Heptral^® (Tablets, Lyophilisate) Instructions for Use

ATC Code

A16AA02 (Ademetionine)

Active Substance

Ademetionine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hepatoprotective agent. Drug with antidepressant activity

Pharmacotherapeutic Group

Other preparations for the treatment of gastrointestinal diseases and metabolic disorders, amino acids and their derivatives

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Ademetionine belongs to the group of hepatoprotectors and also has antidepressant activity. It has a choleretic and cholekinetic effect, and possesses detoxifying, regenerating, antioxidant, antifibrosing and neuroprotective properties.

It replenishes the deficiency of S-adenosyl-L-methionine (ademetionine) and stimulates its production in the body; it is found in all body fluids. The highest concentration of ademetionine is noted in the liver and brain. It plays a key role in the metabolic processes of the body, participating in important biochemical reactions: transsulfuration, transamination. In transmethylation reactions, Ademetionine donates a methyl group for the synthesis of phospholipids of cell membranes, neurotransmitters, nucleic acids, proteins, hormones, etc. In transsulfuration reactions, Ademetionine is a precursor of cysteine, taurine, glutathione (providing the redox mechanism of cellular detoxification), coenzyme A (included in the biochemical reactions of the tricarboxylic acid cycle and replenishes the energy potential of the cell).

It 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 polyamines – putrescine (a stimulator of cell regeneration and hepatocyte proliferation), spermidine and spermine, which are part of the structure of ribosomes, 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 hepatocyte membranes and promotes the passage of bile acids into the biliary tract.

It is effective in the intralobular variant of cholestasis (impaired synthesis and flow of bile). Ademetionine reduces the toxicity of bile acids in the hepatocyte by conjugating and sulfating them. Conjugation with taurine increases the solubility of bile acids and their excretion from the hepatocyte. The process of sulfation of bile acids facilitates their elimination by the kidneys, facilitates passage through the hepatocyte membrane and excretion with bile. In addition, the sulfated bile acids themselves additionally protect liver cell membranes from the toxic effects of non-sulfated bile acids (present in high concentrations in hepatocytes in intrahepatic cholestasis).

Clinical efficacy and safety

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 the concentration of direct bilirubin, alkaline phosphatase activity, aminotransferases, etc. The choleretic and hepatoprotective effect persists for up to 3 months after discontinuation of treatment.

Efficacy has been shown in hepatopathies caused by various hepatotoxic drugs.

Antidepressant activity develops 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 efficacy of ademetionine in the treatment of increased fatigue in patients with chronic liver diseases. A pooled analysis of data obtained from patients with symptoms of increased fatigue before the start of treatment proved the effect of ademetionine treatment in reducing symptoms of increased fatigue in combination with a number of other symptoms, such as depression, jaundice of the skin and mucous membranes, malaise and skin itching.

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

Pharmacokinetics

Absorption

The C_max of ademetionine in plasma is dose-dependent and is 0.5-1 mg/l 3-5 hours after a single oral dose of 400 to 1000 mg. Bioavailability increases when taken on an empty stomach. The C_max of ademetionine in plasma decreases to baseline levels within 24 hours.

Distribution

When using ademetionine at a dose of 500 mg, the V_d is 0.44 l/kg. Binding to plasma proteins is negligible, ≤5%.

Metabolism

The process of formation, consumption and reformation of ademetionine is called the ademetionine cycle. In the first stage 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. As a result, methionine can be converted to Ademetionine by methionine adenosyltransferase type I, completing the cycle.

Elimination

In studies in healthy volunteers after oral administration of labeled (methyl ¹⁴C) S-adenosyl-L-methionine, 15.5±1.5% of radioactivity was found in urine after 48 hours, and 23.5±3.5% of radioactivity was found in feces after 72 hours. Thus, about 60% was deposited.

Indications

For adults aged 18 years and older

• Intrahepatic cholestasis in precirrhotic and cirrhotic conditions, which can be observed in the following diseases:
  • Fatty liver;
  • Chronic hepatitis;
  • Toxic liver lesions of various etiologies, including alcoholic, viral, drug-induced (antibiotics, antitumor, antituberculosis and antiviral drugs, tricyclic antidepressants, oral contraceptives);
  • Chronic acalculous cholecystitis;
  • Cholangitis;
  • Liver cirrhosis;
  • Encephalopathy, including associated with liver failure (including alcoholic);
• Intrahepatic cholestasis in pregnant women;
• Symptoms of depression;
• Increased fatigue in chronic liver diseases.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally. The tablets should be swallowed 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 are of a color other than white to white with a yellowish tint (due to non-hermetic aluminum foil), it is not recommended to use Heptral^®.

The recommended dose of Heptral^® is 10-25 mg of ademetionine per 1 kg of body weight per day.

The usual daily dose is 1-2 tablets/day (400-800 mg of ademetionine per day) and can be increased to 4 tablets/day (up to 1600 mg of ademetionine per day). The effect usually appears after 7-14 days of treatment and persists with further use of the drug.

If there is no positive effect from the therapy with the drug for 2 weeks or if the condition worsens, the patient should consult a doctor.

Elderly patients

Clinical experience with Heptral^® has not revealed any differences in its efficacy between elderly patients and younger patients. However, given the high likelihood of existing impairments of liver, kidney or heart function, other concomitant pathology or simultaneous therapy with other drugs, the dose of Heptral^® for elderly patients should be selected with caution, starting the drug at the lower end of the dose range.

Patients with impaired liver function

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

Patients with impaired renal function

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.

Patients with impaired liver function

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

Children

The safety and efficacy of Heptral^® in children under 18 years of age have not been established to date. Data are not available.

Lyophilisate

IV or IM.

Therapy with Heptral^® can be started with IV or IM administration followed by the use of Heptral^® in tablet form or immediately with the use of Heptral^® in tablet form.

Initial therapy

The recommended dose is 5-12 mg/kg/day IV or IM.

Depression

400-800 mg/day (1-2 vials/day) for 15-20 days.

Intrahepatic cholestasis

400-800 mg/day (1-2 vials/day) for 2 weeks.

Maintenance therapy

If maintenance therapy is necessary, it is recommended to continue taking Heptral^® in tablet form at a dose of 800-1600 mg/day for 2-4 weeks.

Elderly patients

Clinical experience with Heptral^® has not revealed any differences in its efficacy between elderly patients and younger patients. However, given the high likelihood of existing impairments of liver, kidney or heart function, other concomitant pathology or simultaneous therapy with other drugs, the dose of Heptral^® for elderly patients should be selected with caution, starting the drug at the lower end of the dose range.

Patients with impaired renal function

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.

Patients with impaired liver function

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

Children

The safety and efficacy of Heptral^® in children under 18 years of age have not been established to date. Data are not available.

Method of administration

Before use, the lyophilisate for IM and IV administration should be dissolved using the supplied solvent. The residue of the drug must be disposed of. The corresponding dose of the drug for IV administration should then be dissolved in 250 ml of saline or 5% glucose solution and administered slowly over 1-2 hours.

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

The drug should not be mixed with other drugs.

If the lyophilisate is of a color other than almost white to white with a yellowish tint (due to a crack in the vial or heat exposure), it is not recommended to use Heptral^®.

Adverse Reactions

Among the most frequent adverse reactions identified in clinical studies involving approximately 2000 patients were: headache, nausea and diarrhea.

Adverse reactions observed during clinical studies (n=1922) and in the post-marketing surveillance period (spontaneous reports) are listed below and grouped by system-organ class with the frequency of their occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), unknown (cannot be estimated from the available data).

Adverse reactions within each system-organ class are listed in descending order of their severity with an indication of their frequency of occurrence (within the same frequency category).

* Adverse reactions identified during post-marketing use of ademetionine (spontaneous reports), not observed during clinical studies, were classified as adverse reactions with a frequency of "uncommon").

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to ademetionine or to any of the excipients included in the drug;
• Genetic disorders affecting the methionine cycle, and/or causing homocystinuria and/or hyperhomocysteinemia (e.g., cystathionine beta-synthase deficiency, cyanocobalamin metabolism disorder);
• Bipolar disorder (see section "Special warnings and precautions for use");
• Children under 18 years of age (efficacy and safety of ademetionine use have not been established).

With caution

• First trimester of pregnancy;
• Breastfeeding period;
• Concomitant use with SSRIs; tricyclic antidepressants (such as clomipramine), as well as over-the-counter drugs and herbal preparations containing tryptophan (see section "Drug interactions");
• Elderly age;
• Renal failure.

Use in Pregnancy and Lactation

Pregnancy

Clinical studies have shown that the use of ademetionine in the third trimester of pregnancy did not cause adverse reactions.

The use of ademetionine in the first and second trimesters of pregnancy is allowed only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

The use of ademetionine during lactation is allowed only if the expected benefit to the mother outweighs the potential risk to the child.

Fertility

Data are not available.

Use in Hepatic Impairment

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

Use in Renal Impairment

Caution is recommended when using the drug in patients with renal failure.

Pediatric Use

Contraindicated for use under 18 years of age (medical experience in children is limited).

Geriatric Use

Given the high likelihood of existing impairments of liver, kidney or heart function, other concomitant pathology or simultaneous therapy with other drugs, the dose of Heptral^® for elderly patients should be selected with caution, starting the drug at the lower end of the dose range.

Special Precautions

Given the tonic effect of the drug, it is not recommended to use it before bedtime.

When using Heptral^® in patients with liver cirrhosis and hyperazotemia, systematic monitoring of blood nitrogen levels is necessary. During long-term therapy, serum urea and creatinine levels should be determined.

It is not recommended to use Ademetionine in patients with bipolar disorders.

There are reports of depression transitioning into 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 under constant medical supervision to assess and treat symptoms of depression. Patients should inform their doctor if their depressive symptoms do not decrease or worsen during ademetionine therapy.

There are also reports of sudden onset or increase in anxiety in patients taking Ademetionine. In most cases, discontinuation of therapy was not required; in several cases, the anxiety resolved after dose reduction or drug withdrawal.

Since deficiency of cyanocobalamin and folic acid may reduce ademetionine levels in at-risk patients (with anemia, liver diseases, during pregnancy or likelihood of vitamin deficiency due to other conditions or diet, e.g., vegetarians), plasma vitamin levels should be monitored. If deficiency is detected, administration of cyanocobalamin and folic acid is recommended before starting ademetionine treatment or concurrently with ademetionine.

Effect on the results of homocysteine determination by immunological methods

Ademetionine distorts the results of immunological tests for homocysteine determination, which may show a false increase in plasma homocysteine levels in patients being treated with Heptral^®. For this category of patients, it is recommended to use non-immunological methods for determining plasma homocysteine levels.

Effect on the ability to drive vehicles and operate machinery

Heptral^® has an insignificant effect on the ability to drive vehicles or operate machinery. Patients who experience dizziness while taking Heptral^® should refrain from driving vehicles and operating machinery until it resolves.

Patients who experience dizziness while taking Heptral^® should refrain from driving vehicles and operating machinery until it resolves.

Overdose

Overdose of Heptral^® is unlikely.

Treatment in case of overdose, patient observation and symptomatic therapy are recommended.

Drug Interactions

There is a report of serotonin syndrome in a patient taking Ademetionine and clomipramine. It is believed that such interaction is possible, and Ademetionine should be prescribed with caution together with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), as well as herbal preparations and preparations containing tryptophan.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. The drug should not be used after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.