Hepsam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GEPSAM (GEPSAM)

Composition:

Active substance: ademetionine;

1 vial of powder contains 500 mg of ademetionine;

Solvent: 1 ampoule of solvent contains L-lysine, sodium hydroxide, water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: hygroscopic powder, white to almost white.

Solvent: clear solution, free from foreign particles.

Pharmacotherapeutic group. Other agents affecting the digestive system and metabolic processes. Amino acids and their derivatives. ATC code A16A A02.

Pharmacological Properties.

Pharmacodynamics.

Ademetionine (S-adenosyl-L-methionine) is a naturally occurring molecule widely distributed in virtually all tissues and body fluids. Ademetionine is endogenously synthesized from adenosine triphosphate (ATP) and methionine under the action of methionine adenosyltransferase. Ademetionine plays a fundamentally important role in a number of biochemical reactions, including three main types: transmethylation, transsulfuration, and aminopropylation (polyamine synthesis) in various body tissues. It acts as a methyl group donor or enzyme activity modulator, participating in the synthesis, activation, and/or metabolism of compounds such as hormones, neurotransmitters, nucleic acids, proteins, and phospholipids. Ademetionine plays a crucial metabolic role in polyamine synthesis. It is metabolized to decarboxylated ademetionine, and the aminopropyl group is transferred to putrescine. Subsequently, the polyamines spermidine and spermine are formed. During this process, methylthioadenosine is produced, which is then recycled back into methionine. The release of the methyl group from the molecule initiates the transsulfuration pathway, leading to the formation of all endogenous sulfur-containing compounds. After donating its methyl group to various acceptors, ademetionine is converted into S-adenosylhomocysteine, which is rapidly hydrolyzed to adenosine and homocysteine. Homocysteine is quickly converted to cysteine, which exerts its antioxidant effect either directly or as an active component of glutathione—the primary cellular antioxidant.

Oxidative stress has been shown to play a key pathogenic role in numerous disease states, ranging from the hepatotoxic effects of alcohol (and other xenobiotics) to the carcinogenic effects of many compounds. The main natural defense against oxidative stress is reduced glutathione, which scavenges excess free radicals. Glutathione is a tripeptide whose synthesis rate is limited by the amino acid cysteine, and ademetionine plays a fundamental role in cysteine formation. Another major cellular activity of ademetionine is its involvement in transmethylation reactions and—as a precursor of sulfur-containing compounds—in transsulfuration pathway reactions. Both pathways are critically important for liver function, and their impairment has been demonstrated in liver diseases. Transmethylation and transsulfuration reactions are highly important for membrane structure and function. The ability of ademetionine to protect against liver damage caused by various hepatotoxic agents has been demonstrated in multiple experimental models. Ademetionine protected hepatocytes from galactosamine-induced injury and from the toxic effects of drugs that deplete glutathione in vitro. In vivo, it protected animals from liver damage and subsequent death following administration of high doses of acetaminophen, carbon tetrachloride, a combination of carbon tetrachloride with ethanol, and thioacetamide. In experimental animals receiving acute or chronic ethanol administration, ademetionine increased hepatic levels of the methyl donor and Na+/K+-ATPase activity in hepatocyte membranes, counteracted the rise in liver enzyme activity, maintained glutathione levels, and prevented acetaldehyde formation and hepatic fat accumulation. Parenteral administration of ademetionine (2 g/day for 15 days) significantly increased glutathione concentration in erythrocytes of patients with chronic alcoholism and cirrhosis, and significantly reduced cysteine levels in alcoholic patients both with and without cirrhosis.

The anti-cholestatic effect of ademetionine is evidently based on several combined mechanisms, the most important of which are restoration of normal hepatocyte membrane permeability and Na+, K+-ATPase activity by reversing the inhibition of phospholipid methylation reactions caused by hepatotoxic agents. Additionally, ademetionine may exert its effect by promoting transsulfuration reactions, thereby enhancing the detoxifying capacity of this metabolic system. In animal models of cholestasis, ademetionine restored bile flow and promoted regression of pathological liver changes induced by various agents (ethinylestradiol, cyclosporine A, leukotriene D4, etc.), bile duct ligation, or total parenteral nutrition. In clinical studies, oral or parenteral administration of ademetionine reduced pruritus and improved biochemical markers of cholestasis, such as serum bilirubin, alkaline phosphatase, and γ-glutamyltransferase levels. Data on the ability of ademetionine to counteract the cholestatic effects of ethinylestradiol and prevent estrogen-induced changes in bile lipid composition in rats have also been confirmed in humans. Ademetionine prevented ethinylestradiol-induced changes in bile lipid composition without affecting ethinylestradiol kinetics in patients who had undergone cholecystectomy. Oral administration of ademetionine prevented the secretion of lithogenic bile in women taking oral contraceptives. Ademetionine protected women with a history of intrahepatic cholestasis of pregnancy (ICP) from the hepatotoxic effects of ethinylestradiol and normalized the cholesterol saturation index of bile in individuals who exhibited lithogenic bile secretion.

The efficacy of ademetionine in treating cholestasis associated with liver diseases, pregnancy, and use of estrogen-containing oral contraceptives has been established. Parenteral or oral administration of ademetionine over 2 weeks alleviated pruritus symptoms and improved pathological liver function parameters. Long-term use of ademetionine has been shown to improve survival or delay liver transplantation in patients with alcoholic cirrhosis, particularly in those with earlier stages of liver disease. Restoration of glutathione levels in patients with alcoholic liver disease following ademetionine administration has been reported.

Pharmacokinetics.

Absorption

After intramuscular administration, the bioavailability of ademetionine is 93%. Absorption is completed within 1–2 hours after administration.

Distribution

The apparent volume of distribution after doses of 100 and 500 mg is 0.41 and 0.44 L/kg, respectively.

Following intravenous administration, ademetionine crosses the blood-brain barrier, resulting in increased levels in cerebrospinal fluid (CSF). The maximum increase in ademetionine concentration (67%) in CSF was observed 2 hours after administration, but levels remained elevated by 19% even after 24 hours.

Plasma protein binding of ademetionine is 5% or less.

Metabolism

Ademetionine is rapidly metabolized in the liver via three major metabolic pathways: transmethylation, transsulfuration, and aminopropylation.

Elimination

After intravenous administration of ademetionine to healthy volunteers, drug elimination from plasma occurred predominantly within 4 hours after administration and followed clear first-order kinetics. After doses of 100 and 500 mg, terminal half-lives were 81 and 101 minutes, respectively, and total body clearance was 3.7 and 3.1 mL/min/kg, respectively. Urinary excretion accounted for 34% and 40% of the administered dose.

Special patient populations

The pharmacokinetics of ademetionine in patients with chronic liver disease does not differ from that in healthy volunteers.

In a small clinical study, after oral administration of 400 mg ademetionine, maximum plasma concentration was reached faster and was nearly twice as high in women compared to men. This difference is believed to be due to faster gastric emptying in women. The significance of these findings for parenteral administration is unknown.

Clinical characteristics.

Indications.

Treatment of intrahepatic cholestasis in adult patients with cirrhosis or pre-cirrhotic conditions. Treatment of intrahepatic cholestasis in pregnant women.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Genetic disorders affecting the methionine cycle, or genetic disorders leading to increased or decreased levels of the amino acid homocysteine in the body (e.g., cystathionine-beta-synthase deficiency, defects in vitamin B12 metabolism).

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

Theoretically, ademetionine may enhance the effect of medicinal products that increase serotonin concentration. A case of serotonin syndrome has been reported in a patient treated with ademetionine and clomipramine. Due to the possibility of interaction, careful monitoring is recommended for patients using selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, tramadol, pentazocine, medicinal products or dietary supplements containing tryptophan, or St. John's wort preparations concurrently with ademetionine (see section "Special precautions for use").

Hepsam must not be used together with monoamine oxidase inhibitors (MAOIs) and for 2 weeks following discontinuation of such agents.

Special precautions for use.

Vitamin B12 and folic acid deficiency may lead to reduced levels of ademetionine. Patients at risk (those with liver diseases, anemia, pregnant women, individuals with other disorders or dietary habits such as vegetarians) should have plasma ademetionine concentrations monitored regularly.

There is one published report of serotonin syndrome in a patient receiving ademetionine while taking clomipramine. Although such an interaction is theoretically possible, ademetionine should be used with caution in combination with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products or herbal remedies containing tryptophan (see "Interaction with other medicinal products and other forms of interaction").

This medicinal product is not recommended for use in patients with bipolar disorder or in individuals with a family history of bipolar disorder. Cases have been reported in which depression has turned into hypomania or mania during ademetionine therapy.

Patients suffering from depression should be closely monitored during ademetionine treatment due to the risk of suicide and other serious risks.

There have been reports of anxiety development or temporary worsening during ademetionine use. In most cases, discontinuation of therapy was not required. Anxiety resolved after dose reduction or discontinuation of the drug, and in most cases, interruption of treatment was unnecessary.

Effect on immunochemical homocysteine assay.

Ademetionine affects immunochemical homocysteine assays, potentially leading to falsely elevated plasma homocysteine levels in patients taking ademetionine. Therefore, non-immunochemical methods for determining plasma homocysteine levels are recommended in such patients.

Use during pregnancy or breastfeeding.

Pregnancy

Limited data do not indicate any effect of ademetionine on the formation of malformations or its toxic effect on the fetus or newborn.

Animal studies have not revealed reproductive toxicity.

No adverse reactions have been observed in pregnant women receiving ademetionine at therapeutic doses during the last three months of pregnancy. However, ademetionine is not recommended during the first three months of pregnancy except when strictly necessary.

Breastfeeding

It is unknown whether ademetionine or its metabolites are excreted in human milk.

Risk to newborns and infants cannot be excluded.

Use of Hepsam during breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Dizziness may occur in some patients during ademetionine therapy. In such cases, patients should refrain from driving vehicles or operating machinery until symptoms that may affect reaction speed have completely resolved.

Administration and Dosage

Treatment may begin with parenteral administration of the drug followed by oral administration of the tablet form.

The dose depends on the severity of the disease and the patient's body weight.

Initial Therapy

Intravenous or intramuscular administration. The recommended dose is 5–12 mg/kg body weight once or twice daily. The usual starting dose is 500 mg per day. The maximum daily dose is 800 mg. The duration of initial parenteral therapy in liver diseases is 2 weeks.

Maintenance therapy. If treatment needs to be continued after the first 2 weeks, it is recommended to switch to oral administration of the appropriate dosage form. The recommended daily dose is 10–25 mg/kg body weight (equivalent to 800–1600 mg/day). The duration of therapy depends on the severity and course of the disease and is determined individually by the physician.

Elderly patients

Based on available clinical experience, no differences in treatment response have been observed between elderly and younger patients. Treatment in elderly patients should be initiated at the lowest recommended dose, taking into account the higher frequency of hepatic, renal, or cardiac impairments, presence of other concomitant pathological conditions, and use of other medicinal products.

Patients with renal impairment

Ademetionine should be administered with caution in patients with impaired renal function.

Patients with hepatic impairment

Pharmacokinetic parameters of ademetionine were similar in healthy volunteers and patients with chronic liver diseases.

Administration method

The medicinal product is administered intramuscularly or intravenously. The powder must be dissolved in the solvent provided, immediately before use. For intravenous administration, the required dose of ademetionine should be further diluted in 250 mL of physiological saline or 5% dextrose (glucose) solution and infused slowly over 1–2 hours. Any unused portion of the solution must be discarded. The drug must not be used if the powder has any color other than white to almost white (due to cracks in the vial or exposure to elevated temperatures).

Ademetionine must not be mixed with alkaline solutions or solutions containing calcium ions.

After reconstitution, the solution is suitable for administration for up to 6 hours when stored at 2–8°C.

Children

The safety and efficacy of ademetionine in children have not been established.

Overdose

Cases of ademetionine overdose have been rarely reported. In case of overdose, patient monitoring and supportive treatment are recommended.

Adverse reactions.

The most common adverse reactions were nausea, abdominal pain, and diarrhea. The relationship between drug administration and the occurrence of an adverse reaction could not always be assessed.

Description of individual adverse reactions

Rarely and only in particularly sensitive individuals, the drug Hepsam may cause sleep disturbances.

Data obtained after registration of ademetionine

Immune system disorders: anaphylactic reaction.

Respiratory, thoracic and mediastinal disorders: laryngeal edema.

Psychiatric disorders: anxiety.

Skin and subcutaneous tissue disorders: skin reactions at the injection site (very rarely – skin necrosis), rash, angioneurotic edema.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the use of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life.

3 years.

After reconstitution, the preparation is suitable for use within 6 hours when stored at a temperature of 2 to 8 °C.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility.

Ademetionine should not be mixed with alkaline solutions or solutions containing calcium ions.

Packaging.

5 vials with 500 mg powder and 5 ampoules with 5 ml solvent per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIO ITALIANO BIOCHIMICO FARMACEUTICO LIZAFARMA S.P.A.

Manufacturer's address and place of business.

VIA LICINIO 11, 22036 – ERBA, (CO), Italy.

Marketing Authorization Holder.

JSC "Vigifarma"

Address of the Marketing Authorization Holder.

Birzelio 23-osios St., 2-1, Kaunas, LT-50425, Lithuania