Heptral, 400 mg, lyophilisate for the preparation of solution for intravenous and intramuscular administration, complete with solvent, 5 pcs.

Heptral 400 mg tablet No. 20

Description Name: Heptral 400 mg tablet No. 20 (Heptral)

Pharmacological action: Heptral belongs to the group of hepatoprotectors with antidepressant activity. It has choleretic and cholekenetic effects, has detoxification, regenerating, antioxidant, antifibrinolytic and neuroprotective properties. The drug not only compensates for the lack of ademetionine in the body, but also stimulates its production in various organs (primarily in the liver, brain and spinal cord). Ademetionine is a substance that is found in almost all tissues and physiological fluids of the body. Due to its chemical structure, the drug is a methyl group donor in transmethylation reactions. It is the basis for many biochemical thiol compounds (cysteine, taurine, coenzyme A, etc.) in the process of transsulfuration, a precursor of polyamines (putrescine, spermidine, spermine, included in the structure of ribosomes), stimulates cell regeneration.

Transmethylation (transfer of methyl groups) of ademetionine to various substances in the body (hormones, neurotransmitters, proteins, phospholipids) is an important metabolic process. With long-term use, there is an increase in glutamine in the liver, cysteine ​​and taurine in the plasma, a decrease in the amount of methionine in the blood serum, which suggests a normalization of metabolic processes in the liver and an improvement in its function. The drug has a choleretic effect by stimulating the synthesis of phosphatidylcholine in the membranes of hepatocytes and increasing their elasticity and polarization. This leads to an improvement in the function of bile acid transport systems and promotes the release of bile acids into the biliary system. Taking the drug promotes the detoxification of bile acids by sulfating them. This promotes their elimination by the kidneys, facilitates their passage through the hepatocyte membrane and excretion in the bile. When taking the drug, there is a positive dynamics in the level of direct bilirubin, the activity of alkaline phosphatase, and aminotransferases. Choleretic and hepatoprotective effects persist for 3 months after stopping the drug.

The content of ademetionine in the body in children and adolescents is significantly higher than in older people, since its level decreases with age. Also, the level of ademetionine is lower in people suffering from depressive syndrome. A high concentration of ademetionine in brain tissue promotes the metabolism of catecholamines (adrenaline, norepinephrine), indolamines (serotonin, melatonin) and histamine. Taking the drug normalizes the methylation of phospholipids in the membranes of nerve cells, stabilizing the transmission of nerve impulses and prolonging the functioning of nerve cells. The effectiveness of the drug Heptral in the treatment of depressive conditions has been experimentally proven. The antidepressant effect develops quickly and reaches maximum effectiveness on days 5-7 of taking the drug. When taking the drug Heptral, ademetionine undergoes the same stages of transformation as the endogenous substance.

Indications for use: Intrahepatic cholestasis (impaired synthesis and flow of bile); Liver diseases, including chronic acalculous cholecystitis, cholangitis; Cirrhotic and precirrhotic conditions; Toxic liver damage, including viral, alcoholic, medicinal (antibiotics, chemotherapy, anti-tuberculosis, antiviral drugs, contraceptives); Fatty liver, chronic hepatitis; Depressive states; Withdrawal syndrome, including alcohol.

Directions for use: The drug is used for oral administration (coated tablets) and for intramuscular or intravenous administration (lyophilized powder, which is dissolved with the included L-lysine solution immediately before administration). The IV is administered very slowly. In intensive therapy, the drug is prescribed by injection, the daily dose is 400-800 mg (1-2 bottles) during the first 2-3 weeks of treatment. For maintenance therapy, the drug is prescribed orally in a daily dose of 0.8-1.6 g (2-4 tablets). It is recommended to take the drug between meals, preferably in the first half of the day, since the use of the drug may cause some nervous agitation. The tablets are washed down with the required amount of water and swallowed without chewing. A course of maintenance therapy is prescribed by a doctor (on average 2-8 weeks).

Side effects: From the gastrointestinal tract: nausea, gastralgia, dyspepsia, heartburn; From the side of the central nervous system: it is possible to change the rhythm of sleep; for correction it is possible to use sedatives at night; Allergic reactions.

Contraindications: Increased individual sensitivity to the components of the drug.

Pregnancy: Use is contraindicated in the first and second trimester of pregnancy; in the last trimester, the drug may be prescribed if the expected benefit to the mother is higher than the potential risk to the fetus. During lactation, if it is necessary to take the drug, you should consider stopping breastfeeding.

Overdose: There have been no reports of overdose with Heptral.

Release form: Film-coated tablets, 10 or 20 pcs. packaged; Lyophilized powder for the preparation of solution for injection in 5 ml bottles of 5 pcs. complete with solvent.

Storage conditions: The drug must be stored in a dry place at a temperature not exceeding 25 degrees Celsius. Shelf life – 3 years.

Composition: Tablets 1 tablet contains: Ademethionine – 400 mg; Additional substances.

Bottles with powder for preparing a solution for injection 1 bottle contains: Ademethionine – 400 mg; Solvent: L-lysine buffer solution of caustic salt – 5 ml.

Pharmacological group: Medicines used for diseases of the gastrointestinal tract Hepatoprotective medicines

Heptral 400 mg 20 pcs. enteric-coated tablets

pharmachologic effect

Other preparations for the gastrointestinal tract and metabolism, amino acids and their derivatives.

Composition and release form Heptral 400 mg 20 pcs. enteric-coated tablets

Tablets - 1 tablet:

• Active ingredient: ademetionine 1,4-butane disulfonate 760 mg (corresponds to 400 mg of ademetionine ion);
• Excipients: colloidal silicon dioxide - 4.4 mg, microcrystalline cellulose - 93.6 mg, sodium carboxymethyl starch (type A) - 17.6 mg, magnesium stearate - 4.4 mg;
• tablet shell: methacrylic acid and ethyl acrylate copolymer (1:1) - 27.6 mg, macrogol-6000 - 8.07 mg, polysorbate-80 - 0.44 mg, simethicone (30% emulsion) - 0.13 mg, sodium hydroxide - 0.36 mg, talc - 18.4 mg, water - QS

10 tablets in a blister made of PA/PVC/AL and aluminum foil.

1 or 2 blisters along with instructions for use in a cardboard box.

Description of the dosage form

Tablets are oval, biconvex, smooth, white to light yellow in color, film-coated.

Directions for use and doses

Inside. The tablets should be taken whole, without chewing, preferably in the first half of the day between meals.

Heptral® tablets should be removed from the blister immediately before oral administration. If the tablets have a color other than white to white with a yellowish tint (due to leakage of aluminum foil), the use of Heptral® is not recommended.

Initial therapy

The recommended dose is 10-25 mg/kg/day orally.

Intrahepatic cholestasis, increased fatigue in chronic liver diseases

The dose ranges from 800 mg/day to 1600 mg/day.

Depression

The dose ranges from 800 mg/day to 1600 mg/day.

The duration of therapy is determined by the doctor.

Therapy with Heptral® can be started with intravenous or intramuscular administration, followed by the use of Heptral® in tablet form, or immediately with the use of Heptral® in tablet form.

Elderly patients

Clinical experience with the use of the drug Heptral® did not reveal any differences in its effectiveness in elderly patients and younger patients. However, given the high likelihood of existing liver, kidney or cardiac dysfunction, other concomitant pathology or concomitant therapy with other drugs, the dose of Heptral® in elderly patients should be selected with caution, starting the use of the drug from the lower limit of the dose range.

Kidney failure

There are limited clinical data on the use of Heptral® in patients with renal failure; therefore, caution is recommended when using Heptral® in such patients.

Liver failure

The pharmacokinetic parameters of ademetionine are similar in healthy volunteers and in patients with chronic liver diseases.

Children

The use of Heptral® in children is contraindicated (efficacy and safety have not been established).

Pharmacodynamics

Ademetionine belongs to the group of hepatoprotectors and also has antidepressant activity.

It has choleretic and cholekinetic effects, has detoxification, regenerating, antioxidant, antifibrosing and neuroprotective properties.

Replenishes the deficiency of S-adenosyl-L-methionine (ademetionine) and stimulates its production in the body; it is found in all environments of the body. The highest concentration of ademetionine was observed in the liver and brain.

Plays a key role in the metabolic processes of the body, takes part in important biochemical reactions: transmethylation, transsulfurization, transamination. In transmethylation reactions, ademetionine donates a methyl group for the synthesis of cell membrane phospholipids, neurotransmitters, nucleic acids, proteins, hormones, etc. In transsulfuration reactions, ademetionine is a precursor of cysteine, taurine, glutathione (providing a redox mechanism of cellular detoxification), coenzyme A (included in biochemical reactions of the tricarboxylic acid cycle and replenishes the energy potential of the cell).

Increases the content of glutamine in the liver, cysteine ​​and taurine in plasma; reduces the content of methionine in serum, normalizing metabolic reactions in the liver. After decarboxylation, it participates in aminopropylation reactions as a precursor of the polyamines putrescine (stimulator of cell regeneration and hepatocyte proliferation), spermidine and spermine, which are part of the ribosome structure, which reduces the risk of fibrosis.

Has a choleretic effect.

Ademetionine normalizes the synthesis of endogenous phosphatidylcholine in hepatocytes, which increases membrane fluidity and polarization. This improves the function of bile acid transport systems associated with hepatocyte membranes and promotes the passage of bile acids into the biliary tract. Effective for intralobular cholestasis (impaired synthesis and flow of bile). Ademetionine reduces the toxicity of bile acids in hepatocytes by conjugating and sulfating them. Conjugation with taurine increases the solubility of bile acids and their removal from the hepatocyte. The process of sulfation of bile acids facilitates their elimination by the kidneys, facilitates their passage through the hepatocyte membrane and excretion in the bile. In addition, sulfated bile acids themselves additionally protect liver cell membranes from the toxic effects of non-sulfated bile acids (present in high concentrations in hepatocytes during intrahepatic cholestasis).

In patients with diffuse liver diseases (cirrhosis, hepatitis) with intrahepatic cholestasis syndrome, ademetionine reduces the severity of skin itching and changes in biochemical parameters, incl. concentration of direct bilirubin, activity of alkaline phosphatase, aminotransferases, etc.

The choleretic and hepatoprotective effect lasts up to 3 months after cessation of treatment.

It has been shown to be effective against hepatopathy caused by various hepatotoxic drugs.

Antidepressant activity appears gradually, starting from the end of the first week of treatment, and stabilizes within 2 weeks of treatment.

A number of studies have confirmed the effectiveness of ademetionine in the treatment of fatigue in patients with chronic liver diseases. A pooled analysis of data obtained in patients with symptoms of increased fatigue before treatment showed the effect of treatment with ademetionine in reducing symptoms of increased fatigue in combination with a number of other symptoms, such as depression, icterus of the skin and mucous membranes, malaise and itching.

Treatment with ademetionine significantly improved mood in patients with alcoholic liver disease, who simultaneously achieved a positive response to symptoms of increased fatigue. In addition, in patients with alcoholic liver disease and non-alcoholic fatty liver disease who achieved a response to treatment with ademetionine in terms of symptoms of increased fatigue, there was also a significant reduction in symptoms such as icterus of the skin and mucous membranes, malaise and itching.

Pharmacokinetics

The tablets are film-coated, dissolving only in the intestines, due to which ademetionine is released in the duodenum.

Suction

Bioavailability when taken orally is 5%, increases when taken on an empty stomach. The maximum concentrations (Cmax) of ademetionine in plasma are dose-dependent and are 0.5-1 mg/l 3-5 hours after a single oral dose of 400 to 1000 mg. Cmax of ademetionine in plasma decreases to the initial level within 24 hours.

Distribution

The connection with blood plasma proteins is insignificant, amounts to

There is a significant increase in the concentration of ademetionine in the cerebrospinal fluid.

Metabolism

Metabolized in the liver.

The process of formation, consumption and re-formation of ademetionine is called the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methylases use ademetionine as a substrate to produce S-adenosylhomocysteine, which is then hydrolyzed to homocysteine ​​and adenosine by S-adenosylhomocysteine ​​hydrolase. Homocysteine, in turn, undergoes reverse transformation to methionine by transfer of a methyl group from 5-methyltetrahydrofolate. Eventually, methionine can be converted to ademetionine, completing the cycle.

Removal

The half-life (T1/2) is 1.5 hours. It is excreted by the kidneys. In studies of healthy volunteers, ingestion of labeled (methyl 14C) S-adenosyl-L-methaonine resulted in 15.5 ± 1.5% radioactivity in urine after 48 hours and 23.5 ± 3.5% radioactivity in feces. in 72 hours. Thus, about 60% was deposited.

Indications for use Heptral 400 mg 20 pcs. enteric-coated tablets

Intrahepatic cholestasis in pre-cirrhotic and cirrhotic conditions, which can be observed in the following diseases:

• fatty liver;
• chronic hepatitis;
• toxic liver damage of various etiologies, including;
• alcoholic, viral, medicinal (antibiotics; antitumor, antituberculosis and antiviral drugs, tricyclic antidepressants, oral contraceptives);
• chronic acalculous cholecystitis;
• cholangitis;
• cirrhosis of the liver;
• encephalopathy, incl. associated with liver failure (alcohol, etc.).

Intrahepatic cholestasis in pregnant women.

Symptoms of depression.

Increased fatigue in chronic liver diseases.

Contraindications

Genetic disorders affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia (cystathionine beta synthase deficiency, impaired metabolism of vitamin B12).

Hypersensitivity to any of the components of the drug.

Age up to 18 years (experience of medical use in children is limited).

Bipolar disorders.

Carefully:

Pregnancy (first trimester) and breastfeeding (use is possible only if the potential benefit to the mother outweighs the possible risk to the fetus or child).

Concomitant use with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), as well as herbal drugs and drugs containing tryptophan.

Elderly age.

Kidney failure.

Application of Heptral 400 mg 20 pcs. Enteric-coated tablets during pregnancy and breastfeeding

Clinical studies have shown that the use of ademetionine in the third trimester of pregnancy did not cause any undesirable effects.

The use of Heptral® in pregnant women in the first trimester and during breastfeeding is possible only if the potential benefit to the mother outweighs the possible risk to the fetus or child.

special instructions

Given the tonic effect of the drug, it is not recommended to take it before bed.

When using the drug Heptral® in patients with cirrhosis of the liver against the background of hyperazotemia, systematic monitoring of nitrogen levels in the blood is necessary. During long-term therapy, it is necessary to determine the content of urea and creatinine in the blood serum.

There are reports of the transition of depression to hypomania or mania in patients taking ademetionine.

Patients with depression have an increased risk of suicide and other serious adverse events, therefore, during treatment with ademetionine, such patients should be closely monitored by a physician to evaluate and treat symptoms of depression. Patients should inform their physician if their symptoms of depression do not improve or worsen with ademetionine therapy. There are also reports of sudden onset or worsening anxiety in patients taking ademetionine. In most cases, discontinuation of therapy is not required; in several cases, anxiety disappeared after reducing the dose or discontinuing the drug.

Since deficiency of cyanocobalamin and folic acid can reduce the level of ademetionine in patients at risk (with anemia, liver disease, pregnancy or the likelihood of vitamin deficiency due to other diseases or diet, for example, vegetarians), the content of vitamins in the blood plasma should be monitored. If deficiency is detected, it is recommended to take cyanocobalamin and folic acid before starting treatment with ademetionine or simultaneous use with ademetionine.

In immunological analysis, the use of ademetionine may contribute to the false determination of high homocysteine ​​levels in the blood.

For patients taking ademetionine, it is recommended to use non-immunological methods of analysis to determine homocysteine ​​levels.

Impact on the ability to drive vehicles and operate machinery

Some patients may experience dizziness while taking Heptral®. It is not recommended to drive a car or operate machinery while taking the drug until the patient is confident that the therapy does not affect the ability to engage in these types of activities.

Overdose

An overdose of Heptral® is unlikely.

In case of overdose, observation of the patient and symptomatic therapy are recommended.

Side effects Heptral 400 mg 20 pcs. enteric-coated tablets

The most common adverse reactions identified in clinical studies involving approximately 2,000 patients were headache, nausea and diarrhea. Below are data on adverse reactions observed during clinical trials (n=1922) and during post-marketing use of ademetionine (“spontaneous” reports).

All reactions are distributed according to organ systems and frequency of development: very often (≥1/10); often (≥1/100,

* - undesirable effects identified during post-marketing use of ademetionine (occurred more often in “spontaneous” reports), not observed during clinical trials, were classified as undesirable effects with an occurrence frequency of “infrequently” based on the fact that the upper limit of the 95% confidence interval incidence estimates do not exceed 3/X, where X = 1922 (total number of subjects observed in clinical studies).

Drug interactions

No known interactions with other drugs were observed.

There is a report of serotonin excess syndrome in a patient taking ademetionine and clomipramine. It is believed that such an interaction is possible, and ademetionine should be used with caution when administered with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), and herbs and drugs containing tryptophan.