Ukrliv®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT UKRLIVÒ (UKRLIVÒ)

Composition:

Active substance: ursodeoxycholic acid;

One tablet contains ursodeoxycholic acid 500 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), povidone K-30, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round, biconvex tablets, smooth on both sides.

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 (UDCA) is normally present in human bile.

After oral administration, it reduces the cholesterol saturation of bile by inhibiting cholesterol absorption in the small intestine and decreasing cholesterol secretion into bile. As a result of cholesterol dispersion and inhibition of crystal formation, gradual dissolution of cholesterol gallstones occurs.

The therapeutic effect of UDCA in liver diseases and cholestatic disorders is believed to be due to the relative replacement of lipophilic, detergent-like, cytotoxic bile acids with the hydrophilic, cytoprotective, and non-toxic UDCA, as well as to improved secretory function of hepatocytes and immunoregulatory mechanisms.

Pediatric use.

Cystic fibrosis.

There is evidence supporting the long-term use of UDCA (for periods up to 10 years) in the treatment of children with hepatobiliary abnormalities associated with cystic fibrosis. In particular, UDCA therapy may reduce proliferation in bile ducts, halt the progression of histological changes, and even reverse hepatobiliary abnormalities if treatment is initiated at an early stage of cystic fibrosis. For optimal therapeutic efficacy, UDCA treatment should be started as soon as the diagnosis of cystic fibrosis is confirmed.

Pharmacokinetics.

After oral administration, UDCA is rapidly absorbed in the small intestine and the upper part of the ileum via passive transport, and in the terminal ileum via active transport. The extent of absorption is generally 60–80%. Following absorption, the bile acid undergoes almost complete hepatic conjugation with the amino acids glycine and taurine, after which it is excreted into bile. The hepatic first-pass clearance is up to 60%.

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

Under the influence of intestinal bacteria, partial degradation of UDCA occurs, resulting in the formation of 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 into bile and ultimately into feces.

The biological half-life of UDCA is 3.5–5.8 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) provided that there is no 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 biliary tract (blockage of the common bile duct or cystic duct).

Frequent attacks of biliary (hepatic) colic.

Presence of radiopaque, calcified gallstones.

Impaired gallbladder contractility.

Liver cirrhosis in the decompensated stage.

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

Interaction with other medicinal products and other types of interactions.

The medicinal product Ukrliv® must not be used concomitantly with cholestyramine, colestipol, or antacids containing aluminum hydroxide and/or smectite, as these agents bind UDCA in the intestine, thereby interfering with its absorption and reducing efficacy. If administration of a medicinal product containing any of these substances is necessary, it should be taken at least 2 hours before or 2 hours after taking Ukrliv®.

UDCA may enhance intestinal absorption of cyclosporine. Therefore, in patients receiving cyclosporine, the blood concentration of this substance should be monitored and the dose adjusted if necessary.

In individual cases, UDCA may reduce absorption of ciprofloxacin.

Clinical data indicate that concomitant administration of UDCA (500 mg/day) and rosuvastatin (20 mg/day) in healthy volunteers led to a slight increase in rosuvastatin plasma concentration. The clinical significance of this interaction, as well as its relevance to other statins, has not been established.

It has been demonstrated that UDCA 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 nitrendipine and UDCA are used concomitantly. Dose adjustment of nitrendipine may be required.

Additionally, reduced therapeutic effect of dapsone has been reported.

These findings, together with in vitro data, suggest that UDCA may potentially induce cytochrome P450 3A enzymes. However, in a well-designed interaction study between UDCA and budesonide—a proven substrate of cytochrome P450 3A—no such effect was observed.

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

Special precautions for use.

The medicinal product Urkliv® should be taken under medical supervision.

During the first three months of treatment, the following liver function parameters should be monitored every 4 weeks: AST (SGOT), ALT (SGPT), and γ-GT, 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 gallstone calcification in a timely manner, gallbladder imaging (oral cholecystography) with visualization of opacities in both upright and supine positions (under ultrasound control) should be performed 6–10 months after initiation of treatment, depending on stone size.

The medicinal product Urkliv® should not be used if the gallbladder is not visualized on X-ray images, or in cases of gallstone calcification, impaired gallbladder contractility, or frequent biliary colic.

Female patients taking Urkliv® for dissolution of gallstones should use an effective non-hormonal method of contraception, as hormonal contraceptives may promote gallstone formation.

Treatment of patients with advanced-stage PBC.

Rare cases of decompensation of liver cirrhosis have been reported, which may partially regress 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 Urkliv® should be reduced to one 250 mg tablet daily; the dose may then be gradually increased as described in the section "Dosage and administration."

If diarrhea occurs, a dose reduction is recommended; if diarrhea persists, treatment should be discontinued.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have not shown any effect of UDCA on fertility. There are no data available on the effect on human fertility.

Data on the use of UDCA in pregnant women are insufficient. Animal studies indicate reproductive toxicity at early stages of pregnancy. Urkliv® should not be used during pregnancy unless absolutely necessary. Women of childbearing potential may take the product only if they are using reliable contraceptive methods.

Women of childbearing potential

It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Female patients receiving Urkliv® 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.

Breastfeeding.

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

Ability to affect reaction speed when driving vehicles or operating machinery.

No effects on the ability to drive vehicles or operate machinery have been observed.

Dosage and administration.

For patients weighing less than 47 kg or who experience difficulty swallowing tablets of the medicinal product Ukrliv®, an alternative dosage form is available – Ukrliv®, oral suspension.

For dissolution of cholesterol gallstones.

Approximately 10 mg UDCA per kilogram of body weight per day (see Table 1).

Table 1

*Instead of ½ tablet of Ukrliv® 500 mg, 1 tablet of Ukrliv® 250 mg can be used.

Tablets should be swallowed whole, without chewing, with water, once daily at bedtime.

Tablets 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 efficacy should be monitored every 6 months by ultrasound or X-ray imaging. Additional examinations should verify whether calcification of 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 1 ½ to 3 ½ * tablets (14±2 mg UDCA per kilogram of body weight).

During the first 3 months of treatment, the medicinal product Ukrliv® should be taken throughout the day, dividing the daily dose into several administrations. When liver function parameters improve, the daily dose may be taken once daily in the evening.

Table 2

*Instead of ½ tablet of the medicinal product Urkliv®, 500 mg, 1 tablet of the medicinal product Urkliv®, 250 mg, can be used.

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

The use of the medicinal product Urkliv® in PBC may be indefinite.

In patients with PBC, clinical symptoms such as pruritus may rarely worsen at the beginning of treatment. If this occurs, therapy should be continued by taking 1 tablet of Urkliv 250 mg daily, followed by gradual dose escalation (increasing the daily dose by 250 mg weekly) until the recommended dosing 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

*Instead of ½ tablet of the medicinal product Ukrliv®, 500 mg, 1 tablet of the medicinal product Ukrliv®, 250 mg, can be used.

Children.

For dissolution of cholesterol gallstones and symptomatic treatment of PBC

There are no absolute age restrictions for the use of the medicinal product Ukrliv® in children; however, children with body weight less than 47 kg and/or children who have difficulty swallowing should be administered the drug as a suspension.

For the treatment of hepatobiliary disorders in cystic fibrosis

To be used in children aged 6 to 18 years.

Overdose.

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

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

Specific interventions are not required. Management of diarrhea consequences is symptomatic and includes restoration of fluid and electrolyte balance.

Additional information regarding special patient groups.

Long-term therapy with high doses of UDCA (28–30 mg/kg/day) in patients with primary sclerosing cholangitis (use for unregistered indication) has been associated with a higher incidence of serious adverse events.

Adverse Reactions

The adverse reactions listed below are categorized by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000, including isolated cases), frequency not known (cannot be estimated from the available data).

Gastrointestinal disorders: common – pasty stools, diarrhoea; very rare – severe pain in the right upper quadrant of the abdominal cavity.

Hepatobiliary disorders: very rare – calcification of gallstones, decompensation of liver cirrhosis, which partially regressed after discontinuation of treatment.

Immune system disorders: very rare – hypersensitivity reactions, including skin rash (urticaria).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions to the State Expert Centre of the Ministry of Health of Ukraine and to the Marketing Authorization Holder via the feedback form on the website: https://kusum.ua/pharmacovigilance/.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 or 10 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and place of business.

54 Skryabina Street, Sumy, Sumy Oblast, 40020, Ukraine.

or

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and place of business.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.

or

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and place of business.

54 Davydovskoho Hryhoriia Street, Sumy, Sumy Oblast, 40020, Ukraine.