Ursodez^® (Capsules) Instructions for Use

ATC Code

A05AA02 (Ursodeoxycholic acid)

Active Substance

Ursodeoxycholic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hepatoprotective agent with choleretic and cholelitholytic action

Pharmacotherapeutic Group

Means for the treatment of diseases of the liver and biliary tract; agents for the treatment of diseases of the biliary tract; bile acids and their derivatives

Pharmacological Action

Mechanism of action and pharmacodynamic effects

A small amount of ursodeoxycholic acid (UDCA) is contained in bile.

After oral administration, UDCA reduces the cholesterol saturation of bile by inhibiting cholesterol absorption in the intestine and reducing its secretion into bile. Presumably, as a result of cholesterol dispersion and the formation of liquid crystals, gradual dissolution of cholesterol gallstones occurs.

According to current concepts, the action of UDCA in liver diseases and cholestatic diseases is associated with the relative exchange of lipophilic, detergent-like, toxic bile acids for hydrophilic cytoprotective non-toxic UDCA, which leads to an improvement in the secretory function of hepatocytes and immunoregulatory processes.

Children

Cystic fibrosis

According to clinical reports, there is long-term experience (up to 10 years and more) of treating pediatric patients with cystic fibrosis-associated hepatobiliary disease (CFAHD) with UDCA. There is evidence that UDCA therapy can reduce bile duct proliferation, slow the progression of histologically detected damage, and even promote regression of hepatobiliary system changes if therapy is started at early stages of CFAHD. To optimize treatment efficacy, UDCA therapy should be started as early as possible after the diagnosis of CFAHD is established.

Pharmacokinetics

Absorption

After oral administration, UDCA is rapidly absorbed from the small intestine, in the proximal ileum by passive diffusion, and in the distal ileum by active transport. Approximately 60-80% of the administered dose is absorbed.

Distribution

Depending on the daily dose, the type of disease, or the condition of the liver, a greater or lesser amount of UDCA accumulates in the bile. At the same time, a relative decrease in the content of other more lipophilic bile acids is observed.

Metabolism

After absorption, UDCA is almost completely conjugated in the liver with glycine and taurine and excreted in the bile. During the “first pass” through the liver, up to 60% is biotransformed.

Under the action of intestinal bacteria, UDCA is partially decomposed to form 7-keto-lithocholic and lithocholic acids. Lithocholic acid is hepatotoxic and causes parenchymal liver damage in some animal species. In humans, it is absorbed only in small amounts, sulfated in the liver, and thus detoxified before excretion into the bile and elimination in the feces.

Elimination

The T_1/2 of UDCA is 3.5-5.8 days.

Indications

Adults and children aged 3 years and older.

Dissolution of cholesterol gallstones not > 15 mm in diameter with normal gallbladder contractility.

As part of complex therapy

• Primary biliary cholangitis (cirrhosis) without signs of decompensation;
• Primary sclerosing cholangitis;
• Non-alcoholic steatohepatitis;
• Cystic fibrosis in adults and children aged 6 years and older.

ICD codes

Dosage Regimen

Capsules

Orally. Swallow the capsules whole, without chewing, with water.

The drug is recommended to be taken regularly.

For patients who cannot swallow Ursodez^® capsules, or for patients with a body weight < 47 kg, it is recommended to use ursodeoxycholic acid (UDCA) preparations in the form of a suspension.

Dissolution of cholesterol gallstones (diameter not > 15 mm)

The recommended (approximate) dose is 10 mg UDCA per 1 kg of body weight per day (daily in the evening, before bedtime).

Dissolution of gallstones usually requires 6-24 months. If after 12 months of treatment the stone size does not decrease, treatment should be discontinued.

Treatment effectiveness should be assessed every 6 months by ultrasound or radiography. During the interim examination, it should be assessed whether calcification of the stones has occurred during the past period. In case of stone calcification, treatment should be discontinued.

As part of complex therapy

Primary biliary cholangitis (cirrhosis)

The recommended daily dose depends on body weight and ranges from 1 to 3 capsules (500 mg) (approximately 10-15 mg UDCA per 1 kg of body weight) in 2-3 divided doses. During the first 3 months of treatment, the daily dose of the drug should be divided into several doses. In case of improvement in liver function tests, it is possible to switch to a single daily dose in the evening.

The use of Ursodez^® for the treatment of primary biliary cholangitis (cirrhosis) can continue for an unlimited time.

In patients with primary biliary cholangitis (cirrhosis), clinical symptoms may rarely worsen at the beginning of treatment, for example, itching may increase. In this case, treatment should be continued by taking 250 mg (Ursodez^® in a 250 mg dosage or UDCA preparations available in the appropriate dosage) daily, then the dose should be gradually increased (increasing the daily dose weekly by 250 mg) until the recommended dosing regimen is reached again.

Primary sclerosing cholangitis

The recommended daily dose is 12-15 mg/kg in 2-3 divided doses. It has also been shown that a dose of 20 mg/kg per day improves histology and liver function tests in patients with primary sclerosing cholangitis.

Non-alcoholic steatohepatitis

The recommended average daily dose is 10-15 mg/kg in 2-3 divided doses. The duration of therapy is from 6-12 months and longer.

Cystic fibrosis (as part of complex therapy) in adults and children over 6 years

The recommended dose is 20 mg/kg/day in 2-3 divided doses, with a subsequent increase to 30 mg/kg/day if necessary.

Calculation of the daily number of capsules depending on the patient’s body weight and the recommended drug dose per 1 kg of body weight

Children

The dosing regimen for children aged 3 years and older does not differ from the dosing regimen for adults. For children under 3 years of age, it is recommended to use UDCA in the form of a suspension.

Adverse Reactions

Assessment of adverse reactions is based on the following classification: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency unknown (cannot be estimated from the available data).

Immune system disorders very rare – allergic reactions, incl. urticaria.

Gastrointestinal disorders common – unformed stools or diarrhea; very rare – acute pain in the right upper abdomen (when treating primary biliary cholangitis (cirrhosis)).

Hepatobiliary disorders very rare – calcification of gallstones, decompensation of liver cirrhosis, which regresses after drug withdrawal (when treating late stages of primary biliary cholangitis (cirrhosis)).

Skin and subcutaneous tissue disorders very rare – skin rash.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to UDCA, other bile acids, or to any of the excipients of the drug;
• Radiopaque (high calcium content) gallstones;
• Impaired gallbladder contractility;
• Acute inflammatory diseases of the gallbladder and bile ducts;
• Occlusion of the biliary tract (obstruction of the common bile duct or cystic duct);
• Frequent episodes of biliary colic;
• Decompensated liver cirrhosis;
• Severe hepatic and/or renal impairment.

Children

Unsuccessful portoenterostomy or cases of failure to restore normal bile flow in children with biliary atresia.

UDCA has no age restrictions for use; however, to avoid difficulty in swallowing capsules, children under 3 years of age are recommended to use UDCA preparations in the form of a suspension.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of UDCA in pregnant women are limited or absent. Animal studies have shown reproductive toxicity in early pregnancy. UDCA should not be used during pregnancy, except when clearly necessary.

Use of the drug by women of childbearing potential is possible only if they use reliable methods of contraception. It is recommended to use non-hormonal contraceptives or oral contraceptives with low estrogen content. However, patients taking UDCA for gallstone dissolution should use effective non-hormonal contraception, as hormonal oral contraceptives may increase gallstone formation. The possibility of pregnancy must be excluded before starting treatment.

Breastfeeding period

According to several documented cases, the level of ursodeoxycholic acid in breast milk in women is very low, and therefore the occurrence of adverse reactions in breastfed children is not expected.

Fertility

There are no data on the effect of UDCA treatment on human fertility. According to animal studies, UDCA has no effect on fertility.

Use in Hepatic Impairment

The drug is contraindicated in severe liver dysfunction, decompensated liver cirrhosis.

The drug should be prescribed with caution in cholestatic liver diseases.

Use in Renal Impairment

The drug is contraindicated in severe renal impairment.

Pediatric Use

The dosing regimen for children aged 3 years and older does not differ from the dosing regimen for adults. For children under 3 years of age, it is recommended to use UDCA in the form of a suspension.

Special Precautions

Ursodez^® should be taken under medical supervision.

During the first 3 months of treatment, liver function tests should be monitored: AST, ALT, and GGT every 4 weeks, and then every 3 months. Such monitoring will allow early detection of potential liver deterioration, especially in patients with late-stage primary biliary cholangitis (cirrhosis). Furthermore, this can quickly determine whether a patient with primary biliary cholangitis (cirrhosis) is responding to the treatment.

When used in patients for dissolution of cholesterol gallstones

To assess treatment progress and for timely detection of signs of stone calcification, the gallbladder should be visualized (oral cholecystography) with examination of opacities in the standing and supine positions (ultrasound) 6-10 months after the start of treatment.

If the gallbladder cannot be visualized on X-rays or in case of stone calcification, weak gallbladder contractility, or frequent colic attacks, Ursodez^® should not be used.

When treating patients with late-stage primary biliary cholangitis (cirrhosis)

Very rarely, cases of liver cirrhosis decompensation have been noted after discontinuation of therapy.

In patients with primary biliary cholangitis (cirrhosis), clinical symptoms may rarely worsen at the beginning of treatment, for example, itching may intensify. In this case, the drug dose must be reduced to 250 mg (Ursodez^® in a 250 mg dosage or UDCA preparations available in the appropriate dosage), and then gradually increased again.

When used in patients with primary sclerosing cholangitis

Long-term therapy with high doses of UDCA (28-30 mg/kg/day) in patients with this pathology may cause serious adverse reactions.

In case of diarrhea

In patients with diarrhea, the drug dose should be reduced. If diarrhea persists, treatment should be discontinued.

Women of childbearing potential

Women of childbearing potential may take the drug only if they use reliable contraceptive measures. It is recommended to use non-hormonal contraceptives or oral contraceptives with low estrogen content, since hormonal oral contraceptives may increase gallstone formation. Possible pregnancy should be excluded before starting treatment.

Use in pediatrics

UDCA has no age restrictions for use; however, to avoid difficulty in swallowing capsules, children under 3 years of age are recommended to use UDCA preparations in the form of a suspension.

Excipients

Ursodez^® contains the dye sunset yellow, which may cause allergic reactions.

Effect on ability to drive and operate machinery

Ursodez^® has no or negligible influence on the ability to drive and use machines.

Overdose

Symptoms diarrhea is possible in case of overdose. In general, other symptoms of overdose are unlikely, since with an increase in the UDCA dose, its absorption decreases and fecal excretion increases.

Treatment specific treatment is not required, the consequences of diarrhea are treated symptomatically with restoration of water-electrolyte balance.

Drug Interactions

Colestyramine, colestipol, and antacids containing aluminum hydroxide or smectite (aluminum oxide) reduce the intestinal absorption of ursodeoxycholic acid and thus reduce its uptake and effectiveness. If the use of drugs containing at least one of these substances is necessary, they should be taken at least 2 hours before taking the UDCA drug.

UDCA may affect the absorption of cyclosporine from the intestine. Therefore, in patients taking cyclosporine, the physician should check the blood concentration of cyclosporine and adjust the cyclosporine dose if necessary.

In some cases, UDCA may reduce the absorption of ciprofloxacin.

In a clinical study involving healthy volunteers, simultaneous use of UDCA (500 mg/day) and rosuvastatin (20 mg/day) led to a slight increase in plasma levels of rosuvastatin. The clinical significance of this interaction, incl. in relation to other statins, is unknown.

In healthy volunteers, UDCA reduced peak plasma concentrations and AUC of the calcium channel blocker nitrendipine. In case of simultaneous use of nitrendipine and UDCA, careful monitoring is recommended. An increase in the dose of nitrendipine may be required.

There are also reports of interaction with dapsone, which led to a decrease in the therapeutic effect of the latter. These observations, along with in vitro experimental data, suggest that UDCA may induce cytochrome P450 3A enzymes. However, in a planned interaction study with budesonide, which is a known substrate of cytochrome P450 3A, induction was not observed.

Estrogenic hormones and drugs that lower blood cholesterol, such as clofibrate, increase cholesterol secretion by the liver and therefore may stimulate gallstone formation, which counteracts the effect of UDCA used for gallstone dissolution.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.