Heptral, lyophilizate 400 mg 5 pcs

Pharmacotherapeutic group: Other drugs for the gastrointestinal tract and metabolism, amino acids and their derivatives

ATC code: A16AA02

Pharmacological properties

Pharmacodynamics

Ademetionine belongs to the group of hepatoprotectors, also has antidepressant activity. It has choleretic and cholokinetic effect, has detoxifying, regenerating, antioxidant, antifibrotic and neuroprotective properties.

It replenishes the S-adenosyl-L-methionine (ademetionine) deficiency and stimulates its production in the body, contained in all body fluids. The highest concentration of ademetionine is found in the liver and brain. Ademetionine plays a key role in the metabolic processes of the body and takes part in major biochemical reactions: transmethylation, transsulfurization and transamination.

In transmethylation reactions ademetionine donates methyl groups for the synthesis of cell membrane phospholipids, neurotransmitters, nucleic acids, proteins, hormones and others. In transsulfurization reactions ademetionine is a precursor of cysteine, taurine, glutathione (providing redox mechanism of cellular detoxification), coenzyme A (is included into biochemical reactions of tricarboxylic acid cycle and fills the cell energy potential).

Increases glutamine content in the liver, plasma cysteine and taurine, decreases methionine content in the serum, normalizing metabolic reactions in the liver. After decarboxylation it participates in aminopropylation reactions, as precursor of 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. It 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 membranes of hepatocytes and contributes to bile acid passage to biliary tracts.

Effective with intradolocular variant of cholestasis (disorders of bile synthesis and flow). Ademetionine reduces the toxicity of bile acids in the hepatocyte by performing their conjugation and sulfation. Conjugation with taurine increases solubility of bile acids and their excretion from the hepatocyte. The process of sulfation of bile acids allows their elimination by kidneys and facilitates passing through hepatocyte membrane and excretion with bile.

In addition, sulfated bile acids additionally protect liver cell membranes from toxic effects of nonsulfated bile acids (in high concentrations present in hepatocytes with 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, including direct bilirubin concentration, alkaline phosphatase activity, aminotransferases and others. Choleretic and hepatoprotective effect persists up to 3 months after discontinuation of treatment. It is shown to be effective in hepatopathies caused by various hepatotoxic drugs. Antidepressant activity appears gradually from the end of the first week of treatment and stabilizes during 2 weeks of treatment.

Several studies have confirmed the effectiveness of ademetionine in treatment of increased fatigability in patients with chronic liver disease. A pooled analysis of data from patients with pre-treatment symptoms of fatigue proved the effect of ademetionine treatment in reducing symptoms of fatigue in combination with a number of other symptoms, such as depression, hiccuria of the skin and mucous membranes, malaise and skin itching. Ademetionine treatment significantly improved mood in patients with alcoholic liver disease, who simultaneously achieved a positive response from symptoms of increased fatigability. In addition, in patients with alcoholic liver disease and nonalcoholic fatty liver disease with achieved response to ademetionine treatment on the side of symptoms of increased fatigability there was also observed a significant relief of such symptoms as hirsuteness of skin and mucous membranes, malaise and skin itching.

Pharmacokinetics

Tablets are covered with a film coating that dissolves only in the intestine, so that ademetionine is released in the duodenum.

Absorption

Bioavailability when ingested is 5%; it is increased when taken on an empty stomach. Maximal concentrations (Cmax) of ademetionine in plasma are dose-dependent – 0.5-1 mg/l 3-5 hours after a single oral dose from 400 to 1000 mg. Cmax of ademetionine in plasma decrease to the initial level within 24 hours.

Distribution

Binding with blood plasma proteins is insignificant – 5%.
It penetrates through the blood-brain barrier. There is a significant increase in concentration of ademetionine in cerebrospinal fluid.

Metabolism

Metabolized in the liver. The process of ademetionine formation, expenditure and reformation 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 hydralase. Homocysteine, in turn, undergoes a reverse transformation to methionine by transferring the methyl group from 5-methyltetrahydrofolate. Eventually, methionine can be converted to ademethionine, completing the cycle.

Excretion

The half-life (T½) is 1.5 h. It is excreted by the kidneys. In studies in healthy volunteers, when ingested with labeled (methyl 14C) S-adenosyl-L-methionine, 15.5% ± 1.5% radioactivity was detected in the urine after 48 hours, and 23.5% ± 3.5% radioactivity in the feces after 72 hours. Thus, about 60% was deposited.

Indications

Cholecystitis, Liver lesions, Hepatitis, Alcoholism, Liver cirrhosis

• Intrahepatic cholestasis in precirrhotic and cirrhotic conditions, which may be observed in the following diseases:
  • fatty liver dystrophy;
  • chronic hepatitis;
  • toxic liver lesions of various etiologies, including alcoholic, viral, drug (antibiotics; anticancer, anti-tuberculosis and antiviral drugs, tricyclic antidepressants, oral contraceptives);
  • chronic acute cholecystitis;
  • cholangitis;
  • liver cirrhosis;
  • encephalopathy, including those associated with hepatic
• Intrahepatic cholestasis in pregnant women.
• Symptoms of depression.

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Active ingredient

Ademetionine

Composition

A vial of lyophilisate contains:

Active ingredient:

Ademetionine 1,4-butanedisulfonate 760 mg (corresponding to 400 mg of ademetionine ion).

Ampoule with solvent contains:

Excipients:

L-lysine 342.4 mg;

sodium hydroxide 11.5 mg;

water for injection to 5 ml.

How to take, the dosage

Before use the lyophilizate for intramuscular and intravenous administration should be dissolved using the included solvent. The remainder of the drug must be disposed of. The corresponding dose of the drug for intravenous injection should be dissolved in 250 ml of physiological solution or 5% glucose solution and injected slowly during 1-2 hours.

The drug must not be mixed with alkaline solutions and solutions containing calcium ions.

In case the lyophilizate has a color other than almost white to white with yellowish tint (due to a crack in the bottle or heat exposure), the drug Heptral® is not recommended.

Initial therapy: The recommended dose is 5-12 mg/kg/day intravenously or intramuscularly.

Interaction

No known interactions with other drugs have been observed.

There is a report of serotonin excess syndrome in a patient taking ademetionine and clomipramine.

It is believed that this interaction is possible and ademetionine should be prescribed with caution along with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), and herbs and drugs containing tryptophan.

Special Instructions

Taking into account the tonic effect of the drug, it is not recommended to take it before going to bed. When using Heptral® by patients with liver cirrhosis against hyperazotemia background, systematic monitoring of blood nitrogen content is required. During long-term therapy it is necessary to determine the serum urea and creatinine content.

There are reports about the conversion of depression into hypomania or mania in patients taking Ademetionine.

Patients with depression have an increased risk of suicide and other serious adverse events, so such patients should be under constant medical supervision during ademetionine treatment for evaluation and treatment of depression symptoms. Patients should inform the doctor if their symptoms of depression do not decrease or worsen during ademetionine therapy.

There are also reports of the sudden appearance or increase in anxiety in patients taking ademetionine. In most cases it is not necessary to cancel the therapy, in a few cases the anxiety disappeared after reducing the dose or canceling the drug.

Since cyanocobalamin and folic acid deficiency may decrease the content of ademetionine in patients at risk (with anemia, liver disease, pregnancy or the possibility of vitamin deficiency due to other diseases or diet, such as vegetarians), the plasma vitamin content should be controlled. If insufficiency is found, intake of cyanocobalamin and folic acid before ademetionine treatment or concomitant intake with ademetionine is recommended. In immunological analysis the use of ademetionine may contribute to false determination of high homocysteine content in blood.

For patients taking ademetionine, it is recommended to use non-immunological methods of analysis to determine homocysteine content. One bottle of the preparation Heptral® lyophilisate for preparation of solutions for intravenous and intramuscular administration, 400 mg/5 ml contains 6.61 mg of sodium, which is equivalent to the amount of sodium in 16.8 mg of table salt and which is 0.3% of the recommended maximum daily dose of sodium consumption for an adult.

Influence on the ability to drive and operate machinery

Some patients may feel dizzy while taking Heptral®. It is not recommended to drive a car and work with mechanisms while taking the drug until the patient is sure that the therapy does not affect the ability to perform such activities.

Contraindications

• Genetic disorders affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia (cystathionine beta synthase deficiency, impaired cyanocobalamin metabolism);
• Hypersensitivity to any of the components of the drug;
• Age under 18 years of age (experience with medical use in children is limited);
• Bipolar disorders.

Caution

• Pregnancy (first trimester) and breastfeeding (use possible only if the potential benefit to the mother exceeds the possible risk to the fetus or baby).
• Simultaneous use with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), as well as herbal and tryptophan preparations (see “Interaction with other antidepressants”).
• Elderly age.
• Renal insufficiency.

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Side effects

The digestive system: frequently – nausea, abdominal pain, diarrhea; rarely – vomiting, dry mouth, esophagitis, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal bleeding, liver colic.

Nervous system: rare – confusion, insomnia, dizziness, headache, paresthesia.

Musculoskeletal system: rare – arthralgia, muscle cramps.

Urinary system: rare – urinary tract infections.

Skin: rare – hyperhidrosis, itching, skin rash.

Local reactions: rare – reactions at the injection site, very rare – reactions at the injection site, necrosis of the skin at the injection site.

Allergic reactions: rare – anaphylactic reactions, very rare – Quincke’s edema, laryngeal edema.

Other: rare – flushes, superficial phlebitis, asthenia, chills, flu-like symptoms, weakness, peripheral edema, hyperthermia.

Overdose

Overdose of the drug Heptral® is unlikely.

In case of overdose it is recommended to monitor the patient and conduct symptomatic therapy.

Pregnancy use

In clinical trials it has been shown that the use of Ademetionine in III trimester of pregnancy did not cause any undesirable effects. The use of the drug Heptral® in pregnant women in the first trimester and during breastfeeding is possible only if the potential benefit to the mother exceeds the possible risk to the fetus or child.

Similarities

Heptral, Heptor, Samelix, Irritable bowel