Hepametion

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEPAMETION® (HEPAMETION)

Composition:

Active substance: ademetionine;

1 vial of lyophilisate contains: S-adenosyl-L-methionine 1,4 butanedisulfonate 949 mg, equivalent to 500 mg of ademetionine cation;

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

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties:

lyophilisate – lyophilized mass of white to slightly yellow color, free from foreign particles;

solvent – clear liquid, colorless to light yellow;

prepared solution – clear solution without visible particles, colorless to yellow.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolic processes. Amino acids and their derivatives. ATC code A16AA02.

Pharmacological Properties

Pharmacodynamics

Ademetionine, or S-adenosyl-L-methionine, is a derivative of the amino acid methionine. S-adenosyl-L-methionine (ademetionine) is a natural amino acid present in virtually all tissues and body fluids. Primarily, ademetionine acts as a coenzyme and methyl group donor in transmethylation reactions, which are essential metabolic processes in humans and animals. The transfer of methyl groups (transmethylation) is also crucial for the formation of the bilayer phospholipid membrane in cell membranes, promoting membrane fluidity. Ademetionine is capable of crossing the blood-brain barrier. Transmethylation involving ademetionine plays a key role in the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin, and histamine.

Ademetionine also serves as a precursor in the formation of physiological sulfur-containing (thiol) compounds (cysteine, taurine, glutathione, coenzyme A, etc.) in transsulfuration reactions. Glutathione, the most potent antioxidant in the liver, plays a vital role in hepatic detoxification. Ademetionine increases hepatic glutathione levels in patients with liver damage of both alcoholic and non-alcoholic etiology. Folic acid (folates) and vitamin B12 are essential cofactors in the metabolism and regeneration of ademetionine.

Intrahepatic cholestasis

Intrahepatic cholestasis may be one of the complications of acute and chronic liver diseases, occurring independently of their etiology. This pathological condition is characterized by reduced bile secretion by hepatocytes, leading to the accumulation in blood of substances normally excreted via bile, particularly bilirubin, bile salts, and enzymes.

Administration of ademetionine helps overcome metabolic blockage caused by reduced activity of the enzyme ademetionine synthetase, thereby restoring physiological mechanisms that prevent the development of cholestasis. Various experimental studies have demonstrated that the anti-cholestatic effect of ademetionine is achieved through:

1. restoration of microfluidity of cytoplasmic membranes via ademetionine-dependent synthesis of membrane phospholipids (reduction of the cholesterol/phospholipid ratio), and
2. overcoming metabolic blockage in the transsulfuration process, and consequently, restoration of thiol group synthesis involved in endogenous detoxification processes.

Pharmacokinetics

Absorption. In humans, after intravenous administration, the pharmacokinetic profile of ademetionine is biexponential, consisting of a rapid distribution phase into tissues and a terminal elimination phase with a half-life of approximately 1.5 hours. Absorption after intramuscular administration is nearly complete (96%), with maximum plasma concentration reached about 45 minutes after administration. Following oral administration of enteric-coated ademetionine tablets, peak plasma concentration is dose-dependent, ranging from 0.5 to 1 mg/L, and is achieved 3–5 hours after a single dose of 400 mg to 1000 mg. Plasma concentration declines to baseline levels within 24 hours. Bioavailability after oral administration increases when ademetionine is taken between meals. After oral administration, the tablets are absorbed in the intestinal tract and significantly increase plasma ademetionine concentration. Animal studies using isotopic methods have confirmed that oral administration of ademetionine stimulates the formation of methylated compounds in the liver. It has also been confirmed that ademetionine is incorporated into the body via typical metabolic pathways characteristic of endogenous compounds (transmethylation, transsulfuration, decarboxylation, etc.).

Distribution. The volume of distribution is 0.41 and 0.44 L/kg for 100 mg and 500 mg doses of ademetionine, respectively. Plasma protein binding is minimal, at ≤ 5%.

Metabolism. The reactions that produce, utilize, and regenerate ademetionine are collectively known as the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methyltransferase uses ademetionine as a substrate to produce S-adenosylhomocysteine, which is then hydrolyzed to homocysteine and adenosine by S-adenosylhomocysteine hydrolase. Homocysteine, in turn, undergoes remethylation to methionine through transfer of a methyl group from 5-methyltetrahydrofolate. Finally, methionine can be converted back into ademetionine, completing the cycle.

Excretion. In radiolabeled studies, following oral administration of radiolabeled (methyl-14C) ademetionine in healthy volunteers, urinary excretion of radioactivity was 15.5 ± 1.5% within 48 hours, and fecal excretion was 23.5 ± 3.5% within 72 hours, with approximately 60% of the substance incorporated into stable pools.

Clinical characteristics

Indications

• Intrahepatic cholestasis in adults, including patients with chronic hepatitis of various etiologies and liver cirrhosis;
• intrahepatic cholestasis in pregnant women.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition").

Genetic defects affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia (e.g. cystathionine-beta-synthase deficiency, vitamin B12 metabolism defects).

Interaction with other medicinal products and other forms of interaction

Cases of serotonin syndrome have been reported in a patient who received ademetionine while taking clomipramine. Therefore, although the possibility of interaction is theoretically assumed, ademetionine should be used with caution when administered concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), medicinal products and herbal remedies containing tryptophan (see section "Special precautions for use").

Special precautions for use

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is practically sodium-free.

Intravenous administration of ademetionine solution must be performed very slowly (see section "Method of administration and dosage").

Ammonia levels should be monitored in patients with pre-cirrhotic or cirrhotic stages of hyperammonemia who are receiving ademetionine tablets.

Since vitamin B12 and folic acid (folates) deficiency may lead to decreased ademetionine concentrations, patients at risk (e.g. anaemia, liver disease, pregnancy, or potential vitamin deficiency due to other diseases or dietary habits such as vegetarianism) should undergo regular blood tests to check plasma levels of these substances. If deficiency is detected, treatment with vitamin B12 and/or folic acid (folates) is recommended prior to or during ademetionine therapy. In cases where such testing is not feasible, patients at risk should be given vitamin B12 and/or folic acid (folates) according to the instructions for medical use of these medicinal products (see section "Pharmacological properties. Metabolism").

This medicinal product should not be prescribed for the treatment of depressive disorders, but may be used for the treatment of intrahepatic cholestasis in patients with depressive disorders. Therefore, the following warnings regarding patients receiving antidepressant therapy should be considered.

Ademetionine is not recommended for use in patients with bipolar disorders. Cases of transition from depression to hypomania or mania during ademetionine treatment have been reported.

One published case of serotonin syndrome has been reported in a patient receiving ademetionine concomitantly with clomipramine. Although such an interaction is theoretically possible, ademetionine should be used with caution when administered concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal or herbal products containing tryptophan (see section "Interaction with other medicinal products and other forms of interaction").

Patients with depression are generally at risk of suicide or other serious behaviours and therefore require careful monitoring and ongoing psychiatric support during antidepressant therapy to ensure timely identification and management of depressive symptoms. Patients with a history of suicidal behaviour or ideation, or those exhibiting significant suicidal intent, are at increased risk of suicidal thoughts or attempts and should be closely monitored during treatment.

There have been reports of transient onset or worsening of anxiety in patients taking ademetionine. In most cases, treatment interruption was not necessary. Anxiety symptoms sometimes resolved after dose reduction or discontinuation of therapy.

Effect on immunoassay of homocysteine

Ademetionine affects the immunoassay measurement of homocysteine, potentially leading to falsely elevated plasma homocysteine levels in patients receiving ademetionine. Therefore, non-immunological methods for determining plasma homocysteine levels are recommended for such patients.

Renal impairment. Clinical data on the use of ademetionine in patients with renal impairment are limited. Ademetionine should be used with caution in these patients.

Hepatic impairment. Pharmacokinetic characteristics do not differ between healthy volunteers and patients with chronic liver disease.

Elderly patients

Clinical studies of ademetionine have not included sufficient numbers of patients aged 65 years and older to determine whether they respond differently compared to younger patients. Based on available clinical experience, no differences in response to treatment between elderly and younger patients have been observed. In general, dose selection for elderly patients should be cautious, usually starting with the lowest recommended dose, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, presence of concomitant diseases, and use of other medicinal products.

Use during pregnancy or breastfeeding

Clinical studies in women treated with ademetionine during the third trimester of pregnancy have not shown any adverse reactions. Ademetionine should be used during the first two trimesters of pregnancy only if clearly needed.

During breastfeeding, ademetionine should be used only if the potential benefit justifies the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery

Dizziness may occur in some patients during treatment with ademetionine. Patients should refrain from driving or operating machinery until they are fully certain that ademetionine therapy does not affect their ability to perform such activities.

Method of Administration and Dosage

Treatment may be initiated with parenteral administration of the drug followed by switching to tablets, or treatment may start directly with tablets.

For intramuscular or intravenous administration, the lyophilized powder must be dissolved immediately before use in the solvent provided. For intravenous administration, the required dose of ademetionine should be further diluted in 250 ml of 0.9% sodium chloride solution or 5% glucose solution, and infused slowly over 1–2 hours. Any unused portion of the solution must be discarded.

Ademetionine should not be mixed with alkaline solutions or solutions containing calcium ions. If the lyophilized powder has a color other than white to yellowish (due to cracks in the vial or exposure to elevated temperatures), its use should be avoided.

Initial Therapy

Intravenous or intramuscular administration: The recommended dose is 5–12 mg/kg body weight per day for 2 weeks. The usual initial dose is 500 mg/day; the total daily dose should not exceed 1000 mg.

Maintenance Therapy

Administer orally (by mouth) according to the instructions for medical use of ademetionine tablets.

Duration of therapy depends on the severity and course of the disease and is determined individually by the physician.

Children

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

Overdose

Cases of ademetionine overdose have been rarely observed. In case of overdose, physicians should contact local toxicology centers. Generally, patient monitoring and supportive treatment are recommended.

Adverse Reactions

Ademetionine has been administered to approximately 2000 patients in clinical studies. The most commonly reported adverse reactions during ademetionine treatment were headache, diarrhea, and nausea.

The adverse reactions listed below were reported with the specified frequencies during clinical studies of ademetionine (n=1922) and in spontaneous reports. Adverse reactions are classified by system organ class (according to MedDRA) and by frequency of occurrence: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).

Gastrointestinal disorders:
Common – abdominal pain, diarrhea, nausea;
Uncommon – dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal hemorrhage, gastrointestinal discomfort, vomiting, esophagitis;
Rare – abdominal distension.

General disorders and administration site conditions:
Common – asthenia;
Uncommon – edema, hyperthermia, chills*, injection site reactions*, necrosis at injection site*;
Rare – malaise.

Immune system disorders:
Uncommon – hypersensitivity*, anaphylactoid reactions* or anaphylactic reactions (e.g., hyperemia, dyspnea, bronchospasm, back pain, chest discomfort, changes in blood pressure (hypotension, hypertension) or pulse rate (tachycardia, bradycardia))*.

Infections and infestations:
Uncommon – urinary tract infections.

Musculoskeletal and connective tissue disorders:
Uncommon – arthralgia, muscle cramps.

Nervous system disorders:
Common – headache;
Uncommon – dizziness, paresthesia, dysgeusia*.

Psychiatric disorders:
Common – anxiety, insomnia;
Uncommon – agitation, confusion.

Respiratory, thoracic and mediastinal disorders:
Uncommon – laryngeal edema*.

Skin and subcutaneous tissue disorders:
Common – pruritus;
Uncommon – hyperhidrosis, angioneurotic edema*, allergic skin reactions (e.g., rash, pruritus, urticaria, erythema)*.

Vascular disorders:
Uncommon – flushing, hypotension, phlebitis.

Rare cases of suicidal thoughts/behaviour have been reported in patients with depressive disorders (see section "Special precautions").

*Adverse reactions from spontaneous reports, which are more frequently known from spontaneous reporting or were not observed in clinical studies, are classified as "uncommon" because the upper limit of the 95% confidence interval for the expected frequency does not exceed 3/X, where X = 1922 (total number of subjects in clinical studies).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua/.

Shelf life

Lyophilisate – 3 years.
Solvent – 3 years.

The shelf life of the lyophilisate in combination with the solvent is determined by the component (lyophilisate or solvent) with the earlier expiry date.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities

Ademetionine (injection solution) must not be mixed with alkaline solutions or solutions containing calcium ions.

Packaging

Lyophilisate in a vial; 5 vials of lyophilisate together with 5 ampoules of 5 ml solvent in a blister pack; 1 blister pack per carton.

Prescription status

Prescription only.

Manufacturer

JSC "Kyivmedpreparat", Ukraine.

Manufacturer's address and location of business activity

139 Saksaganskogo St., Kyiv, 01032, Ukraine.