Ursohol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT

Composition:

Active ingredient: ursodeoxycholic acid;

1 capsule contains 250 mg of ursodeoxycholic acid;

Excipients: potato starch, methylcellulose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard, opaque, white gelatin capsules with white cap and body, containing white powder or granules.

Pharmacotherapeutic group. Agents used in biliary disorders.

ATC code A05A A02.

Agents used in liver diseases, lipotropic agents.

ATC code A05B.

Pharmacological properties.

Pharmacodynamics.

A small amount of ursodeoxycholic acid is naturally present in human bile. After oral administration, ursodeoxycholic acid reduces cholesterol saturation in bile by inhibiting intestinal cholesterol absorption and decreasing cholesterol secretion into bile. Cholesterol gallstones may gradually dissolve due to dispersion of cholesterol and formation of liquid crystals.

According to current data, 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, and non-toxic ursodeoxycholic acid, improvement of secretory function of hepatocytes, and immunoregulatory processes.

Use in children

Mucoviscidosis (Cystic Fibrosis)

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

Pharmacokinetics.

After oral administration, the drug is rapidly and completely absorbed: in the small intestine and upper ileum via passive transport, and in the terminal ileum via active transport. The average bioavailability is 60–80%. Peak plasma concentration is reached within 30–60 minutes. Ursodeoxycholic acid crosses the placental barrier. It is metabolized in the liver by conjugation with the amino acids glycine and taurine. The hepatic first-pass clearance is up to 60%. The drug is excreted from the body via bile. Depending on the daily dose and the underlying liver disorder or condition, the more hydrophilic ursodeoxycholic acid accumulates in bile, while there is a relative reduction in other, more lipophilic bile acids. Partial degradation by intestinal bacteria results in the formation of 7-ketolithocholic and lithocholic acids. Lithocholic acid is hepatotoxic and may cause liver parenchyma damage in some animal species. In humans, only a small amount is absorbed, which undergoes sulfation in the liver, thereby being detoxified before excretion into bile and ultimately in feces.

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

Clinical characteristics.

Indications.

• 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.
• Treatment of gastritis with bile reflux.
• Symptomatic treatment of primary biliary cirrhosis (PBC) in the absence of decompensated liver cirrhosis.
• For the 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.
• Biliary tract obstruction (blockage of the common bile duct or cystic duct).
• Frequent episodes of biliary colic.
• Radiopaque calcified gallstones.
• Impaired gallbladder contractility.
• Failed portoenterostomy or absence of adequate biliary drainage in children with biliary atresia.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the drug with other medicinal products may result in:

with aluminum-containing antacids; cholestyramine, colestipol – reduced intestinal absorption of ursodeoxycholic acid. Do not use these medicinal products simultaneously. If use of agents containing any of these substances is necessary, they should be administered at least 2 hours before or after taking Ursohol® capsules;

with cyclosporine – increased intestinal absorption of the latter. Periodic monitoring of cyclosporine blood levels is required and, if necessary, dose adjustment;

with ciprofloxacin – reduced intestinal absorption of the latter;

with oral hypoglycemic agents – enhanced effect of the latter;

with lipid-lowering agents (clofibrate, bezafibrate, probucol), estrogens – reduced efficacy of ursodeoxycholic acid due to increased cholesterol levels in bile.

Ursodeoxycholic acid reduces the maximum plasma concentration (Cmax) and area under the curve (AUC) for the calcium antagonist nitrendipine. Based on this, as well as a single report of interaction with dapsone (reduced therapeutic effect) and in vitro studies, it can be assumed that the drug induces the activity of the cytochrome P450 3A4 enzyme, which is involved in drug metabolism.

Therefore, when using drugs that are metabolized by this enzyme, caution should be exercised and it should be considered that dose adjustment may be necessary.

Estrogenic hormones, as well as drugs used to reduce blood cholesterol levels, may enhance hepatic cholesterol secretion and thus promote gallstone formation, which is an opposite effect to that of ursodeoxycholic acid used for their dissolution.

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.

Special precautions for use.

The administration of the medicinal product Ursochol® should be carried out under medical supervision.

During the first three 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 the presence or absence of treatment response in patients with PBC, as well as timely detection of potential liver function abnormalities, especially 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 examination of opacities in both upright and supine positions (under ultrasound monitoring) should be performed 6–10 months after initiation of treatment, depending on stone size.

Ursochol® should not be used if the gallbladder cannot be visualized on radiographic imaging or in the presence of stone calcification, impaired gallbladder contractility, or frequent biliary colic.

Women taking Ursochol® 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

Decompensation of liver cirrhosis has been reported very rarely, which may partially regress after discontinuation of therapy.

In patients with PBC, an exacerbation of symptoms may very rarely occur at the beginning of treatment, such as worsening pruritus. In such cases, the dose of Ursochol® should be reduced to 1 capsule per day; the dose should then be gradually increased as described in the section "Method of administration and dosage."

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. 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. Ursochol® should not be used during pregnancy except in cases of clear necessity. Women of childbearing potential may take the medicinal product only if they use reliable contraceptive methods.

It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Patients receiving Ursochol® for gallstone dissolution should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded before initiating 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 infants receiving such milk are not expected.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product does not affect the ability to drive or operate machinery.

Method of Administration and Dosage.

There are no age restrictions for the use of Ursochol®. The medicinal product should be administered orally to patients with a body weight greater than 47 kg. For patients with a body weight less than 47 kg or for those who have difficulty swallowing capsules, the medicinal product should be used in the form of a suspension.

For dissolution of cholesterol gallstones.

The medicinal product should be administered once daily in the evening before bedtime at a dose of approximately 10 mg/kg body weight.

Swallow the capsules whole with a small amount of liquid. The drug should be taken regularly.

The duration of treatment is usually 6–24 months. If no reduction in gallstone size is observed after 12 months, treatment with the drug should be discontinued.

The effectiveness of treatment should be monitored by ultrasound or radiological examination every 6 months. Additional investigations should be performed to detect possible calcification of stones. If calcification occurs, treatment should be discontinued.

For the treatment of gastritis with bile reflux.

Administer the drug once daily in the evening before bedtime at a dose of 1 capsule. Swallow the capsules whole with a small amount of liquid.

The duration of treatment depends on the patient's condition and usually lasts 10–14 days. The physician should decide on the duration of treatment individually in each case.

For symptomatic treatment of primary biliary cholangitis (PBC).

The daily dose of the drug depends on body weight and is approximately 14 ± 2 mg/kg body weight. During the first 3 months of treatment, divide the daily dose into 3 doses. Later, upon improvement of liver function parameters, administer the drug once daily in the evening.

Swallow the capsules whole with a small amount of liquid. The medication should be taken regularly.

The duration of treatment with this drug in primary biliary cirrhosis may be indefinite.

In patients with primary biliary cirrhosis, clinical symptoms may worsen at the beginning of treatment, for example, itching may intensify. If this occurs, therapy should be continued by taking the medication at a dose of 1 capsule per day, followed by gradual dose escalation (increasing the daily dose by 1 capsule each week) until the prescribed 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 needed.

Children

For dissolution of cholesterol gallstones, treatment of gastritis with bile reflux, and symptomatic treatment of PBC

There are no absolute age restrictions for the use of Ursohol® in children; however, if a child weighs less than 47 kg and/or has difficulty swallowing, it is recommended to use the medicinal product in the form of a suspension.

For treatment of hepatobiliary disorders in cystic fibrosis

Administer to children aged 6 to 18 years.

Overdose

In cases of overdose, diarrhea may occur. Other symptoms of overdose are unlikely, since the absorption of ursodeoxycholic acid decreases with increasing dose, and therefore most of the drug is excreted in feces.

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

Specific interventions are not required. Consequences of diarrhea should be treated symptomatically, with restoration of fluid and electrolyte balance.

Additional information regarding special patient groups.

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

Side effects.

The assessment of the frequency of adverse reactions is based on the following data:

Very common: >1/10.

Common: >1/100 and <1/10.

Uncommon: >1/1000 and <1/100.

Rare: >1/10,000 and <1/1000.

Very rare: <1/10,000, including single cases.

Gastrointestinal disorders: in clinical studies, mushy 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.

During therapy for advanced stages of primary biliary cirrhosis, very rare cases of hepatic decompensation have been observed, which partially regressed after discontinuation of treatment.

Immune system disorders: very rarely, allergic reactions including rash and urticaria may occur.

Skin and subcutaneous tissue disorders: very rarely, allergic reactions including rash and urticaria may occur.

Shelf life. 3 years.

Storage conditions.

Keep in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

10 capsules in a blister pack; 5 or 10 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Borispilska Street, Kyiv, 02093, Ukraine.