Ursophalk

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSOFALK (URSOFALK®)

Composition:

Active substance: ursodeoxycholic acid;

1 film-coated tablet contains 500 mg of ursodeoxycholic acid;

Excipients: microcrystalline cellulose, povidone K25, crospovidone type A, talc, magnesium stearate, colloidal anhydrous silicon dioxide, polysorbate 80, hypromellose, macrogol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white elongated tablets with notches 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 disease, lipotropic agents.

ATC code A05B.

Pharmacological properties.

Pharmacodynamics.

A small amount of ursodeoxycholic acid is found in human bile. After oral administration, ursodeoxycholic acid reduces cholesterol saturation in bile by inhibiting its intestinal absorption and decreasing cholesterol secretion into bile. Cholesterol dispersion and formation of liquid crystals may lead to gradual dissolution of gallstones.

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 by the hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of hepatocyte secretory function, and immunoregulatory processes.

Use in children

Mucoviscidosis (Cystic Fibrosis)

Available clinical data report long-term use of ursodeoxycholic acid (for periods up to 10 years) in the treatment of children with hepatobiliary complications associated with cystic fibrosis. Evidence suggests that ursodeoxycholic acid administration may reduce proliferation in bile ducts, halt the progression of histological changes, and even reverse hepatobiliary abnormalities, provided 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, ursodeoxycholic acid is rapidly absorbed in the jejunum and upper part of the ileum via passive transport, and in the terminal ileum via active transport. The absorption rate typically ranges from 60% to 80%. Following absorption, the bile acid undergoes nearly complete hepatic conjugation with the amino acids glycine and taurine, and is subsequently excreted into bile. Hepatic first-pass clearance is up to 60%.

Depending on the daily dose and the underlying disorder or hepatic 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 parenchymal liver damage in certain animal species. In humans, only a small amount is absorbed, which is sulfated in the liver and thereby detoxified before being excreted into bile and subsequently into feces.

The biological half-life of ursodeoxycholic acid ranges from 3.5 to 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) in the absence of decompensated liver cirrhosis.
• For treatment of hepatobiliary disorders in children with cystic fibrosis 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 bile duct (obstruction of the common bile duct or cystic duct).

• Frequent episodes of biliary colic.

• Radiopaque calcified gallstones.

• Impaired gallbladder contractility.

• Decompensated liver cirrhosis.

• Failed portoenterostomy or absence of adequate biliary drainage in children with biliary atresia.

Interaction with other medicinal products and other types of interactions.

Ursofalk must not be used concomitantly with cholestyramine, colestipol, or antacid preparations containing aluminium hydroxide and/or smectite (aluminium oxide), as these agents bind ursodeoxycholic acid in the intestine and thereby interfere with its absorption and reduce efficacy. If administration of preparations containing any of these substances is necessary, they should be taken at least 2 hours before or 2 hours after taking Ursofalk.

Ursofalk may enhance intestinal absorption of cyclosporine. In patients receiving cyclosporine, the physician should monitor blood concentration of this substance and adjust the cyclosporine dose if necessary.

In individual cases, the drug may reduce absorption of ciprofloxacin.

In a clinical study involving healthy volunteers, concomitant administration of ursodeoxycholic acid (500 mg/day) and rosuvastatin (20 mg/day) resulted in a slight increase in rosuvastatin plasma levels. The clinical significance of this interaction with regard to other statins is unknown. Ursodeoxycholic acid reduces the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) for the calcium antagonist nitrendipine.

Careful monitoring is recommended when nitrendipine and ursodeoxycholic acid are used concomitantly. An increase in nitrendipine dosage may be necessary. In view of this, and considering reports of a single case of interaction with dapsone (reduced therapeutic effect) and in vitro studies, it can be concluded that ursodeoxycholic acid induces the cytochrome P450 3A enzyme, which metabolizes medicinal products. However, induction was not observed in a well-designed interaction study with budesonide, a known substrate of cytochrome P450 3A.

Estrogenic hormones and cholesterol-lowering agents such as clofibrate increase cholesterol secretion in the liver and thus may promote biliary lithiasis, counteracting the effect of ursodeoxycholic acid used for dissolution of gallstones.

Therefore, when medicinal products metabolized by the P450 3A enzyme are used concomitantly, particular caution is required, and dose adjustment should be considered if necessary.

Special precautions for use.

Ursophalk tablets must be taken under medical supervision.

During the first 3 months of therapy, the physician should monitor liver function parameters—AST (SGOT), ALT (SGPT), and γ-GT—every 4 weeks, and thereafter every 3 months. This allows assessment of the appropriate response to treatment 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

After 6–10 months from the start of treatment, oral cholecystography should be performed to evaluate the overall appearance of the stone and the filling defect of the gallbladder in both upright and supine positions (ultrasound examination). This is necessary to assess therapeutic progress and to detect possible calcification of gallstones in a timely manner.

The drug must not be administered to patients with a gallbladder that is not visualized by radiographic methods, with calcified stones, impaired gallbladder contractility, or those experiencing frequent biliary colic.

Female patients taking Ursophalk 500 mg film-coated tablets for dissolution of gallstones should use an effective non-hormonal method of contraception, since hormonal contraceptives may enhance 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

Very rare cases of decompensation of liver cirrhosis have been reported, which partially regressed 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 Ursophalk 500 mg film-coated tablets should be reduced to half a tablet (250 mg) per day; the dose should then be gradually increased as described in the section "Method of administration and dosage."

If diarrhea develops, the dosage should be reduced; if diarrhea becomes persistent, treatment should be discontinued.

Use during pregnancy or lactation

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. Ursophalk 500 mg film-coated tablets should not be used during pregnancy unless clearly needed. Women of childbearing potential should only take the drug if reliable contraception is ensured.

It is recommended to use non-hormonal contraceptives or low-dose estrogen oral contraceptives. Patients receiving Ursophalk 500 mg film-coated tablets for dissolution of gallstones should use effective non-hormonal contraceptive methods, since hormonal oral contraceptives may enhance gallstone formation. Pregnancy should be excluded before starting 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 breastfed infants are not expected.

Effect on ability to drive vehicles or operate machinery

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

Method of administration and dosage

There are no age restrictions for the use of Ursofalk tablets.

Patients with body weight less than 47 kg or those who experience difficulty swallowing tablets may be administered Ursofalk in another pharmaceutical form (capsules or suspension).

For dissolution of cholesterol gallstones

Approximately 10 mg of ursodeoxycholic acid per 1 kg of body weight per day (see Table 1)

Table 1

The tablets should be swallowed whole, without chewing, with a small amount of liquid, in the evening before bedtime.

The tablets should be taken regularly.

The time required for dissolving 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.

The success of treatment should be monitored every 6 months using ultrasound or X-ray imaging. Additional examinations should verify whether calcification of the stones has occurred over time. If calcification has developed, treatment should be discontinued.

For symptomatic treatment of primary biliary cholangitis (PBC)

The daily dose depends on body weight and ranges from 1½ to 3½ tablets (14 ± 2 mg of ursodeoxycholic acid per kilogram of body weight), see Table 2.

During the first 3 months of treatment, Ursofalk tablets should be taken throughout the day, dividing the daily dose into several doses. When liver function parameters improve, the daily dose may be taken once daily in the evening.

Table 2

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

Ursosfalk can be used for a prolonged period in patients with primary biliary cirrhosis.

In patients with primary biliary cirrhosis, clinical symptoms may rarely worsen at the beginning of treatment; for example, itching may intensify. In such cases, therapy should be continued by taking half a tablet of Ursosfalk daily, followed by a gradual increase in dose (increasing the daily dose by half a tablet of Ursosfalk weekly until the recommended dosage regimen is achieved).

Use in children

Children with cystic fibrosis aged 6 to 18 years

The dose is 20 mg/kg/day, divided into 2–3 doses, with subsequent dose escalation up to 30 mg/kg/day, if necessary.

Table 3

Children.

For dissolution of cholesterol gallstones and symptomatic treatment of PBC

There are no fundamental age restrictions for the use of Ursofalk in children; however, Ursofalk suspension is recommended for children with body weight less than 47 kg and/or children who have difficulty swallowing.

For the treatment of hepatobiliary disorders in cystic fibrosis

Administered to children aged 6 to 18 years.

Overdose.

In case of overdose, diarrhea may occur. Other symptoms of overdose are unlikely because absorption of ursodeoxycholic acid 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.

Treatment is symptomatic and includes restoration of fluid and electrolyte balance.

Additional information regarding special patient groups

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

Adverse reactions.

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

very common: more than 1 in 10 treated patients;

common: more than 1 in 100 to 1 in 10 treated patients;

uncommon: more than 1 in 1,000 to 1 in 100 treated patients;

rare: more than 1 in 10,000 to 1 in 1,000 treated patients;

very rare/unknown: 1 in 10,000 treated patients or cannot be estimated from available data.

Gastrointestinal disorders

During clinical trials, loose stools or diarrhea were frequently reported during treatment with ursodeoxycholic acid.

Very rarely, severe right upper abdominal pain has been observed during treatment of PBC.

Hepatobiliary disorders

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

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

Hypersensitivity reactions

Very rarely, allergic reactions including rash and urticaria may occur.

Shelf life. 4 years. Do not use after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 25 tablets in a blister; 1, 2, or 4 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Dr. Falk Pharma GmbH.

Manufacturer's address and address of the site of operation.

Leinenweberstrasse 5, 79108 Freiburg im Breisgau, Germany.