Holudexan

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

Composition:

Active substance: ursodeoxycholic acid;

1 capsule contains ursodeoxycholic acid 300 mg;

Excipients: maize starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Capsule shell composition: iron oxide red (E 172), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: opaque, hard gelatin capsules, body pink in color, cap red-brown in color, containing white or almost white powder.

Pharmacotherapeutic group.

Agents used in diseases of the liver and biliary tract. Agents used in biliary pathology. ATC code A05AA02.

Pharmacological properties.

Pharmacodynamics.

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

After oral administration, it reduces the cholesterol saturation of bile by inhibiting intestinal cholesterol absorption and decreasing cholesterol secretion into bile. Possibly due to cholesterol dispersion and formation of liquid crystals, gradual dissolution of gallstones occurs.

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.

Use in children.

Cystic fibrosis

Clinical reports provide information 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 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 treatment efficacy, ursodeoxycholic acid therapy should be started immediately after confirmation of the diagnosis of cystic fibrosis.

Pharmacokinetics.

After oral administration, ursodeoxycholic acid is rapidly absorbed in the small intestine and upper ileum via passive transport, and in the terminal ileum via active transport. The absorption rate is typically 60–80%.

Following absorption, the bile acid undergoes nearly 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 disorder or liver condition, the more hydrophilic ursodeoxycholic acid 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 acid and lithocholic acid. Lithocholic acid is hepatotoxic and causes liver parenchyma damage in some animal species. In humans, only a small amount is absorbed, which is sulfated in the liver and thus detoxified before being excreted in bile and ultimately in feces.

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

Clinical characteristics.

Indications.

• Diseases associated with impaired bile production function, including cholesterol supersaturation.

• Prevention of formation and dissolution of radiolucent cholesterol gallstones in patients with a functioning gallbladder, and stones in the common bile duct (residual or recurrent stones after surgery on the bile ducts).

• Biliary dyspepsia.

• Hepatobiliary disorders in cystic fibrosis in children aged 6 to 18 years.

Contraindications.

• Hypersensitivity to the active substance, bile acids, or to any of the other excipients 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 contractility of the gallbladder.
• Active phase of peptic ulcer of the stomach and duodenum.
• Failed portoenterostomy or absence of adequate biliary drainage in children with biliary atresia.

Interaction with other medicinal products and other forms of interaction.

Cholestyramine, colestipol, antacids containing aluminium hydroxide and/or smectite

Concomitant use with these agents results in binding of ursodeoxycholic acid in the intestine, thereby preventing its absorption and reducing efficacy. The medicinal product must not be used concomitantly with cholestyramine, colestipol, or antacids containing aluminium hydroxide and/or smectite. If use of these agents is necessary, they should be administered at least 2 hours before or 2 hours after administration of the medicinal product.

Cyclosporine

Concomitant use with ursodeoxycholic acid may enhance intestinal absorption of cyclosporine. When these agents are used together, plasma concentration of cyclosporine should be monitored and its dose adjusted if necessary.

Ciprofloxacin

Concomitant use with ursodeoxycholic acid may, in individual cases, reduce absorption of ciprofloxacin.

Rosuvastatin

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.

Nitrendipine

It has been demonstrated that ursodeoxycholic acid reduces the maximum plasma concentration (Cmax) and area under the curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers. When these agents are used concomitantly, careful monitoring of the patient is recommended. An increase in the dose of nitrendipine may be required.

Dapsone

Reduced therapeutic effect of dapsone has been reported with concomitant use of ursodeoxycholic acid.

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

Estrogenic hormones, agents for reducing plasma cholesterol concentration

Concomitant use with these agents may enhance hepatic cholesterol secretion and thus promote gallstone formation, which is an opposite effect to that of ursodeoxycholic acid, which is used for gallstone dissolution.

Hepatotoxic agents

The medicinal product is not recommended for concomitant use with such agents.

Special precautions for use

The use of the medicinal product should be under medical supervision.

The basis for using ursodeoxycholic acid to dissolve gallstones is the cholesterol nature of the stones themselves, indicated by their radiolucency.

The medicinal product is not recommended for patients with frequent biliary colic, gallbladder infections, severe pancreatic disorders, or intestinal diseases that may alter the enterohepatic circulation of bile acids (e.g., ileal resection or ileostomy).

At the beginning of long-term treatment for stone dissolution, monitoring of transaminase and alkaline phosphatase levels should be performed.

During the first three months of treatment, liver function parameters (AST, ALT, and GGT) should be monitored every 4 weeks, and thereafter once every 3 months. This allows assessment of treatment response in patients with primary biliary cholangitis (PBC) and 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 early signs of stone calcification, visualization of the gallbladder (oral cholecystography) should be performed 6–10 months after initiation of treatment, including imaging in both upright and supine positions (under ultrasound control). Subsequent efficacy assessments should be conducted every 6 months using cholecystography or ultrasound.

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

Women using the medicinal product for gallstone dissolution should use an effective non-hormonal method of contraception, as hormonal contraceptives may increase gallstone formation (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or lactation").

Treatment of patients with advanced-stage PBC

Decompensation of liver cirrhosis has been reported very rarely during treatment with ursodeoxycholic acid, which may partially regress after discontinuation of therapy.

Very rarely, at the beginning of treatment in patients with PBC, worsening of symptoms may occur, such as increased pruritus. In such cases, the dose of the medicinal product should be reduced.

The likelihood of successful dissolution is higher for small stones in a functioning gallbladder. Cholesterol desaturation of bile is an important prognostic factor for successful treatment outcome, but it is not definitive, as dissolution may also occur through a physical process of liquid crystal formation, independent of saturation status.

If diarrhea occurs, the dosage should be reduced. If diarrhea persists, treatment with the medicinal product should be discontinued.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of ursodeoxycholic acid in pregnant women are insufficient. Animal studies indicate reproductive toxicity in early pregnancy.

The medicinal product should not be used during pregnancy except in cases of clear medical necessity.

Women of childbearing potential may use the medicinal product only if they are using reliable contraceptive methods. It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Patients using the medicinal product for gallstone dissolution should use effective non-hormonal contraception, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be ruled out before initiating treatment.

Breastfeeding

Available data from several reported cases of ursodeoxycholic acid use in breastfeeding women indicate very low levels of the drug in breast milk; therefore, adverse effects in breastfed infants are not expected.

Fertility

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

Ability to influence reaction speed when driving or operating machinery

Ursodeoxycholic acid has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product is intended for oral administration.

Long-term use for reducing lithogenic properties of bile

The recommended daily dose of the medicinal product is 5–10 mg/kg body weight. On average, this corresponds to 300–600 mg per day (taken after or during meals and in the evening).

To maintain conditions favorable for stone dissolution, treatment duration should be continuous and last at least 4–6 months, and up to 12 months or longer. The medicinal product should be continued for an additional 3–4 months after radiological or echographic confirmation of stone disappearance. However, the total duration of treatment should not exceed 2 years.

Digestive disorders and maintenance therapy

The recommended dose of the medicinal product is 300 mg per day, divided into 2–3 doses (ursodeoxycholic acid preparations should be used at appropriate dosage).

Dosage may be adjusted at the physician's discretion.

There are no fundamental restrictions for the use of ursodeoxycholic acid preparations in children; however, ursodeoxycholic acid in capsule form should not be administered to children with body weight below 47 kg. If a child weighs less than 47 kg and/or has difficulty swallowing, it is recommended to use ursodeoxycholic acid in another pharmaceutical form, such as a suspension.

Cystic fibrosis

Children aged 6 to 18 years

The recommended daily dose of the medicinal product is 20 mg/kg body weight, divided into 2–3 doses. If necessary, the dose may be increased up to 30 mg/kg body weight.

Children

The medicinal product may be used in children aged 6 to 18 years with hepatobiliary disorders associated with cystic fibrosis.

Overdose

Diarrhea may occur in case of ursodeoxycholic acid overdose. Generally, other overdose symptoms are unlikely, as increased dosage leads to reduced absorption of ursodeoxycholic acid, with most of the administered dose being excreted in feces. Cases of overdose exceeding 4 g/day have not been reported (this dose is well tolerated).

In case of overdose, specific interventions are not required; diarrhea-related effects should be managed symptomatically, with restoration of fluid and electrolyte balance.

In the event of accidental oral ingestion of a very high dose of ursodeoxycholic acid, standard precautionary measures recommended for poisoning should be taken, and cholestyramine should be administered, considering its ability to form chelates with bile acids.

Additional information for special patient groups

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

Side effects

Side effects are classified according to frequency: very common (>1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (frequency cannot be estimated from the available data).

Gastrointestinal disorders

Cases of pasty stools or diarrhea have been reported during treatment with ursodeoxycholic acid.

Very rare cases of severe abdominal pain localized in the right hypochondrium have been observed during treatment of primary biliary cirrhosis.

Hepatobiliary disorders

Very rarely, calcification of gallstones may occur during treatment with ursodeoxycholic acid.

During treatment of advanced stages of PBC, decompensation of liver cirrhosis has been observed very rarely, which partially regressed after discontinuation of treatment.

Immune system disorders

Very rare allergic reactions, including rash and urticaria, are possible.

Tolerance to ursodeoxycholic acid when used at recommended doses is generally good. Isolated cases of gastrointestinal disturbances have been reported, which usually resolved during continued treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions through the national reporting system.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging

10 capsules per blister, 2, 5, 6, or 10 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

UORLД MEDICINE ILAC SAN. VE TIC. A.Ş./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey

Marketing Authorization Holder

LLC "WORLD MEDICINE", Ukraine
WORLD MEDICINE, LLC, Ukraine