required for dissolution of gallstones is usually 6–24 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 using ultrasound or X-ray imaging. Additional examinations are necessary to determine whether calcification of stones has occurred over time. If calcification has occurred, treatment should be discontinued.

For the treatment of biliary reflux gastritis

1 capsule of Ursocher® once daily with some liquid in the evening before bedtime.

Usually, Ursocher® capsules are taken for 10–14 days for the treatment of bile reflux gastritis. The duration of treatment 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, the medicinal product Ursocher® 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 administration must be maintained.

The use of ursodeoxycholic acid in primary biliary cirrhosis may be indefinite.

In patients with primary biliary cirrhosis, clinical symptoms may rarely worsen at the beginning of treatment; for example, itching may intensify. In such cases, therapy should be continued, starting with 1 capsule of UrsoKer® daily, then gradually increasing the dose (by 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 dose is 20 mg/kg/day, divided into 2–3 doses, with subsequent increase up to 30 mg/kg/day if necessary.

Children.

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

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

For the treatment of hepatobiliary disorders in cystic fibrosis.

Administer to children aged 6 to 18 years.

Overdose.

In cases of overdose, diarrhea may occur. Other symptoms of overdose are unlikely because 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. The consequences of diarrhea should be treated symptomatically, with 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 events.

Adverse Reactions

The frequency of adverse reactions is classified as follows: 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), not known (cannot be estimated from the available data).

Within each group, adverse events are listed in order of decreasing severity.

Gastrointestinal disorders

In clinical trials, reports of pasty stools or diarrhoea were common 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 treatment of advanced stages of primary biliary cirrhosis, very rarely decompensation of liver cirrhosis has been observed, which partially regressed after discontinuation of therapy.

Hypersensitivity reactions

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

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging. 20 capsules in a blister; 1 blister in a cardboard box; 25 capsules in a blister; 2 or 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

A.B. C. FARMACEUTICI S.P.A.

ABC FARMACEUTICI S.P.A.

Manufacturer's address and location of operations.

Via Canton Moretti, 29 (Loc. Località San Bernardo) - 10015 Ivrea (TO), Italy.

Via Cantone Moretti, 29 (Loc. Localita’ San Bernardo) - 10015 Ivrea (TO), Italy.

Marketing Authorization Holder.

EURODRUG LABORATORIES.

Address of the Marketing Authorization Holder.

Kortrijksesteenweg 214 bus 2, 9830 Sint-Martens-Latem, Belgium.