Pms-ursodiol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT pms-URSODIOL

Composition:

Active substance: ursodeoxycholic acid;

One tablet contains 250 mg or 500 mg of ursodeoxycholic acid;

Excipients: sodium starch glycolate (type A), povidone, sodium lauryl sulfate, microcrystalline cellulose, polyethylene glycol, magnesium stearate, tablet coating (hypromellose, polyethylene glycol).

Pharmaceutical form. Coated tablets.

Main physicochemical characteristics:

250 mg tablets: white, elliptical, biconvex, coated tablets, with the imprint "250" on one side and the logo "P" or blank on the other;

500 mg tablets:
white, elliptical, biconvex, coated tablets, with black inscription "UR 500" or imprint "500" on one side and imprint "P" or smooth surface on the other.

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.

Ursodeoxycholic acid is a natural minor component of bile acids. Oral administration of ursodiol results in a dose-dependent increase in the proportion of this fraction in the composition of bile acids.

When ursodeoxycholic acid is administered to patients with primary biliary cirrhosis, a reduction in cholesterol content is observed, which is due to decreased cholestasis and changes in cholesterol metabolism.

A small amount of ursodeoxycholic acid is normally 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. Possibly, due to cholesterol dispersion and formation of liquid crystals, gradual dissolution of gallstones occurs.

According to current knowledge, the effect of ursodeoxycholic acid in liver diseases and cholestasis is believed to be due to the relative replacement of lipophilic, detergent-like toxic bile acids with hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of hepatocyte secretory function, and immunoregulatory processes.

Use in children

Mucoviscidosis

Available clinical data support long-term use of ursodeoxycholic acid (for periods up to 10 years) in the treatment of children with hepatobiliary complications associated with mucoviscidosis (cystic fibrosis). Evidence suggests that ursodeoxycholic acid may reduce bile duct proliferation, halt progression of histological changes, and even reverse hepatobiliary abnormalities, provided therapy is initiated at an early stage of the disease. For optimal therapeutic efficacy, treatment with ursodeoxycholic acid should begin immediately after confirmation of the diagnosis of mucoviscidosis.

Pharmacokinetics.

After oral administration, ursodeoxycholic acid is rapidly absorbed in the fasting state in the upper part of the 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 nearly complete hepatic conjugation with the amino acids glycine and taurine, and is subsequently excreted in 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.

In the liver, ursodeoxycholic acid is conjugated with glycine or taurine and then secreted into bile. The conjugates of ursodeoxycholic acid are absorbed in the small intestine via both passive and active mechanisms. The conjugates may be hydrolyzed in the ileum by bacterial enzymes. The free ursodeoxycholic acid formed can then be reabsorbed and reconjugated in the liver. Unabsorbed ursodeoxycholic acid passes into the colon, where it is predominantly subjected to 7-dehydroxylation to form lithocholic acid. A portion of ursodeoxycholic acid undergoes epimerization to chenodeoxychol via a 7-oxo intermediate. Chenodeoxychol is also subject to 7-dehydroxylation, forming lithocholic acid. These metabolites are poorly soluble and are excreted in feces. A small amount of lithocholic acid undergoes enterohepatic recirculation, followed by conjugation in the liver with glycine or taurine and sulfation at the 3-position.

Ursodeoxycholic acid undergoes 7-dehydroxylation more slowly than chenodeoxychol. When equimolar amounts of ursodeoxycholic acid and chenodeoxychol are compared, the steady-state level of lithocholic acid in the bile acid pool is lower with ursodeoxycholic acid administration.

Under the influence of intestinal bacteria, partial degradation occurs to 7-ketolithocholic and lithocholic acids. Lithocholic acid is hepatotoxic and causes parenchymal liver damage in certain animal species. In humans, only a small amount is absorbed and undergoes hepatic sulfation, thereby being detoxified before excretion in bile and subsequently in feces.

Although cholestatic liver injury does not develop in humans during ursodeoxycholic acid administration, individual variations in the extent of lithocholic acid sulfation should be considered. However, deficiency in the capacity to sulfate lithocholic acid appears to be extremely rare and has not been practically observed despite the extensive clinical experience with long-term use of ursodeoxycholic acid.

In healthy individuals, approximately 70% of unconjugated ursodeoxycholic acid is bound to plasma proteins. Data on the protein binding of conjugated ursodeoxycholic acid are lacking. The volume of distribution for ursodeoxycholic acid has not been established, but it is expected to be small, considering that the drug is primarily concentrated in bile and the small intestine. Ursodeoxycholic acid is mainly excreted in feces. Administration of ursodeoxycholic acid increases its urinary excretion, although this remains minimal (less than 1%), except in cases of severe cholestatic liver disease.

With chronic administration of ursodeoxycholic acid, it becomes the predominant bile acid component; at a dose of 13–15 mg/kg/day, it accounts for 30–50% of total bile acids.

The biological half-life of ursodeoxycholic acid is 3.5–5.8 days.

Clinical characteristics.

Indications.

For dissolution of radiolucent cholesterol gallstones not exceeding 15 mm in diameter in patients with a functioning gallbladder, regardless of the presence of gallstone(s) in it.

For treatment of gastritis with bile reflux.

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 duct (obstruction of the common bile duct or cystic duct).

Frequent episodes of biliary colic.

Radiopaque calcified gallstones.

Impaired contractility of the gallbladder.

Liver cirrhosis in the decompensated stage.

Failure of portoenterostomy or absence of adequate bile drainage in children with biliary atresia.

Interaction with other medicinal products and other forms of interaction.

pms-Ursodiol 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, 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 pms-Ursodiol.

pms-Ursodiol 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, 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 respect 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 dose may be necessary.

Considering the above, and taking into account reports of one case of interaction with dapsone (reduced therapeutic effect) and in vitro study results, it may be concluded that ursodeoxycholic acid induces the cytochrome P450 3A enzyme responsible for drug metabolism. 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 co-administering medicinal products metabolized by this enzyme, particular caution is required, and dose adjustments may be necessary.

Special precautions for use.

pms-Ursodiol tablets should be taken under medical supervision.

Patients with variceal bleeding, hepatic encephalopathy, ascites, or those requiring liver transplantation should receive appropriate specific treatment.

Use in patients aged 65 years and older. No specific studies have been conducted. However, based on available data, no age-related problems specific to elderly patients are expected that would limit the use of ursodeoxycholic acid.

Monitoring and laboratory test data

Monitoring the efficacy of ursodeoxycholic acid in the treatment of cholestatic liver diseases is based on the analysis of biochemical parameters of cholestasis and detection of signs of hepatic cytolysis (increased aspartate aminotransferase and alanine aminotransferase activities), which often accompany progression of cholestasis.

During the first 3 months of therapy, the physician should monitor liver function parameters—levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase—every 4 weeks, and thereafter every 3 months. This allows assessment of an adequate response to treatment 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

After 6–10 months 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 medicinal product must not be administered to patients in whom the gallbladder is not visualized by radiological methods, patients with calcified stones, impaired gallbladder contractility, or those experiencing frequent biliary colic.

Female patients taking pms-Ursodiol for dissolution of gallstones should use an effective non-hormonal method of contraception, as hormonal contraceptives may promote gallstone formation (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding").

Treatment of patients with advanced-stage PBC

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 pms-Ursodiol 500 mg coated tablets should be reduced to 1 tablet per day; the dose should then be gradually increased as described in the section "Dosage and administration".

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

Excipients

This medicinal product contains sodium starch glycolate (type A) and sodium lauryl sulfate. This should be taken into account by patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Animal studies did not reveal any effect of ursodeoxycholic acid on fertility.

There are no data on the effect on human fertility.

Data on the use of ursodeoxycholic acid in pregnant women are insufficient. Animal studies indicate reproductive toxicity in early pregnancy. pms-Ursodiol coated tablets should not be used during pregnancy unless clearly needed. Women of childbearing potential should only take the medication if using reliable contraception.

It is recommended to use non-hormonal contraceptives or low-dose estrogen oral contraceptives. Female patients receiving pms-Ursodiol coated tablets for dissolution of gallstones should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be excluded before initiating treatment.

Based on several reported cases of use in breastfeeding women, the concentration of ursodeoxycholic acid in breast milk was extremely low; therefore, no adverse effects in breastfed infants are expected.

Ability to affect reaction speed when operating vehicles or other machinery

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

Method of administration and dosage.

pms-Ursodiol is taken orally.

There are no age restrictions for the use of this medicinal product. Patients weighing less than 47 kg or who have difficulty swallowing tablets should be administered ursodeoxycholic acid in another pharmaceutical form (capsules or suspension).

For dissolution of cholesterol gallstones

Administer approximately 10 mg of ursodeoxycholic acid/kg body weight, equivalent to:

for patients with body weight up to 60 kg 500 mg

61 – 80 kg 750 mg

81 – 100 kg 1000 mg

over 100 kg 1250 mg

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 a reduction in gallstone size is not observed after 12 months of treatment, therapy should not be continued.

Treatment efficacy should be monitored every 6 months using ultrasound or X-ray imaging. Additional examinations should verify whether gallstones have become calcified over time. If calcification occurs, treatment should be discontinued.

For treatment of gastritis with bile reflux

Administer 250 mg once daily with some liquid in the evening before bedtime.

Treatment of gastritis with bile reflux usually requires 10–14 days of administration. The duration of treatment depends on the patient's condition. The physician must decide on the treatment duration individually in each case.

For symptomatic treatment of primary biliary cholangitis (PBC)

The daily dose depends on body weight and ranges from 750 mg to 1750 mg (14±2 mg of ursodeoxycholic acid/kg body weight).

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

The tablets should be swallowed whole with liquid. The regularity of administration must be observed.

The use of PMS-Ursodiol in primary biliary cirrhosis may be unlimited in duration.

In patients with primary biliary cirrhosis, clinical symptoms may rarely worsen at the beginning of treatment; for example, itching may intensify. If this occurs, therapy should be continued at a dose of 250 mg per day, followed by gradual dose escalation (increasing the daily dose by 250 mg weekly) until the prescribed dosage regimen is reached.

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.

Children

For dissolution of cholesterol gallstones and symptomatic treatment of PBC:

There are no absolute age restrictions for the use of ursodeoxycholic acid in children. However, for children with body weight below 47 kg and/or children who have difficulty swallowing, ursodeoxycholic acid in the form of a 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; therefore, most of the administered dose is excreted in feces.

If diarrhea occurs, the dose should be reduced. If diarrhea persists, treatment should be discontinued.

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

Additional information regarding special patient groups

Long-term, high-dose ursodeoxycholic acid therapy (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

The frequency of adverse effects is defined as follows:

Very common: more than 1 in 10 patients treated;
Common: from more than 1 in 1,000 to 1 in 10 patients treated;
Uncommon: from more than 1 in 10,000 to 1 in 1,000 patients treated;
Rare: from more than 1 in 100,000 to 1 in 10,000 patients treated;
Very rare / Frequency unknown: less than 1 in 100,000 patients treated / cannot be estimated from available data.

Gastrointestinal disorders: dyspepsia; nausea and abdominal pain have been reported, as well as cases of anorexia, esophagitis, and peptic ulcer.

During clinical trials, pasty stools or diarrhea were commonly reported during treatment with ursodeoxycholic acid.

Very rarely, severe right upper quadrant abdominal pain has been observed during treatment of primary biliary cholangitis (PBC).

Hepatobiliary disorders: very rarely, gallstone calcification may occur during treatment with ursodeoxycholic acid.

Decompensation of liver cirrhosis has been observed during treatment of advanced stages of primary biliary cholangitis, which partially regressed after discontinuation of therapy.

Skin and subcutaneous tissue disorders: cases of pruritus. Very rarely, allergic reactions including rash and urticaria may occur.

Metabolic and nutritional disorders: cases of increased serum creatinine and elevated blood glucose levels.

General disorders: asthenia, chest pain, and peripheral edema.

Cardiovascular system: increased arterial blood pressure.

Blood and lymphatic system disorders: cases of leukopenia.

Hypersensitivity reactions: very rarely, allergic reactions including rash and urticaria may occur.

Shelf life. 5 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging.

100 tablets in bottles.

10 tablets in blisters, 5 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmascience Inc.

Manufacturer's address and place of business.

6111 Royalmount Avenue, Suite 100, Montreal, Quebec H4P 2T4, Canada.