Fosfogliv URSO, 35 mg+250 mg capsules 50 pcs

Pharmacotherapeutic group: drugs for the treatment of the liver and biliary tract in combination.

ATX code: A05C

Pharmacological properties.

Pharmacodynamics

Combined drug, hepatoprotective agent, also has choleretic, cholitholytic, antioxidant, anti-inflammatory actions, affects fibrogenesis.

Ursodeoxycholic acid

Ursodeoxycholic acid has a choleretic effect. It reduces the synthesis of cholesterol in the liver, its absorption in the intestine and its concentration in the bile, increases the solubility of cholesterol in the biliary system, stimulates the formation and excretion of bile. It decreases bile lithogenicity and increases bile acids content; it causes intensification of gastric and pancreatic secretion, increases lipase activity and has hypoglycemic effect. Causes partial or complete dissolution of cholesterol stones in enteral administration, reduces bile saturation with cholesterol, which promotes mobilization of cholesterol from gallstones. It has immunomodulatory effect, influences immunological reactions in the liver: it decreases the expression of some antigens on the membrane of hepatocytes, affects the number of T-lymphocytes, formation of introleukin-2, decreases the number of eosinophils.

Glycyrrhizic acid

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

Glycyrrhizic acid binds free oxygen radicals and inhibits enzymes that initiate lipid peroxidation (LPO) in hepatocytes.

Glycyrrhizic acid reduces inflammation through its inhibitory effect on NF-kB- and TLR4-signaling pathways; inhibition of pro-inflammatory cytokine production (TNF α, IL-1, IL-6, IL-8); stimulation of anti-inflammatory cytokine production (IL-2, IL-10, IL-12). Glycyrrhizic acid inhibits 11β-oxysteroid dehydrogenase, which increases endogenous cortisol in the blood (pseudocorticosteroid effect).

The effect on fibrogenesis is associated with reduction of collagen type 1 gene expression and reduction of collagen production by stellate liver cells (Ito cells), as well as destruction of activated Ito cells through the natural killer system, which helps to slow the progression of fibrosis.

Pharmacokinetics

Ursodeoxycholic acid

. After ingestion, ursodeoxycholic acid is rapidly absorbed in the jejunum and proximal ileum by passive diffusion and in the distal ileum by active transport. Absorption is approximately 60-80%.

After absorption ursodeoxycholic acid almost completely conjugates in the liver with glycine and taurine and is excreted with bile. During the first passage through the liver it is metabolized up to 60%.

Depending on the daily dose, type of disease or liver condition, more or less ursodeoxycholic acid accumulates in the bile. At the same time, there is a relative decrease in other more lipophilic bile acids.

In the intestinal bacteria, ursodeoxycholic acid is partially broken down to form 7-keto-lithocholic and lithocholic acids. In humans, lithocholic acid is absorbed only in small amounts, sulfated in the liver, excreted in the bile and excreted in the feces.

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

Glycyrrhizic acid

. After oral administration in the intestine, under the influence of β-glucuronidase enzyme produced by bacteria of normal microflora, glycyrrhizic acid forms an active metabolite – β-glycyrrhetic acid, which is absorbed into the systemic bloodstream. The maximum concentration (C_max) of β-glycyrrhetic acid in plasma is reached after 11 hours, being 267.319 ng/ml. The area under the pharmacokinetic curve (AUC_0-∞) is 5123.9 ng*h/ml. In blood β-glycyrrhetate binds to albumin and is almost completely transported to the liver. Excretion of β-glycyrrhetic acid occurs mainly in bile, with residual amounts in the urine. The elimination half-life reaches 19.23 hours.

Indications

– non-alcoholic steatohepatitis;

– alcoholic liver disease;

– chronic hepatitis of various genesis;

– biliary reflux gastritis;

– biliary dyskinesia;

– dissolution of cholesterol gallstones;

– primary biliary cirrhosis in the absence of signs of decompensation;

– primary sclerosing cholangitis.

Active ingredient

Glycyrrhizic acid, Ursodeoxycholic acid

Composition

Composition per capsule:

Active substances:

Ursodeoxycholic acid – 250.0 mg,

Glycyrrhizinate sodium converted to 100% substance (trisodium salt of glycyrrhizic acid) – 35.0 mg.

Supplementary substances: microcrystalline M 101 cellulose – 30.5 mg, croscarmellose sodium – 6.6 mg, hyprolose (hydroxypropyl cellulose) – 3.3 mg, magnesium stearate – 2.8 mg, colloidal silicon dioxide (aerosil) – 1.8 mg.

Capsule shell (body and cap): titanium dioxide (E 171) – 1.92 mg, gelatin – 94.08 mg.

How to take, the dosage

To be taken orally. Children over 12 years of age and adults with body weight over 47 kg should swallow the capsule whole. The drug should be taken regularly.

For convenience, the dosage regimens for different indications are presented in terms of ursodeoxycholic acid.

Non-alcoholic steatohepatitis:

The average daily dose is 10-15 mg/kg in 2-3 doses. The duration of therapy is 6-12 months or more.

Alcoholic liver disease:

The average daily dose is 10-15 mg/kg in 2-3 doses. The duration of therapy is 6-12 months or longer.

Symptomatic treatment of chronic hepatitis of various genesis:

Average daily dose 10-15 mg/kg in 2-3 bouts. The duration of therapy is 6-12 months or more.

Biliary reflux gastritis:

1 capsule of the drug daily in the evening before bedtime. The course of treatment from 10-14 days to 6 months, if necessary, up to 2 years.

Dyskinesia of the biliary tract :

The average daily dose is 10 mg/kg in 2 doses for 2 weeks to 2 months. If necessary, the course of treatment is recommended to be repeated.

Dissolution of cholesterol gallstones:

The average daily dose of ursodeoxycholic acid is 10 mg/kg per day, which corresponds to:

The drug should be taken in a daily dose once daily in the evening, before bedtime. It usually takes 6 to 24 months to dissolve stones. If after 12 months of treatment the size of the stones has not decreased, the treatment should be stopped.

The effectiveness of treatment should be evaluated every 6 months with ultrasound or radiography. In an interim evaluation, it should be assessed whether calculi have calcified during this period. If calculi have calcified, treatment should be discontinued.

Primary biliary cirrhosis:

The daily dose depends on body weight and is 2 to 6 capsules (approximately 10 to 15 mg of ursodeoxycholic acid per 1 kg body weight).

In the first 3 months of treatment, the drug intake should be divided into several intakes during the day. After improvement of hepatic parameters the daily dose of the drug can be taken once, in the evening. The following regimen of administration is recommended:

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The capsules should be taken regularly without chewing, with a small amount of water.

The use of Fosfogliv Urso for treatment of primary biliary cirrhosis may be continued indefinitely.

In patients with primary biliary cirrhosis, in rare cases, clinical symptoms may worsen at the start of treatment, for example, itching may increase. In this case, treatment should be continued with one capsule daily and then the dosage should be gradually increased (increasing the daily dose weekly by one capsule) until the recommended dosage regimen is reached again.

Primary sclerosing cholangitis:

The daily dose is 12-15 mg/kg; if necessary, the dose may be increased to 20 mg/kg in 2-3 doses. The duration of therapy ranges from 6 months to several years.

Interaction

Ursodeoxycholic acid

Colestyramine, colestipol and antacids containing aluminum hydroxide or smectite (aluminum oxide) reduce absorption of ursodeoxycholic acid in the intestine and thus reduce its absorption and effectiveness. If the use of drugs containing at least one of these substances is still necessary, they should be taken at least 2 hours before taking Fosfogliv^® URSO.

In concomitant use ursodeoxycholic acid may increase absorption of cyclosporine from the intestine. Therefore, in patients taking cyclosporine it is necessary to determine cyclosporine concentration in blood and adjust the dose of cyclosporine, if necessary.

Ursodeoxycholic acid may decrease absorption of ciprofloxacin.

In concomitant use ursodeoxycholic acid may cause a slight increase in plasma levels of rosuvastatin. The clinical significance of this interaction, including with other statins, is not known.

Ursodeoxycholic acid reduces the concentration and the area under the pharmacokinetic curve “concentration-time” of slow calcium channel blocker nitrendipine. In case of concomitant use of nitrendipine and ursodeoxycholic acid, close monitoring is recommended. Increased dose of nitrendipine may be required. In addition, a decrease in therapeutic effect of dapsone has been reported.

These data, as well as data obtained in vitro, suggest that ursodeoxycholic acid may induce CYP3A isoenzymes. However, the results of controlled clinical trials suggest that ursodeoxycholic acid has no pronounced inducing effect on CYP3A isoenzyme.

Estrogens, hypolipidemic drugs such as clofibrate increase bile cholesterol saturation and may decrease the litholytic effect of ursodeoxycholic acid.

Glycyrrhizic acid

In cases of interdrug interactions have not been described.

Special Instructions

The drug should be taken under medical supervision.

When used to dissolve cholesterol gallstones

. To assess the progress of treatment and for timely detection of signs of calcinosis of stones depending on their size, the gallbladder should be imaged (oral cholecystography) with observation of darkenings in standing and lying on the back (ultrasound examination) 6-10 months after the start of treatment.

If the gallbladder cannot be visualized on X-rays or if there is calcification of the stones, poor gallbladder contractility, or frequent attacks of colic, the drug should not be used.

Treatment of patients in advanced stages of primary biliary cirrhosis

There have been extremely rare cases of decompensation of liver cirrhosis. After discontinuation of treatment, regression of decompensation manifestations was noted.

In patients with primary biliary cirrhosis in rare cases at the beginning of treatment an increase of clinical symptoms, for example, pruritus may intensify. In this case, the dose of the drug should be reduced to 250 mg (in terms of ursodeoxycholic acid), and then gradually increased again, as described in the section “Dosage and administration”.

In patients with primary sclerosing cholangitis

Long-term therapy with high doses of ursodeoxycholic acid (28-30 mg/kg/day) in patients with this pathology may cause serious adverse events.

In patients with diarrhea, the drug dosage should be reduced. In persistent diarrhea, treatment should be discontinued.

Women of childbearing age can take the drug only if they use reliable contraception. It is recommended to use non-hormonal contraceptives, or oral contraceptives with low content of estrogen, because hormonal oral contraceptives may increase gallstone formation. Possible pregnancy should be excluded before starting treatment.

In case of high blood pressure, treatment with the drug should be stopped.

Influence on driving and operating ability

The drug has no adverse effect on the ability to drive vehicles or perform other work requiring increased concentration and quick psychomotor reactions. Or this effect is minimal.

Synopsis

Solid gelatin capsules #0. The body and cap are white. The contents of the capsules are powder of white or white with a creamy tint.

Contraindications

– hypersensitivity to the drug components or other bile acids;
– X-ray-positive (with high calcium content) gallstones;
– impairment of gallbladder contractility;
– frequent episodes of biliary colic;
– biliary tract occlusion (occlusion of common bile or gall ducts);
– acute inflammatory diseases of gallbladder and bile ducts;
– Severe hepatic cirrhosis at the decompensation stage;
– expressed hepatic and/or renal insufficiency;
– pregnancy;
– breastfeeding period;
– children under 12 years of age;
– adults and children with body mass – Adults and children with body weight less than 47 kg (for this dosage form)
– Unsuccessful portoenterostomy or cases of absence of restoration of normal bile flow in children with biliary tract atresia.

With caution
– in patients with portal hypertension;
– in patients with arterial hypertension.

Side effects

The evaluation of adverse events is based on the following classification:

Very common (≥1/10), common (≥1/100 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000), very rare (< 1/10000).

Gastrointestinal tract disorders:

often – loose stools or diarrhea; very rarely – dyspepsia (belching, nausea, bloating), abdominal discomfort, sharp pain in the right upper abdomen.

Hepatic and biliary tract disorders:

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

Cardiovascular system disorders:very rarely – transient increase in blood pressure, peripheral edema.

Allergic reactions: very rare – urticaria, skin rash, difficulty in nasal breathing, conjunctivitis, cough.

Overdose

In case of overdose of ursodeoxycholic acid, diarrhea is possible. In general, other symptoms of overdose are unlikely, because with increasing dose of ursodeoxycholic acid its absorption decreases, and excretion in the feces increases. Consequences of diarrhea are treated symptomatically (restoration of water-electrolyte balance). Cases of glycyrrhizic acid overdose have not yet been identified.

Pregnancy use

The drug is contraindicated during pregnancy and breastfeeding (due to insufficient data on its use in these groups of patients).