Ukrliv®

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

Composition:

Active substance: ursodeoxycholic acid (ursodeoxycholic acid);

5 ml of suspension contain 250 mg of ursodeoxycholic acid;

Excipients: microcrystalline cellulose - sodium carboxymethylcellulose, benzoic acid (E 210), xylitol, glycerin, sodium saccharin, sodium chloride, citric acid monohydrate; sodium citrate, lemon flavoring, purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: viscous white suspension with lemon odor.

Pharmacotherapeutic group.

Agents used in the treatment of liver and biliary tract. 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 cholesterol saturation in bile by inhibiting cholesterol absorption in the small intestine and decreasing cholesterol secretion into bile. As a result, cholesterol dispersion and formation of liquid crystals lead to gradual dissolution of gallstones.

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

Pediatric use

Mucoviscidosis

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

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%. After absorption, the bile acid undergoes almost complete hepatic conjugation with the amino acids glycine and taurine, and is then excreted into bile. Hepatic first-pass clearance is up to 60%.

Depending on the daily dose and the underlying liver disorder or condition, 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 occurs to 7-ketolithocholic and lithocholic acids. Lithocholic acid is hepatotoxic and causes parenchymal liver damage in some animal species. In humans, only a small amount is absorbed, which undergoes sulfation in the liver and is thus detoxified before being excreted in bile and ultimately in feces.

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

Clinical characteristics.

Indications.

Symptomatic treatment of primary biliary cholangitis (PBC) in the absence of decompensated liver cirrhosis.

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 the treatment of hepatobiliary disorders in cystic fibrosis in children aged 1 month to 18 years.

Contraindications.

Hypersensitivity to bile acids or to any of the excipients of the medicinal product.

Acute cholecystitis or acute cholangitis.

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.

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 Ukrliv® must not be used concomitantly with cholestyramine, colestipol, or antacids containing aluminium hydroxide and/or smectite (aluminium oxide), as these agents bind UDCA in the intestine, thereby interfering with its absorption and reducing efficacy. If administration of a 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 affect intestinal absorption of cyclosporine. Therefore, in patients receiving cyclosporine, blood levels of this substance should be monitored and the dose adjusted if necessary.

In individual cases, UDCA may reduce absorption of ciprofloxacin.

There are clinical data showing 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. An increase in nitrendipine dosage 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, when investigating the interaction between UDCA and budesonide—a well-established substrate of cytochrome P450 3A—no such effect was observed.

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

Special precautions for use.

The medicinal product Ukliv® 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 (aspartate aminotransferase), ALT (alanine aminotransferase), and γ-GT (γ-glutamyl transferase). Subsequently, these parameters should be monitored 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, visualization of the gallbladder (oral cholecystography) with imaging 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 Ukliv® should not be used if the gallbladder is not visualized on X-ray images, in the presence of calcified stones, impaired gallbladder contractility, or frequent biliary colic.

Women taking the medicinal product Ukliv® for dissolution of gallstones should use an effective non-hormonal contraceptive method, as hormonal contraceptives may increase the risk of gallstone formation.

Treatment of patients with advanced-stage PBC.

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 (e.g. increased pruritus) may rarely occur. In such cases, the dose of Ukliv® should be reduced to 250 mg per day; the dose should then be gradually increased as described in the section "Dosage and administration".

In case of diarrhea, a dose reduction is recommended; if diarrhea persists, treatment should be discontinued.

One measuring spoon (equivalent to 5 ml) of the medicinal product Ukliv®, oral suspension, 250 mg/5 ml contains 0.34 mmol (7.95 mg) of sodium. Patients who are on a sodium-restricted diet should take this into account.

The medicinal product Ukliv®, oral suspension, 250 mg/5 ml contains xylitol: 1 ml of suspension contains 0.35 g of xylitol. The energy value of 1 g of xylitol is 2.4 kcal. When administered according to the recommended dosage, the single dose of xylitol ranges from 0.44 g (1.25 ml of suspension) to 12.25 g (35 ml of suspension). A single dose of xylitol exceeding 10 g (over 28.57 ml of suspension) may have a laxative effect.

Use during pregnancy and lactation.

Pregnancy

Animal studies have not shown any effect of UDCA on fertility. Data on effects on human fertility are lacking.

There is insufficient data on the use of UDCA in pregnant women. Animal studies indicate reproductive toxicity in early pregnancy. The medicinal product Ukliv® should not be used during pregnancy except when clearly necessary. Women of childbearing potential should only take this product if they are using reliable contraceptive methods.

Women of childbearing potential

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

Lactation.

Available data from several reported cases of use in breastfeeding women indicate that UDCA levels in breast milk are extremely low; therefore, adverse effects in breastfed infants are not expected.

Ability to influence the speed of reactions when driving or operating machinery.

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

Method of administration and dosage.

The following daily doses are recommended for various indications.

For dissolution of cholesterol gallstones.

Approximately 10 mg UDCA/kg body weight per day (see Table 1).

Table 1

* 1 measuring spoon (= 5 mL of suspension) contains 250 mg of UDCA.

The medicinal product Urkliv® should be taken in the evening, before bedtime. The suspension 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 by ultrasound or X-ray imaging. Additional examinations should be performed to check whether calcification of the stones has occurred over time. If calcification occurs, treatment should be discontinued.

For symptomatic treatment of primary biliary cholangitis (PBC).

The daily dose depends on body weight and is approximately 14±2 mg UDCA/kg body weight.

During the first 3 months of treatment, the medicinal product Urkliv® should be taken throughout the day, dividing the daily dose into several administrations. Once liver function parameters improve, the daily dose may be taken as a single dose in the evening.

Table 2

* 1 measuring spoon (= 5 ml of suspension) contains 250 mg of UDCA.

For dose measurement, a plastic disposable syringe without a needle can be used.

The medicinal product Ukrliv® should be taken according to the dosing regimen provided in Table 2. Regularity of administration must be maintained.

The use of the medicinal product Ukrliv® 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 initially taking a reduced daily dose of Ukrliv® suspension, followed by gradual dose escalation (increasing the daily dose weekly) until the recommended dosing regimen is achieved.

For the treatment of hepatobiliary disorders in cystic fibrosis.

For children with cystic fibrosis aged 1 month 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 needed.

Children weighing less than 10 kg are very rarely affected. In such cases, disposable syringes available over the counter are recommended for administering the oral suspension.

Single doses for children weighing less than 10 kg should be drawn from the measuring spoon provided in the package into a syringe up to a volume of 1.25 ml. A 2 ml disposable syringe with 0.1 ml graduations should be used for this purpose.

Note that disposable syringes are not included in the packaging.

To administer the required dose using a syringe:

1. Shake the suspension well before opening the bottle/vial.
2. Pour a small amount of suspension into the measuring spoon.
3. Draw slightly more suspension into the syringe than needed.
4. Press the syringe plunger with your finger to expel air bubbles from the suspension.
5. Check the volume of suspension in the syringe and adjust if necessary.
6. Carefully administer the syringe contents directly into the child’s mouth.

Do not draw suspension directly into the syringe from the bottle/vial. Do not pour unused suspension from the measuring spoon or syringe back into the bottle/vial.

Table 3

Dosing regimen for children weighing less than 10 kg: 20 mg UDCA/kg/day

(volume measuring device – disposable syringe)

Table 4

Dosing regimen for children with body weight over 10 kg: 20-25 mg UDCA/kg/day

(volume measuring device – measuring spoon)

Table 5

* Comparative table

Children.

For dissolution of cholesterol gallstones and symptomatic treatment of PBC

There are no age restrictions for the use of this medicinal product. Dosage according to the section "Method of administration and dosage".

For the treatment of hepatobiliary disorders in cystic fibrosis

To be used in children from 1 month of age.

Overdose.

Diarrhea may occur in case of overdose. Overdose is unlikely because 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.

No specific measures are required; consequences of diarrhea should be treated symptomatically, maintaining fluid and electrolyte balance.

Additional information regarding special patient groups.

Long-term high-dose UDCA therapy (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), not known (frequency cannot be estimated from 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 of suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report all 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 of children.

After first opening of the bottle or jar, the medicinal product should not be stored for more than 4 months.

Packaging.

30 ml or 200 ml of suspension in a bottle; or 40 ml in a jar. Each bottle or jar in a cardboard package together with a measuring spoon.

Prescription status.

Prescription only.

Manufacturer.

TOV "KUSUM PHARM".

Manufacturer's location and address of the place of business activity.

40020, Ukraine, Sumy region, Sumy city, Skryabina St., 54.

or

Manufacturer.

TOV "GLEDPHARM LTD".

Manufacturer's location and address of the place of business activity.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriia St., 54.