Ursis®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URSIS® (URSIS)
Composition:
Active substance: ursodesoxycholic acid;
One tablet contains ursodesoxycholic acid 250 mg;
Excipients: microcrystalline cellulose, crospovidone, povidone, polysorbate 80, talc, colloidal anhydrous silicon dioxide, magnesium stearate;
Coating: film-coating mixture Opadry Clear: hypromellose (hydroxypropylmethylcellulose), talc, polyethylene glycol (macrogol).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white or almost white, round, biconvex film-coated tablets.
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 the cholesterol saturation of bile by inhibiting intestinal absorption of cholesterol and decreasing cholesterol secretion into bile. Cholesterol gallstones may dissolve gradually due to dispersion of cholesterol and formation of liquid crystals.
Current understanding suggests that the therapeutic effect of ursodeoxycholic acid in liver diseases and cholestasis is due to the relative replacement of lipophilic, detergent-like toxic bile acids with the hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of secretory function of hepatocytes, 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 abnormalities 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 therapy is initiated at an early stage of cystic fibrosis. For optimal therapeutic efficacy, treatment with ursodeoxycholic acid should begin immediately after confirmation of the diagnosis of cystic fibrosis.
Pharmacokinetics
After oral administration, ursodeoxycholic acid is rapidly absorbed in the fasting state from the proximal jejunum via passive transport and in the terminal ileum via active transport. The absorption rate is typically 60–80%. After absorption, the bile acid undergoes nearly complete hepatic conjugation with the amino acids glycine and taurine, and is subsequently excreted in bile. The first-pass hepatic clearance is up to 60%.
Depending on the daily dose and the underlying liver condition or dysfunction, 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 may cause liver parenchyma damage in certain animal species. In humans, only a small amount is absorbed; this is sulfated in the liver and thereby detoxified before being excreted in bile and subsequently in 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 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.
-
Decompensated liver cirrhosis.
-
Failed outcome of portoenterostomy or absence of adequate bile flow in children with biliary atresia.
Interaction with other medicinal products and other forms of interaction.
The medicinal product UrSis® must not be used concomitantly with cholestyramine, colestipol, or antacid preparations containing aluminium hydroxide and/or smectite, as these agents bind ursodeoxycholic acid in the intestine and thereby interfere with its absorption and reduce 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 taking the product.
Ursodeoxycholic acid 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, ursodeoxycholic acid may reduce absorption of ciprofloxacin.
It has been shown in a clinical study in healthy volunteers that concomitant administration of ursodeoxycholic acid (500 mg daily) and rosuvastatin (20 mg daily) led to 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 concentration-time curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers. Careful 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 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 thereby promote gallstone formation, which is an effect opposite to that of ursodeoxycholic acid used for their dissolution.
Therefore, when co-administering medicinal products metabolized by the P450 3A enzyme, caution is advised and dose adjustments should be considered if necessary.
Special precautions for use.
The use of the medicinal product Ursis® 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 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 any signs of stone calcification in a timely manner, visualization of the gallbladder (oral cholecystography) with radiographic examination in both upright and supine positions (under ultrasound monitoring) should be performed 6–10 months after initiation of treatment, depending on stone size.
The medicinal product Ursis® should not be used if the gallbladder cannot be visualized on radiographic images, or in case of stone calcification, impaired gallbladder contractility, or frequent biliary colic episodes.
Women taking Ursis® 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
Very rare cases of decompensation of liver cirrhosis have 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 Ursis® should be reduced to 1 tablet per day, and then gradually increased as described in the section "Method of administration and dosage".
If diarrhea occurs, the dose should be reduced; if diarrhea persists, treatment 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 urgent medical need. Women of childbearing potential should only take the product if they are using reliable contraceptive methods.
It is recommended to use non-hormonal contraceptives or low-dose estrogen oral contraceptives. Patients taking Ursis® for dissolution of gallstones should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded before starting treatment.
Breastfeeding period. Available data from several reported cases of use in breastfeeding women indicate that the concentration of ursodeoxycholic acid in breast milk is very low; therefore, adverse effects in breastfed infants are not expected.
Fertility. Animal studies have not shown any effect of ursodeoxycholic acid on fertility. There are no data available on effects on human fertility.
Ability to influence 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 tablets, ursodeoxycholic acid in another pharmaceutical form, for example, as a suspension, is recommended.
For dissolution of cholesterol gallstones
Approximately 10 mg of ursodeoxycholic acid/kg body weight.
| Body weight |
Number of tablets |
| up to 60 kg 61‒80 kg 81‒100 kg over 100 kg |
2 3 4 5 |
The tablets should be swallowed whole with water, once daily in the evening before bedtime.
The tablets must 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 using ultrasound or radiographic imaging. Additional examinations are necessary to determine whether calcification of stones has occurred over time. If calcification develops, treatment should be discontinued.
For symptomatic treatment of primary biliary cholangitis (PBC)
The daily dose depends on body weight and ranges from 3 to 7 tablets (14 ± 2 mg of ursodeoxycholic acid/kg body weight).
During the first 3 months of treatment, the medication should be taken throughout the day, dividing the daily dose into 3 doses. Once liver function parameters improve, the daily dose may be taken once daily in the evening.
| Body weight (kg) |
Daily dose (mg/kg body weight) |
Tablets |
|||
| 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 tablets should be swallowed whole with liquid. Regular administration must be maintained.
The use of Ursis® in patients with 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 taking 1 tablet of 250 mg daily, followed by gradual dose escalation (increasing the daily dose by 1 tablet weekly) until the prescribed dosage regimen is achieved.
Use in children
For children aged 6 to 18 years with cystic fibrosis, the dosage is 20 mg/kg/day, divided into 2–3 doses, with subsequent dose increase up to 30 mg/kg/day if necessary.
| Body weight (kg) |
Daily dose (mg/kg) |
250 mg tablets |
||
| morning |
afternoon |
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 fundamental age restrictions for the use of Ursis® in children; however, if a child weighs less than 47 kg and/or has difficulty swallowing, ursodeoxycholic acid in the form of a suspension is recommended.
For treatment of hepatobiliary disorders in cystic fibrosis: to be used 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; 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 interventions 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 (use outside registered indication) has been associated with a higher frequency of serious adverse reactions.
Side effects.
Gastrointestinal tract: during treatment with ursodeoxycholic acid, there have been sporadic reports of pasty stools or diarrhea.
During treatment of primary biliary cirrhosis, severe abdominal pain localized in the right hypochondrium has been observed.
Liver and gallbladder: ursodeoxycholic acid treatment may lead to calcification of gallstones.
In advanced stages of primary biliary cirrhosis, decompensation of liver cirrhosis has been observed during therapy, which partially regressed after discontinuation of treatment.
Hypersensitivity reactions: allergic reactions are possible, including rash and urticaria.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
10 tablets in a blister; 3 blisters per pack.
10 tablets in a blister; 5 blisters per pack.
10 tablets in a blister; 10 blisters per pack.
Prescription status. Prescription only.
Manufacturer. JSC "KYIV VITAMIN PLANT".
Manufacturer's address and location of business activity.
38 Kopilivska Street, Kyiv, 04073, Ukraine.
Web-site: www.vitamin.com.ua