Ursis®

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

Composition:

Active substance: ursodeoxycholic acid;

One tablet contains ursodeoxycholic acid 500 mg;

Excipients: microcrystalline cellulose, crospovidone, povidone, polysorbate 80, talc, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: film-coating mixture Opadry Clear: hypromellose (hydroxypropylmethylcellulose), talc, polyethylene glycol (macrogol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: prolonged-shaped, biconvex tablets with a score line on both sides, coated with a film coating of white or almost white 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 disease, lipotropic agents.

ATC code A05B.

Pharmacological Properties

Pharmacodynamics

A small amount of ursodeoxycholic acid is naturally found in human bile. After oral administration, ursodeoxycholic acid reduces cholesterol saturation in 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 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 immunomodulatory processes.

Use in children

Mucoviscidosis

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

Pharmacokinetics

After oral administration, ursodeoxycholic acid is rapidly absorbed in the jejunum and upper part of the ileum via passive transport, and in the terminal ileum via active transport. The absorption rate is typically 60–80%. After absorption, the bile acid undergoes nearly complete hepatic conjugation with the amino acids glycine and taurine, and is subsequently excreted into bile. The hepatic first-pass 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 may cause liver parenchyma 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 into bile and ultimately eliminated 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 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 any component of the medicinal product.
• Acute inflammation of the gallbladder or bile ducts.
• Obstruction of the bile duct (common bile duct or cystic duct obstruction).
• Frequent episodes of biliary colic.
• Radiopaque calcified gallstones.
• Impaired gallbladder contractility.
• Decompensated liver cirrhosis.
• Failed portoenterostomy or absence of adequate biliary drainage in children with biliary atresia.

Interaction with other medicinal products and other forms of interaction.

The medicinal product Urzis® 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 preparations containing any of these substances is necessary, they should be taken at least 2 hours before or 2 hours after taking Urzis®.

Urzis® 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 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 dose may be necessary. In addition, due to reports of an 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 has not been observed in a well-designed interaction study with budesonide, a known substrate of cytochrome P450 3A.

Estrogenic hormones and cholesterol-lowering agents such as clofibrate increase cholesterol secretion in the liver and may therefore promote biliary lithiasis, counteracting the effect of ursodeoxycholic acid used for gallstone dissolution.

Therefore, when co-administering medicinal products metabolized by the P450 3A enzyme, caution is advised, and dose adjustments should be considered if necessary.

Special precautions for use.

Ursis® 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 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

After 6–10 months from the start of treatment, oral cholecystography should be used to evaluate the overall appearance of the stone and the patency 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 medicinal product must not be administered to patients with a gallbladder that is not visualized by radiographic methods, with calcified stones, impaired gallbladder contractility, or those experiencing frequent biliary colic.

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

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 may very rarely occur at the beginning of treatment, for example, pruritus may intensify. In such cases, the dose of Ursis® 500 mg film-coated tablets should be reduced to half a tablet (250 mg) per day; the dose should then be gradually increased as described in the section "Posology and method of administration."

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

Use during pregnancy or breastfeeding.

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. Ursodeoxycholic acid should not be used during pregnancy unless clearly necessary. Women of childbearing potential should only take the drug if reliable contraception is ensured.

It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Female patients receiving ursodeoxycholic acid for dissolution of gallbladder stones should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded before starting 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 vehicles or operate machinery has been observed.

Method of administration and dosage.

There are no age restrictions for the use of Ursis® tablets.

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

For dissolution of cholesterol gallstones

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

Table 1

The tablets should be swallowed whole with a small amount of liquid in the evening before bedtime.

The tablets 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.

Treatment efficacy should be monitored every 6 months using ultrasound or radiographic imaging. Additional examinations should be performed to determine whether gallstones have become calcified 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 in divided daily doses administered three times a day. 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 medication should be taken regularly.

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

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 by taking half a tablet of Ursis® per day, followed by a gradual increase of the dose (increasing the daily dose by half a tablet of Ursis® weekly 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 absolute age restrictions for the use of Ursis® in children. However, children with body weight below 47 kg and/or children who have difficulty swallowing should be administered ursodeoxycholic acid in the form of a suspension.

For the treatment of hepatobiliary disorders in cystic fibrosis:

to be administered to children aged 6 to 18 years.

Overdose.

In case of overdose, diarrhea may occur. Other symptoms of overdose are unlikely because 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.

Specific antidotes are not required.

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

Additional information for special patient groups

Long-term therapy with high doses of ursodeoxycholic acid (28–30 mg/kg/day) in patients with primary sclerosing cholangitis (used off-label) has been associated with a higher incidence of serious adverse events.

Adverse reactions.

Assessment of the frequency of adverse effects is based on the following data:

very common: more than 1 in 10 treated;

common: more than 1 in 100 treated to 1 in 10 treated;

uncommon: more than 1 in 1000 treated to 1 in 100 treated;

rare: more than 1 in 10,000 treated to 1 in 1000 treated;

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

Gastrointestinal disorders:
During treatment with ursodeoxycholic acid, soft stools or diarrhea have been reported.

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 for advanced stages of PBC, very rarely decompensation of liver cirrhosis may develop, which partially improves after discontinuation of treatment.

Hypersensitivity reactions.

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters per pack.

10 tablets in a blister; 5 blisters per pack.

10 tablets in a blister; 10 blisters per pack.

Prescription category. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and address of its business activity.

04073, Ukraine, Kyiv, Kopilivska St., 38.

Web-site: www.vitamin.com.ua