Phosphogliv^® Urso (Capsules) Instructions for Use

Marketing Authorization Holder

Pharmstandard-Lexredstva OJSC (Russia)

ATC Code

A05C (Drugs for the treatment of biliary tract diseases and lipotropic agents in combination)

Active Substances

Glycyrrhizinic acid (BP British Pharmacopoeia)

Ursodeoxycholic acid (Rec.INN WHO registered)

Dosage Form

Phosphogliv® Urso

Capsules 35 mg+250 mg: 50 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size 0, white; contents – powder white or white with a creamy tint.

* calculated as 100% substance (trisodium salt of glycyrrhizic acid)

Excipients: microcrystalline cellulose M101 – 30.5 mg, croscarmellose sodium – 6.6 mg, hypromellose (hydroxypropyl cellulose) – 3.3 mg, magnesium stearate – 2.8 mg, colloidal silicon dioxide (aerosil) – 1.8 mg.

Capsule shell composition (body and cap): titanium dioxide (E171) – 1.92 mg, gelatin – 94.08 mg.

10 pcs. – blister packs (5) – cardboard packs.

Clinical-Pharmacological Group

Hepatoprotective agent with choleretic and cholelitholytic action

Pharmacotherapeutic Group

Drugs for the treatment of liver and biliary tract disorders in combination

Pharmacological Action

Combined medicinal product. It has hepatoprotective, choleretic, cholelitholytic, antioxidant, anti-inflammatory action; affects fibrogenesis.

Ursodeoxycholic acid

Bile acid. Reduces the cholesterol content in bile mainly by dispersing cholesterol and forming a liquid crystal phase. It affects the enterohepatic circulation of bile salts, reducing the intestinal reabsorption of endogenous more hydrophobic and potentially toxic compounds. In vitro studies have shown that Ursodeoxycholic acid has a direct hepatoprotective effect and reduces the hepatotoxicity of hydrophobic bile salts. It affects immunological reactions by reducing the pathological expression of HLA class I antigens on hepatocytes and suppressing the production of cytokines and interleukins.

Ursodeoxycholic acid reduces the lithogenic index of bile by increasing the content of bile acids in it. Promotes partial or complete dissolution of cholesterol gallstones when taken orally. It has a choleretic effect.

Glycyrrhizic acid

It has a hepatoprotective effect due to antioxidant, anti-inflammatory effects, as well as an effect on fibrogenesis.

It binds free oxygen radicals and inhibits enzymes that initiate lipid peroxidation in hepatocytes. Reduces inflammation by inhibiting the NF-kB, TLR4 signaling pathways; suppressing the production of pro-inflammatory cytokines; stimulating the production of anti-inflammatory cytokines. Glycyrrhizic acid inhibits 11β-hydroxysteroid dehydrogenase, which contributes to an increase in endogenous cortisol in the blood.

The effect on fibrogenesis is associated with a decrease in the expression of the type 1 collagen gene and a decrease in collagen production by hepatic stellate cells, as well as the destruction of activated cells.

Pharmacokinetics

Ursodeoxycholic acid

Ursodeoxycholic acid is absorbed from the small intestine by passive diffusion (about 90%), and from the ileum by active transport. After oral administration of a 250 mg dose, approximately 60-80% is absorbed. After a single oral dose of 500 mg, the C_max in blood serum at 30, 60, 90 min is 3.8 mmol/l, 5.5 mmol/l and 3.7 mmol/l, respectively.

Plasma protein binding is high – up to 96-99%. Penetrates the placental barrier. With systematic administration, Ursodeoxycholic acid becomes the main bile acid in the blood serum (48% of the total amount of bile acids). The therapeutic effect of the drug depends on the concentration of ursodeoxycholic acid in the bile.

It is metabolized in the liver (first-pass clearance through the liver) with the formation of taurine and glycine conjugates. The resulting conjugates are secreted into the bile.

About 50-70% of the total dose of the drug is excreted in the bile. A small amount of unabsorbed ursodeoxycholic acid enters the large intestine, where it is broken down by bacteria (7-dehydroxylation); the resulting lithocholic acid is partially absorbed from the large intestine but is sulfated in the liver and rapidly excreted as a sulfolithocholylglycine or sulfolithocholyltaurine conjugate.

Glycyrrhizic acid

After oral administration, under the influence of the enzyme β-glucuronidase produced by the bacteria of the normal microflora in the intestine, glycyrrhizic acid is converted into an active metabolite – β-glycyrrhetinic acid, which is absorbed into the systemic circulation. The C_max of β-glycyrrhetinic acid in blood plasma is reached after 11 hours, amounting to 267.319 ng/ml.

In the blood, β-glycyrrhetinic acid binds to albumin and is almost completely transported to the liver.

Excretion of β-glycyrrhetinic acid occurs mainly with bile, and residual amounts – with urine. T_1/2 reaches 19.23 h.

Indications

Non-alcoholic steatohepatitis, alcoholic liver disease, chronic hepatitis of various origins, biliary reflux gastritis, biliary dyskinesia, dissolution of cholesterol gallstones, primary biliary cirrhosis without signs of decompensation, primary sclerosing cholangitis.

ICD codes

Dosage Regimen

Administer orally with a sufficient amount of water.

For dissolution of cholesterol gallstones, the daily dose is 10-12 mg/kg. Take the total daily dose once in the evening before bedtime.

For non-alcoholic steatohepatitis and chronic hepatitis of various origins, the daily dose is 10-15 mg/kg. Divide the daily dose into 2-3 doses.

For biliary reflux gastritis, the daily dose is 250 mg (one capsule). Take once in the evening.

For primary biliary cirrhosis without decompensation, the daily dose is 12-16 mg/kg. Divide the daily dose into 2-3 doses.

For primary sclerosing cholangitis, the daily dose is 12-16 mg/kg. Divide the daily dose into 2-3 doses.

The duration of treatment is determined by the physician. For gallstone dissolution, continue treatment for 6-24 months after confirmed dissolution to prevent recurrence.

Monitor liver transaminases, ALP, GGT, and bilirubin every 4 weeks for the first 3 months, then every 3 months.

Perform ultrasound or cholecystography at 6-10 months to assess treatment efficacy for gallstone dissolution.

Reduce dose or discontinue in case of persistent diarrhea.

Adverse Reactions

From the digestive system often – unformed stools, diarrhea; very rarely – dyspepsia (belching, nausea, bloating), abdominal discomfort, acute pain in the right upper abdomen.

From the liver and biliary tract very rarely – calcification of gallstones, decompensation of liver cirrhosis (when treating advanced stages of primary biliary cirrhosis), which disappears after drug withdrawal.

From the cardiovascular system very rarely – transient increase in blood pressure, peripheral edema.

From the respiratory system very rarely – difficult nasal breathing, cough.

From the organ of vision very rarely – conjunctivitis.

Allergic reactions urticaria, skin rash.

Contraindications

Hypersensitivity, radiopaque gallstones, impaired contractility of the gallbladder, frequent episodes of biliary colic, occlusion of the biliary tract, acute inflammatory diseases of the gallbladder and bile ducts, liver cirrhosis in the stage of decompensation, severe hepatic and/or renal failure, pregnancy, breastfeeding period, children under 12 years of age, adults and children weighing less than 47 kg, unsuccessful portoenterostomy or cases of no restoration of normal bile outflow in children with biliary atresia.

With caution

In patients with portal hypertension, in patients with arterial hypertension.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and during breastfeeding.

Use in Hepatic Impairment

The drug is contraindicated for use in hepatic impairment.

Use in Renal Impairment

The drug is contraindicated for use in renal impairment.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 12 years of age.

Geriatric Use

Use with caution in elderly patients to avoid the risk of exacerbation of chronic diseases.

Special Precautions

During the first 3 months of treatment, it is necessary to monitor the activity of “liver” transaminases, ALP, GGT, serum bilirubin concentration every 4 weeks, and then every 3 months.

To assess treatment progress, visualization (oral cholecystography) with examination of opacities in standing and supine positions (ultrasound) should be performed 6-10 months after the start of treatment.

If the gallbladder is not visualized on X-rays or in case of stone calcification, weak gallbladder contractility, or frequent colic attacks, the drug should not be used.

Long-term therapy in patients with primary sclerosing cholangitis with high doses of ursodeoxycholic acid (28-30 mg/kg/day) may cause serious side effects.

In patients with diarrhea, the dosage of the drug should be reduced or discontinued in case of persistent diarrhea.

Drug Interactions

Cholestyramine, colestipol and antacids containing aluminum hydroxide or smectite (aluminum oxide), reduce the absorption of ursodeoxycholic acid in the intestine and reduce its uptake and effectiveness.

When used concomitantly with cyclosporine, the absorption unpredictably increases and the concentration of cyclosporine in the blood plasma increases.

A case of decreased concentration of ciprofloxacin in the blood plasma in a patient receiving ursodeoxycholic acid has been described.

Ursodeoxycholic acid reduces the concentration of the slow calcium channel blocker nitrendipine.

Estrogens, hypolipidemic drugs (clofibrate), increase the saturation of bile with cholesterol and may reduce the litholytic effect of ursodeoxycholic acid.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.