Ursoliv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSLIV (URSOLIV)

Composition:

Active substance: ursodesoxycholic acid;

1 capsule contains ursodesoxycholic acid 250 mg;

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

Pharmaceutical form. Capsules.

Main physicochemical properties: opaque, elongated, white or almost white hard gelatin capsules of size “0” containing a white or almost white granular powder.

Pharmacotherapeutic group.

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

ATC code A05A A02.

Agents used in liver diseases, lipotropic agents.

ATC code A05B.

Pharmacological Properties.

Pharmacodynamics.

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

After oral administration, it reduces cholesterol saturation in bile by inhibiting cholesterol absorption in the intestine and decreasing cholesterol secretion into bile. Gradual dissolution of gallstones may occur due to cholesterol dispersion 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 hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of hepatocyte secretory function, and immunoregulatory processes.

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 generally 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 first-pass hepatic clearance is up to 60%.

Depending on the daily dose and the underlying liver disorder or 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 and lithocholic acids. Lithocholic acid is hepatotoxic and causes parenchymal liver damage in several animal species. In humans, only a small amount is absorbed, which is sulfated in the liver and thereby 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 no larger than 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 children aged 6 to 18 years with cystic fibrosis.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Acute inflammation of the gallbladder or bile ducts.

Obstruction of the 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 lack of adequate biliary drainage in children with biliary atresia.

Interaction with other medicinal products and other forms of interaction.

The medicinal product must not be used concomitantly with cholestyramine, colestipol, or antacid agents containing aluminium hydroxide and/or smectite, as these agents bind ursodeoxycholic acid in the intestine and thus interfere with its absorption and efficacy. If treatment with agents containing any of these substances is necessary, they should be taken at least 2 hours before or 2 hours after taking UrsoLiv capsules.

The medicinal product 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 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 and the area under the concentration-time curve of the calcium antagonist nitrendipine in healthy volunteers.

Careful monitoring is recommended when nifedipine and ursodeoxycholic acid are used concomitantly. An increase in the nifedipine dose may be required.

Furthermore, reduced therapeutic effect of dapsone has been reported.

These findings, together with in vitro data, suggest that ursodeoxycholic acid could potentially induce cytochrome P450 3A enzymes. However, in a well-designed interaction study with budesonide, a well-established substrate of cytochrome P450 3A, no such effect was observed.

Estrogenic hormones, as well as lipid-lowering agents, 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 UrsoLiv 250 mg capsules should be conducted under medical supervision.

During the first 3 months of treatment, liver function parameters (AST, ALT, and GGT) should be monitored 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

To evaluate treatment progress and to detect any signs of stone calcification in a timely manner, 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.

UrsoLiv 250 mg capsules should not be used if the gallbladder is not visualized on X-ray imaging, or in cases of gallstone calcification, impaired gallbladder contractility, or frequent biliary colic.

Women receiving UrsoLiv 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

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

In patients with PBC, worsening of symptoms at the beginning of treatment, such as increased pruritus, may very rarely occur. In such cases, the dose should be reduced to one capsule daily, and then 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 its effect on human fertility.

There is insufficient data on the use of ursodeoxycholic acid in pregnant women. Animal studies indicate reproductive toxicity at early stages of pregnancy. The drug should not be used during pregnancy except in cases of clear necessity. Women of childbearing potential should only take the drug if they are using reliable contraceptive methods.

Non-hormonal contraceptives or low-estrogen oral contraceptives are recommended. Patients receiving UrsoLiv 250 mg capsules 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 starting treatment.

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

Ability to affect driving and operating machinery

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

Dosage and administration.

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 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 are necessary to check whether calcification of the stones has occurred over time. If calcification has developed, treatment should be discontinued.

For the treatment of biliary reflux gastritis

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

For the treatment of bile reflux gastritis, 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 PBC

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

During the first 3 months of treatment, the medication should be taken with the daily dose divided 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 the drug 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 daily, then gradually increasing the dose (by increasing the daily dose by 1 capsule weekly) until the prescribed dosage regimen is achieved.

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 escalation up to 30 mg/kg/day if needed.

Table 3

Children.

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

There are no absolute age restrictions for the use of UrsoLiv in children; however, capsules should not be administered to children with body weight less than 47 kg and/or to children who have difficulty swallowing.

For treatment of hepatobiliary disorders in cystic fibrosis:

To be administered to children aged 6 to 18 years.

Overdose.

In cases of overdose, diarrhea may occur. Other symptoms of overdose are unlikely because the absorption of ursodeoxycholic acid decreases with increasing dose, so 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 antidotes are not required. Consequences of diarrhea should be managed symptomatically, including 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 (use not registered indication) has been associated with a higher frequency of serious adverse events.

Side effects.

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

Very common: ≥ 1/10.
Common: ≥ 1/100 and < 1/10.
Uncommon: ≥ 1/1,000 and < 1/100.
Rare: ≥ 1/10,000 and < 1/1,000.
Very rare: < 1/10,000, including isolated cases.

Gastrointestinal disorders

In clinical trials, pasty stools or diarrhea were 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.

In 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.

Shelf life. 3 years.

The drug must not be used after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

10 capsules in a blister; 5 or 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Mega Lifesciences Public Company Limited.

Manufacturer's address and place of business.

Plant 2, 515/1 Moo 4, Soi 8, Bangpoo Industrial Estate, Pattana 3 Road, Phraeksa, Mueang, 10280 Samutprakarn, Thailand.