Ursosan®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSOSAN® (URSOSAN®)
Composition:
Active substance: ursodeoxycholic acid;
1 capsule contains 250 mg of ursodeoxycholic acid;
Excipients: corn starch, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate;
Capsule shell composition: gelatin, titanium dioxide (E 171).
Dosage form. Capsules.
Main physicochemical properties: white hard gelatin capsules size № 0, containing white or almost white powder; or white or almost white powder with agglomerates of mass; or white or almost white powder compressed into a column which disintegrates upon pressure.
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 cholesterol 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 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 hepatocyte secretory function, and immunoregulatory mechanisms.
Use in children
Mucoviscidosis (Cystic Fibrosis)
Clinical data are available 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. Evidence suggests that ursodeoxycholic acid may reduce bile duct proliferation, halt the progression of histological changes, and even reverse hepatobiliary abnormalities, provided that therapy is initiated early in the course of cystic fibrosis. For optimal treatment efficacy, ursodeoxycholic acid therapy should be started as soon as the diagnosis of cystic fibrosis is confirmed.
Pharmacokinetics.
After oral administration, ursodeoxycholic acid is rapidly absorbed in the fasting state from the proximal and upper ileal segments of the small intestine via passive transport, and in the terminal ileum via active transport. The absorption rate typically ranges between 60% and 80%. Following absorption, the bile acid undergoes nearly complete hepatic conjugation 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 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 some animal species. In humans, only a small amount is absorbed, which is then sulfated in the liver and thereby detoxified prior to biliary excretion and subsequent fecal elimination.
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 the treatment of biliary reflux gastritis.
For symptomatic treatment of primary biliary cholangitis (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.
Obstruction of the bile ducts (obstruction of the common bile duct or cystic duct).
Frequent episodes of biliary colic.
Radiopaque calcified gallstones.
Impaired gallbladder contractility.
Failed outcome of portoenterostomy or absence of adequate bile drainage in children with biliary atresia.
Interaction with other medicinal products and other forms of interaction.
Ursosan 250 mg capsules must not be used concomitantly with cholestyramine, colestipol, or antacid preparations containing aluminum hydroxide and/or smectite, as these agents bind ursodeoxycholic acid in the intestine, thereby interfering with its absorption and reducing 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 Ursosan 250 mg capsules. Ursosan 250 mg capsules may enhance intestinal absorption of cyclosporine. In patients receiving cyclosporine, the physician should monitor blood levels of this substance and adjust the cyclosporine dose if necessary.
In individual cases, Ursosan 250 mg capsules may reduce 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 of the effect of concomitant use of nitrendipine and ursodeoxycholic acid is recommended. An increase in nitrendipine dosage may be required.
In addition, 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 well-established 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 is an effect opposite to that of ursodeoxycholic acid used for gallstone dissolution.
Special precautions for use.
Administration of Ursofan® 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 three 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 imaging in both upright and supine positions (under ultrasound monitoring) should be performed 6–10 months after initiation of therapy, depending on stone size.
Ursofan® 250 mg capsules should not be used if the gallbladder cannot be visualized on X-ray imaging, or in cases of stone calcification, impaired gallbladder contractility, or frequent biliary colic.
Women taking Ursofan® 250 mg capsules 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, exacerbation of symptoms at the beginning of treatment is very rare, for example, pruritus may worsen. In such cases, the dose of Ursofan® 250 mg capsules should be reduced to one 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. Ursofan® 250 mg capsules should not be used during pregnancy except in cases of urgent medical need. Women of childbearing potential may take the drug only if they use reliable contraceptive methods.
It is recommended to use non-hormonal contraceptives or low-estrogen oral contraceptives. Patients receiving Ursofan® 250 mg capsules 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.
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.
No influence on the ability to drive or operate machinery has been observed.
Method of administration and dosage.
For patients with body weight less than 47 kg or who experience difficulties swallowing capsules, it is recommended to use ursodeoxycholic acid in another pharmaceutical form.
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.
Treatment success should be monitored every 6 months by ultrasound or X-ray examination. Additional examinations are necessary to determine whether calcification of the stones has occurred over time. If calcification has occurred, 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, for the treatment of bile reflux gastritis, Ursofalk 250 mg capsules are taken for 10–14 days. The duration of treatment depends on the patient's condition. The physician must decide on the duration of treatment 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/kg 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 |
day |
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. Regularity of intake must be maintained.
The use of Ursofan 250 mg capsules in primary cholangitis may be indefinite.
In patients with primary biliary cholangitis, clinical symptoms may rarely worsen at the beginning of treatment; for example, itching may intensify. In such cases, therapy should be continued, starting with 1 capsule of Ursofan 250 mg daily, then gradually increasing the dose (by 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 escalation up to 30 mg/kg/day if necessary.
Table 3
| Body weight (kg) |
Daily dose (mg/kg) |
Ursofalk®, capsules, 250 mg |
||
| 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 biliary reflux gastritis, and symptomatic treatment of PBC.
There are no absolute age restrictions for the use of ursodeoxycholic acid in children; however, if a child weighs less than 47 kg and/or has difficulty swallowing, it is recommended to use ursodeoxycholic acid in another pharmaceutical form.
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 absorption of ursodeoxycholic acid decreases with increasing dose, and therefore 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, 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 (off-label use) has been associated with a higher frequency of serious adverse events.
Side effects
Evaluation of the frequency of adverse reactions 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 disorders
In clinical studies, reports of pasty stools or diarrhea during treatment with ursodeoxycholic acid were common.
Very rarely, severe abdominal pain localized in the right hypochondrium has been observed during treatment of primary biliary cholangitis.
Hepatobiliary disorders
Very rarely, calcification of gallstones may occur during treatment with ursodeoxycholic acid.
During therapy in advanced stages of primary biliary cholangitis, very rare cases of decompensation of liver cirrhosis have been observed, which partially regressed after discontinuation of treatment.
Hypersensitivity reactions
Very rarely, allergic reactions including rash and urticaria may occur.
Shelf life. 5 years.
Storage conditions. No special storage conditions required. Keep out of reach of children.
Packaging. 10 capsules in a blister; 1, 5, or 10 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
PRO.MED.CS Praha a.s.
Manufacturer's address and place of business.
Telčská 377/1, Michle, Praha 4, 140 00, Czech Republic.