Hepametion

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

Composition:

1 vial of lyophilisate contains:

Active substance: S-adenosyl-L-methionine 1,4 butanedisulfonate 760 mg, equivalent to 400 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

S-adenosyl-L-methionine (adenosylmethionine) is a natural amino acid present in virtually all tissues and body fluids. Adenosylmethionine acts primarily 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 a necessary metabolic process in the formation of the bilayer phospholipid membrane in cell membranes and contributes to membrane fluidity. Adenosylmethionine is able to cross the blood-brain barrier. The transmethylation process involving adenosylmethionine is key in the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin, and histamine.

Adenosylmethionine is also a precursor in the formation of physiological sulfur-containing compounds (cysteine, taurine, glutathione, coenzyme A, etc.) in transsulfuration reactions. Glutathione, the most potent antioxidant in the liver, plays a crucial role in hepatic detoxification. Adenosylmethionine 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 adenosylmethionine.

Pharmacokinetics

Absorption. In humans, after intravenous administration, the pharmacokinetic profile of adenosylmethionine is biexponential and consists 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 approximately 45 minutes after administration. After oral administration of enteric-coated tablets of adenosylmethionine, maximum plasma concentration is dose-dependent, ranging from 0.5–1 mg/L, and is achieved within 3–5 hours after a single dose of 400 mg to 1000 mg. Plasma concentration decreases to baseline levels within 24 hours. Bioavailability after oral administration increases when adenosylmethionine is administered between meals.

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

Metabolism. The reactions that produce, utilize, and regenerate adenosylmethionine are known as the adenosylmethionine cycle. In the first step of this cycle, adenosylmethionine-dependent methyltransferase uses adenosylmethionine 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 via transfer of a methyl group from 5-methyltetrahydrofolate. Ultimately, methionine can be converted back into adenosylmethionine, completing the cycle.

Excretion. In radiolabeled studies, following oral administration of radioactively labeled (methyl-14C) adenosylmethionine 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 administered 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.
• Depressive syndromes.

Contraindications.

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

Hypersensitivity to any component of the drug.

Interaction with other medicinal products and other forms of interactions.

There is information about the development of serotonin syndrome in a patient who was taking ademetionine while receiving clomipramine. Although the role of ademetionine in this case is theoretically possible, ademetionine should be used with caution when administered concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and drugs or herbal products containing tryptophan (see section "Special precautions for use").

Special precautions for use.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e. it is practically sodium-free. One dose of the medicinal product contains 6.61 mg of sodium (equivalent to the sodium content in 16.80 mg of table salt). This constitutes 0.3% of the WHO recommended maximum daily sodium intake for adults (5 g of table salt).

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

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

Since vitamin B12 and folic acid (folates) deficiency may lead to reduced concentrations of ademetionine, patients at risk (e.g. anemia, liver disease, pregnancy, or potential for 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 advised to take vitamin B12 and/or folic acid (folates) according to the instructions for medical use of these medicinal products (see section "Pharmacological properties. Metabolism").

Ademetionine is not recommended for use in patients with bipolar psychosis. Cases have been reported in which patients experienced a switch from depression to hypomania or mania during treatment with ademetionine.

One case of serotonin syndrome has been reported in a patient receiving ademetionine while taking 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 other medicinal products or herbal preparations containing tryptophan (see section "Interaction with other medicinal products and other forms of interaction").

The efficacy of ademetionine in the treatment of depression has been demonstrated in short-term clinical studies (3–6 weeks). The efficacy of ademetionine treatment lasting longer than 6 weeks for depression is unknown. Since there are many treatment options for depression, patients should consult their physician to determine optimal therapy. Patients should be advised to inform their physician if their symptoms (of depression) do not improve or worsen during ademetionine therapy.

Patients with depression are generally at increased risk of suicide or other serious behaviors and therefore require careful monitoring and ongoing psychiatric support during ademetionine treatment to ensure adequate control of depressive symptoms.

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

Impact 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 measuring plasma homocysteine levels are recommended for such patients.

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

Renal impairment. Limited clinical data are available regarding the use of ademetionine in patients with renal impairment. Ademetionine should be used with caution in such patients.

Suicide/suicidal thoughts. Depression is associated with an increased risk of suicidal thoughts, suicidal behavior, and suicide (suicidal events). The risk persists until remission occurs. Significant improvement may not occur during the first weeks of treatment or for several weeks after initiation of therapy; therefore, close monitoring of patients with depression is necessary until improvement is observed.

Other psychiatric disorders for which this medicinal product is prescribed may also be associated with an increased risk of suicidal behavior. Moreover, such disorders may be associated with major depressive disorder. Particular caution should be exercised when treating patients with major depressive disorder, and the same safety measures should be applied as for patients with other psychiatric disorders.

Use during pregnancy or breastfeeding.

No adverse reactions were observed in clinical studies involving women treated with ademetionine during the third trimester of pregnancy. Ademetionine should be used during the first and second trimesters of pregnancy only after careful physician assessment of the benefit-risk balance for the pregnant woman and the fetus.

During breastfeeding, ademetionine may be used only when the potential benefit outweighs the potential risk to the infant.

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 or operating machinery until symptoms that may affect reaction speed have completely resolved.

Method of Administration and Dosage

Treatment may begin with parenteral administration of the drug followed by switching to tablets, or it may start directly with tablet administration. The daily dose of tablets can be divided into 2–3 doses. The injection solution must be prepared immediately before use.

Initial Therapy

Intravenous or intramuscular administration: the recommended dose is 5–12 mg/kg body weight per day. The usual initial dose is 400 mg/day; the total daily dose should not exceed 800 mg. The duration of initial parenteral therapy is 15–20 days when treating depressive syndromes and 2 weeks when treating liver diseases.

Oral (by mouth): for oral administration, the drug ademetionine in tablet form should be used. The recommended dose is 10–25 mg/kg body weight per day. The usual initial dose is 800 mg/day (2 tablets); the total daily dose should not exceed 1600 mg (4 tablets).

Maintenance Therapy

Administer orally 2–4 tablets daily (800–1600 mg/day).

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

For intramuscular or intravenous use, dissolve the lyophilized powder in the special solvent provided, immediately before administration. For intravenous infusion, 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.

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.

Elderly Patients

Clinical studies with ademetionine have not included a sufficient number of elderly patients (i.e., patients aged 65 years and older) to determine whether they respond differently from younger patients. However, based on available clinical experience, no differences in responses to treatment between elderly and younger patients have been observed. In general, dosage selection for elderly patients should be cautious, usually starting with the lowest recommended dose, taking into account the higher likelihood of decreased hepatic, renal, or cardiac function, presence of concomitant diseases, and use of other medicinal products.

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

Overdose
Cases of ademetionine overdose have been rarely reported. In the event of overdose, physicians should contact local toxicology centers. Patient monitoring is recommended, and symptomatic treatment should be administered as needed.

Adverse Reactions

The most commonly observed adverse reactions during administration of ademetionine are headache, diarrhea, and nausea.

Adverse reactions are classified by system organ classes (according to MedDRA) and frequency of occurrence: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), and very rare (<1/10,000).

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

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

Immune system disorders:
Uncommon – hypersensitivity, anaphylactoid 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 syndromes (see section "Special precautions for use").

Shelf life

Lyophilisate – 3 years.
Solvent – 3 years.
The shelf life of the final product is determined by the component (lyophilisate or solvent) with the earlier expiration date.

Storage conditions

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

Incompatibility

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

Packaging

400 mg of lyophilisate in a vial; 5 vials of lyophilisate with solvent (5 ml), 5 ampoules per cardboard pack.

Prescription category

Prescription only.

Manufacturer

JSC "Kyivmedpreparat"

Manufacturer's address and place of business

139 Saksaganskogo Street, Kyiv, 01032, Ukraine