Ursophalk

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

Composition:

Active substance: ursodeoxycholic acid;

5 ml of suspension (one measuring cup) contains 250 mg of ursodeoxycholic acid;

Excipients: benzoic acid (E 210), Avicel RC-591, sodium chloride, sodium citrate, anhydrous citric acid, glycerol, propylene glycol, xylitol, sodium cyclamate, lemon flavor, purified water.

Pharmaceutical form. Oral suspension.

Main physico-chemical properties: white homogeneous suspension with fine air bubbles and lemon odor.

Pharmacotherapeutic group.

Agents used in the treatment of liver and biliary tract disorders. Agents used in biliary pathology.

ATC code A05A A02.

Agents used in liver diseases, lipotropic agents.

ATC code A05B.

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 absorption of cholesterol and decreasing cholesterol secretion into bile. Gradual dissolution of gallstones may occur due to dispersion of cholesterol and formation of liquid crystals.

According to current knowledge, the therapeutic effect of ursodeoxycholic acid in liver diseases and cholestatic disorders 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

• Cystic fibrosis *

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

Pharmacokinetics.

After oral administration, ursodeoxycholic acid is rapidly absorbed in the fasting state from the upper and proximal ileum via passive transport, and in the terminal ileum via active transport. The absorption rate is typically 60–80%. After absorption, the bile acid undergoes almost complete conjugation in the liver with the amino acids glycine and taurine, and is then excreted in 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 of 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 some animal species. In humans, only a small amount is absorbed, which is then sulfated in the liver and thus detoxified before being excreted in bile and subsequently in feces.

The biological half-life of ursodeoxycholic acid 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) within 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 contractility of the gallbladder.

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

Interaction with other medicinal products and other forms of interaction.

Ursofalk, oral suspension 250 mg/5 ml, must not be administered concomitantly with cholestyramine, colestipol, or antacids containing aluminium hydroxide or smectite (aluminium oxide), as these agents bind ursodeoxycholic acid in the intestine, thereby interfering with its absorption and reducing efficacy. If administration of a medicinal product containing any of these substances is necessary, it should be taken at least 2 hours before or 2 hours after taking Ursofalk, oral suspension 250 mg/5 ml.

Ursofalk, oral suspension, may affect intestinal absorption of cyclosporine. Therefore, in patients receiving cyclosporine, blood concentrations of this substance should be monitored and the dose adjusted if necessary.

In individual cases, Ursofalk, oral suspension 250 mg/5 ml, may reduce the absorption of ciprofloxacin.

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, has not been established.

It has been demonstrated that ursodeoxycholic acid reduces the peak plasma concentration (Cmax) and area under the curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring is recommended when nifedipine and ursodeoxycholic acid are used concomitantly. An increase in the nifedipine dose may be required. In addition, reduced therapeutic effect of dapsone has been reported.

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

Estrogenic hormones, as well as lipid-lowering agents, may enhance hepatic cholesterol secretion and thus promote gallstone formation, which is an effect opposite to that of ursodeoxycholic acid used for their dissolution.

Special precautions for use

Ursophalk suspension should be taken under medical supervision.

During the first three months of treatment, liver function parameters (AST [SGOT], ALT [SGPT], and γ-GT) should be monitored every 4 weeks, and thereafter every 3 months. This monitoring allows assessment of treatment response in patients with PBC and enables timely detection of potential liver function abnormalities, particularly in patients with advanced-stage PBC.

Use for dissolution of cholesterol gallstones

To evaluate treatment efficacy and detect early calcification of gallstones, imaging of the gallbladder (oral cholecystography) and assessment of possible obstruction in both upright and supine positions (ultrasound monitoring) should be performed 6–10 months after initiation of treatment, depending on stone size.

Ursophalk oral suspension 250 mg/5 ml is not recommended if the gallbladder is not visualized on X-ray images or in the presence of radiopaque, calcified gallstones, impaired gallbladder contractility, or frequent biliary (hepatic) colic attacks.

Women taking Ursophalk oral suspension 250 mg/5 ml 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

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

In patients with PBC, symptom exacerbation may very rarely occur at the beginning of treatment, such as worsening pruritus. In such cases, the dose of Ursophalk oral suspension should be reduced to 250 mg/5 ml daily; the dose may then be gradually increased as described in the section "Dosage and administration".

If diarrhea occurs, a reduction in dose is recommended. Persistent diarrhea requires discontinuation of treatment.

One measuring cup (equivalent to 5 ml) of Ursophalk oral suspension 250 mg/5 ml contains 0.50 mmol (11.39 mg) of sodium. This should be taken into account by patients on a sodium-restricted diet (low-sodium diet).

Use during pregnancy and breastfeeding

Animal studies have not shown any effect of ursodeoxycholic acid on fertility. There are no data available on its effect on human fertility.

Data on the use of ursodeoxycholic acid in pregnant women are insufficient. Animal studies indicate reproductive toxicity at early stages of pregnancy. Ursophalk oral suspension 250 mg/5 ml should not be used during pregnancy unless clearly necessary. Women of childbearing potential should only take the medication if using reliable contraceptive methods.

Non-hormonal contraceptives or low-dose estrogen oral contraceptives are recommended. Patients receiving Ursophalk oral suspension 250 mg/5 ml for dissolution of gallbladder stones should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded before starting treatment.

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

Effect on ability to drive or operate machinery

No effects on the ability to drive or operate machinery have been observed.

Dosage and Administration

Opening the bottle with a child-resistant cap

To open the bottle, press the cap down firmly and turn it to the left.

For different indications, the daily doses specified below are recommended.

For dissolution of cholesterol gallstones

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

Table 1

* 1 measuring cup (= 5 ml of suspension) contains 250 mg of ursodeoxycholic acid.

Ursophalk suspension 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 the size of gallstones 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 has occurred, treatment must be discontinued.

For symptomatic treatment of primary biliary cirrhosis (PBC)

The daily dose depends on body weight and is approximately 14 ± 2 mg of ursodeoxycholic acid per kg of body weight.

During the first 3 months of treatment, Ursophalk suspension should be taken throughout the day, dividing the daily dose into several administrations. Once liver function parameters have improved, the daily dose may be taken once daily in the evening.

Table 2

* 1 measuring cup ( = 5 ml of suspension) contains 250 mg of ursodeoxycholic acid.

Ursophalk suspension should be taken according to the dosing regimen provided in Table 2. Regularity of administration must be maintained.

The use of Ursophalk suspension in primary biliary cirrhosis may be long-term without time limitation.

In patients with primary biliary cirrhosis, clinical symptoms may rarely worsen at the beginning of treatment; for example, pruritus may intensify. In such cases, therapy should be continued by initially administering a reduced daily dose of Ursophalk suspension, followed by gradual dose escalation (increasing the daily dose weekly) until the recommended dosing regimen is achieved.

Treatment of hepatobiliary disorders in cystic fibrosis

For children with cystic fibrosis aged 1 month to 18 years, the dose is 20 mg/kg/day, divided into 2–3 doses, which may be increased up to 30 mg/kg/day if necessary.

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 cup provided in the package into a syringe up to a volume of 1.25 ml. For this purpose, a 2 ml disposable syringe with 0.1 ml graduations should be used. Please note that disposable syringes are not included in the package but are freely available in pharmacies.

To administer the required dose using a syringe:

1. Shake the glass bottle well before opening.
2. Pour a small amount of suspension into the measuring cup.
3. Draw slightly more suspension into the syringe than required.
4. Press the syringe plunger with your finger to expel air bubbles from the drawn 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 the suspension directly into the syringe from the bottle. Do not pour unused suspension from the measuring cup or syringe back into the bottle.

Table 3

Dosing regimen for children weighing less than 10 kg: 20 mg of ursodeoxycholic acid/kg/day (measuring device – disposable syringe)

Table 4

Dosage regimen for children with body weight over 0.25 mg of ursodeoxycholic acid/kg/day (measuring device – measuring cup)

Table 4

* Conversion 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 aged 1 month and older.

Overdose.

Diarrhea may occur in case of overdose. Overdose is unlikely because the absorption of ursodeoxycholic acid decreases with increasing dose, and most of the administered amount is excreted in feces.

In case of diarrhea, the dose should be reduced; if diarrhea persists, therapy must be discontinued.

No specific antidotes are required; consequences of diarrhea should be treated symptomatically, maintaining 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 outside registered indication) has been associated with a higher frequency of serious adverse events.

Adverse Reactions.

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

Very common: >1/10.

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

Uncommon: >1/1,000 and <1/100.

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

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

Gastrointestinal adverse effects

Diarrhea or loose stools have been commonly reported during therapy with ursodeoxycholic acid.

Very rarely, severe pain in the right upper quadrant of the abdomen has been observed during treatment of primary biliary cirrhosis.

Hepatobiliary disorders

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

In the treatment of advanced stages of primary biliary cirrhosis, very rare cases of decompensation of liver cirrhosis have been observed, which partially regressed after discontinuation of therapy.

Hypersensitivity reactions

Very rarely, skin rashes (urticaria) may occur.

Shelf life. 4 years.

The shelf life after opening the bottle is 4 months.

The medicinal product must not be used after the expiry date stated on the packaging.

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

Packaging. Oral suspension (250 mg/5 mL), 250 mL in a glass bottle No. 1 with a measuring cup No. 1 in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Dr. Falk Pharma GmbH.

Manufacturer's address.

Leyenweberstrasse 5, 79108 Freiburg im Breisgau, Germany.