Ursophalk
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSOFALK (URSOFALK®)
Composition:
Active substance: ursodeoxycholic acid;
1 capsule contains 250 mg of ursodeoxycholic acid;
Excipients: maize starch, colloidal anhydrous silicon dioxide, magnesium stearate, titanium dioxide (E 171), gelatin, purified water, sodium lauryl sulfate.
Pharmaceutical form. Capsules.
Main physicochemical properties: white, opaque hard gelatin capsules of size "0", containing a white compacted powder or granules.
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 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 cholesterol saturation in bile by inhibiting intestinal absorption of cholesterol and decreasing cholesterol secretion into bile. The gradual dissolution of gallstones may occur due to cholesterol dispersion and formation of liquid crystals.
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 the hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of hepatocyte secretory function, and immunoregulatory processes.
Use in children
Mucoviscidosis (Cystic Fibrosis)
Clinical data are available on 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 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, 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 and in the upper 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 subsequently excreted into bile. The hepatic first-pass clearance is up to 60%.
Depending on the daily dose and the underlying liver disorder or 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 liver parenchyma 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.
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) therein.
For the treatment of biliary reflux gastritis.
For symptomatic treatment of primary biliary cholangitis (PBC) provided that decompensated liver cirrhosis is absent.
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 (obstruction of the common bile duct or cystic duct).
Frequent episodes of biliary colic.
Radiopaque calcified gallstones.
Impaired gallbladder contractility.
Failed portoenterostomy or lack of adequate biliary drainage in children with biliary atresia.
Interaction with other medicinal products and other forms of interaction.
Capsules Ursofalk 250 mg must not be administered simultaneously with cholestyramine, colestipol, or antacid preparations containing aluminium hydroxide and/or smectite, as these agents bind ursodeoxycholic acid in the intestine, thereby interfering with its absorption and reducing efficacy. If administration of agents containing any of these substances is necessary, they should be taken at least 2 hours before or 2 hours after Ursofalk 250 mg capsules.
Capsules Ursofalk 250 mg may enhance intestinal absorption of cyclosporine. In patients receiving cyclosporine, the physician should monitor blood concentrations of this substance and adjust the cyclosporine dose if necessary.
In individual cases, Ursofalk 250 mg capsules 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, is unknown.
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. Dose adjustment of nifedipine may be required.
Additionally, reduced therapeutic effect of dapsone has been reported.
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, as well as lipid-lowering agents such as clofibrate, may enhance hepatic cholesterol secretion and thus promote gallstone formation, which represents an effect opposite to that of ursodeoxycholic acid used for gallstone dissolution.
Special precautions for use.
The administration of Ursophalk 250 mg capsules 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 treatment response in patients with PBC, as well as timely detection of potential liver function abnormalities, particularly 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 assessment of opacities in both upright and supine positions (under ultrasound monitoring) should be performed 6–10 months after initiation of therapy, depending on stone size.
Ursophalk 250 mg capsules should not be used if the gallbladder cannot be visualized on radiographic imaging, or in cases of stone calcification, impaired gallbladder contractility, or frequent biliary colic.
Women taking Ursophalk 250 mg capsules for dissolution of gallstones should use an effective non-hormonal method of contraception, since hormonal contraceptives may increase the risk of gallstone formation.
Treatment of patients with advanced-stage PBC
Rarely, decompensation of liver cirrhosis has been reported, which may partially regress after discontinuation of therapy.
In patients with PBC, worsening of symptoms at the beginning of treatment (e.g. increased pruritus) may very rarely occur. In such cases, the dose of Ursophalk 250 mg capsules should be reduced to one capsule of Ursophalk 250 mg daily; 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 effects on human fertility are lacking.
There is insufficient data on the use of ursodeoxycholic acid in pregnant women. Animal studies indicate reproductive toxicity at early stages of pregnancy. Ursophalk 250 mg capsules should not be used during pregnancy except when clearly necessary. Women of childbearing potential should only take the medication if they are using reliable contraceptive methods.
Non-hormonal contraceptives or low-estrogen oral contraceptives are recommended. Patients receiving Ursophalk 250 mg capsules for gallstone dissolution should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded prior to 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 breastfed infants are not expected.
Ability to affect reaction speed when driving or operating machinery
No influence on the ability to drive or operate machinery has been observed.
Dosage and Administration
For patients weighing less than 47 kg or who have difficulty swallowing Ursofalk capsules, an alternative dosage form of Ursofalk is available — the suspension.
For dissolution of cholesterol gallstones
Approximately 10 mg of ursodeoxycholic acid per kg of body weight (see Table 1).
Table 1
| Body weight |
Number of capsules |
| up to 60 kg 61‒80 kg 81‒100 kg over 100 kg |
2 3 4 5 |
The capsules should be swallowed whole with water, once daily in the evening before bedtime.
The capsules should be taken regularly.
The time required for dissolution of 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 are necessary to determine whether calcification of the stones has occurred over time. If calcification occurs, treatment should be discontinued.
For the treatment of biliary reflux gastritis
1 capsule of Ursofalk 250 mg once daily with some liquid in the evening before bedtime.
Usually, Ursofalk 250 mg capsules are taken for 10–14 days for the treatment of bile reflux gastritis. The duration of treatment depends on the patient's condition. The physician must decide on the duration of therapy individually in each case.
For symptomatic treatment of primary biliary cholangitis (PBC)
The daily dose depends on body weight and ranges from 3 to 7 capsules (14 ± 2 mg of ursodeoxycholic acid per kg of body weight).
During the first 3 months of treatment, Ursofalk 250 mg capsules should be taken throughout the day, dividing the daily dose into 3 doses. When liver function parameters improve, the daily dose may be taken once daily in the evening.
Table 2
| Body weight (kg) |
Daily dose (mg/kg body weight) |
Capsules |
|||
| first 3 months |
thereafter |
||||
| morning |
afternoon |
evening |
evening (once daily) |
||
| 47–62 |
12–16 |
1 |
1 |
1 |
3 |
| 63–78 |
13–16 |
1 |
1 |
2 |
4 |
| 79–93 |
13–16 |
1 |
2 |
2 |
5 |
| 94–109 |
14–16 |
2 |
2 |
2 |
6 |
| over 110 |
2 |
2 |
3 |
7 |
|
The capsules should be swallowed whole with liquid. Regular administration must be maintained.
The use of Ursofalk 250 mg capsules in primary biliary cirrhosis may be indefinite.
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 taking 1 capsule of Ursofalk 250 mg daily, followed by gradual dose escalation (increasing the daily dose by 1 capsule weekly) until the prescribed dosage regimen is achieved.
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 necessary.
Table 3
| Body weight (kg) |
Daily dose (mg/kg) |
Ursofalk, 250 mg capsules |
||
| Morning |
Day |
Evening |
||
| 20–29 |
17‒25 |
1 |
-- |
1 |
| 30–39 |
19‒25 |
1 |
1 |
1 |
| 40–49 |
20‒25 |
1 |
1 |
2 |
| 50–59 |
21‒25 |
1 |
2 |
2 |
| 60–69 |
22‒25 |
2 |
2 |
2 |
| 70–79 |
22‒25 |
2 |
2 |
3 |
| 80–89 |
22‒25 |
2 |
3 |
3 |
| 90–99 |
23‒25 |
3 |
3 |
3 |
| 100–109 |
23‒25 |
3 |
3 |
4 |
| >110 |
3 |
4 |
4 |
|
Children.
For dissolution of cholesterol gallstones, treatment of bile reflux gastritis, and symptomatic treatment of PBC.
There are no absolute age restrictions for the use of Ursofalk in children. However, if a child weighs less than 47 kg and/or has difficulty swallowing, Ursofalk suspension is recommended.
For the treatment of hepatobiliary disorders in cystic fibrosis.
Use in children aged 6 to 18 years.
Overdose.
In case of overdose, diarrhea may occur. Other symptoms of overdose are unlikely because the absorption of ursodeoxycholic acid decreases with increasing dose, so most of the administered amount is excreted in feces.
If diarrhea occurs, the dose should be reduced; if diarrhea persists, treatment should be discontinued.
Specific antidotes are not required. Consequences of diarrhea should be managed symptomatically, including 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 not registered indication) has been associated with a higher incidence of serious adverse events.
Adverse Reactions
Assessment of the frequency of adverse reactions is based on the following data:
Very common: >1/10
Common: >1/100 to <1/10
Uncommon: >1/1,000 to <1/100
Rare: >1/10,000 to <1/1,000
Very rare: <1/10,000, including isolated cases
Gastrointestinal disorders
In clinical studies, pasty stools or diarrhea during treatment with ursodeoxycholic acid were commonly reported.
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 treatment of advanced stages of primary biliary cirrhosis, very rarely decompensation of liver cirrhosis has been observed, which partially regressed after discontinuation of therapy.
Hypersensitivity reactions
Very rarely, allergic reactions including rash and urticaria may occur.
Shelf life. 5 years.
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. 10 capsules in a blister; 1 blister per cardboard box.
25 capsules in a blister; 2 or 4 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Dr. Falk Pharma GmbH
Manufacturer's address and place of business.
Leinenweberstrasse 5, 79108 Freiburg im Breisgau, Germany.