Hep-art

INSTRUCTIONS for medical use of the medicinal product HEP-ART® (HEP-ART)

Composition:

Active substance: 1 vial of lyophilisate contains 760 mg of ademetionine 1,4-butanedisulfonate equivalent to 400 mg of ademetionine;

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

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: lyophilized mass of white to light yellow color, free from foreign particles.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolic processes. ATC code A16AA02.

Pharmacological Properties

Pharmacodynamics

S-adenosyl-L-methionine (adenosylmethionine) is a natural amino acid present in almost all tissues and body fluids. Adenosylmethionine primarily acts as a coenzyme and methyl group donor in numerous transmethylation reactions, which are important metabolic processes in humans and animals. The transfer of methyl groups (transmethylation) by adenosylmethionine is also a crucial metabolic process in the formation of cellular phospholipid membranes and plays a role in membrane fluidity.

Adenosylmethionine is capable of crossing the blood-brain barrier. High concentrations of adenosylmethionine affect transmethylation processes, which are highly important in brain tissue, by influencing the metabolism of catecholamines (dopamine, adrenaline, noradrenaline), indoleamines (serotonin, melatonin), and histamine.

Adenosylmethionine serves as a precursor in the formation of physiological sulfur-containing compounds (cysteine, taurine, glutathione, coenzyme A) in transsulfuration reactions. Glutathione, the most potent antioxidant, is an essential component in hepatic detoxification. Adenosylmethionine increases glutathione levels in patients with liver damage of both alcoholic and non-alcoholic etiology.

Folic acid and vitamin B12 are essential cofactors in the metabolism and regeneration processes of adenosylmethionine.

Pharmacokinetics

Absorption. In humans, after intravenous administration, the pharmacokinetic profile of adenosylmethionine is biexponential, with a rapid distribution phase into tissues and clearance, with a half-life of approximately 1.5 hours. Absorption after intramuscular administration is 96%, with maximum plasma concentrations reached within 45 minutes after administration. Following oral administration of enteric-coated tablets of adenosylmethionine, the 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 declines 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 L/kg and 0.44 L/kg for doses of adenosylmethionine of 100 mg and 500 mg, respectively. Plasma protein binding is minimal, at ≤ 5%.

Metabolism. The metabolism of adenosylmethionine follows a cyclic pathway 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, is converted to methionine via transfer of a methyl group from 5-methyltetrahydrofolate. Methionine can then be converted back to adenosylmethionine, thus completing the cycle.

Excretion. In radiolabeled studies, following oral administration of radiolabeled (methyl-14C) adenosylmethionine to healthy volunteers, urinary excretion of radioactivity accounted for 15.5 ± 1.5% within 48 hours, and fecal excretion amounted to 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 defect).

Hypersensitivity to any component of the drug.

Interaction with other medicinal products and other forms of interactions.

There has been a report of serotonin syndrome developing in a patient who was receiving ademetionine while taking clomipramine. Although the role of ademetionine in this case is theoretically assumed, ademetionine should be used with caution when administered concomitantly with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), and with medicinal products and herbal remedies containing tryptophan.

Special precautions for use.

Intravenous administration must be performed very slowly.

Since vitamin B12 and folic acid deficiency may lead to decreased concentrations of ademetionine, patients at risk (anemia, liver disease, pregnancy, or potential vitamin deficiency due to other diseases or dietary habits such as vegetarianism) should undergo regular blood tests to monitor plasma levels of these substances. If deficiency is detected, treatment with vitamin B12 and/or folic acid is recommended before or during ademetionine therapy. In cases where such testing is not feasible, patients at risk should be given vitamin B12 and/or folic acid 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 disorders. Cases have been reported in which patients experienced a shift from depression to hypomania or mania during treatment with ademetionine.

One published case reported the development of serotonin syndrome 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, tricyclic antidepressants (such as clomipramine), and 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 for longer than 6 weeks in treating depression is unknown. Since there are many approaches to treating depression, patients should consult their physician to determine optimal therapy. Patients should be advised to inform their physician if symptoms of their condition (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 assess treatment efficacy for depressive symptoms.

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

Effect on immunoassay measurement of homocysteine

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

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

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

Renal impairment. Limited data are available; therefore, 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 (or related 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, patients with depression require close monitoring until improvement is observed.

Other psychiatric disorders for which this drug is used may also be associated with an increased risk of suicidal behavior. Moreover, these disorders may be associated with major depressive disorder. When treating patients with major depressive disorder, particular caution should be exercised, and the same safety measures should be applied as for patients with other psychiatric disorders.

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

Use during pregnancy or breastfeeding.

Administration of high doses of ademetionine during the third trimester of pregnancy has not caused any adverse reactions. Ademetionine should be used during the first and second trimesters of pregnancy only after careful physician assessment of the benefit-risk ratio to the mother and fetus.

During breastfeeding, ademetionine should be used only when the benefit to the mother 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 vehicles or operating machinery until symptoms that may affect reaction speed have completely resolved.

Dosage and Administration

Treatment usually begins with parenteral administration of the drug, followed by administration of ademetionine in tablet form. The injection solution should 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 per day; the total daily dose should not exceed 1000 mg. The duration of initial parenteral therapy is 15–20 days when treating depressive disorders and 2 weeks when treating liver diseases.

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

The lyophilized powder should be dissolved in the solvent provided, immediately before use. The drug may be administered as intramuscular or intravenous injections. 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.

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

Elderly Patients

Based on available clinical experience, no differences in treatment response have been observed between elderly patients and younger patients. However, treatment of elderly patients should begin with the lowest recommended dose, taking into account possible reduced hepatic, renal, or cardiac function, presence of concomitant pathological conditions, 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. In general, 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 treatment with ademetionine 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/behavior have been reported in patients with depressive syndromes (see section "Special precautions").

* Adverse reactions from spontaneous reports, observed more frequently in spontaneous reports or not observed during clinical studies, classified as "uncommon" due to the upper limit of the 95% confidence interval for the expected frequency not exceeding 3/X, where X=1922 (total number of subjects in clinical studies).

Shelf life.

2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

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

Packaging.

In vials of 5 units, with 5 ml solvent in ampoules of 5 units.

Prescription status.
By prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.