Hep-art®

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

Composition:

Active ingredient: ademetionine;

1 tablet contains: ademetionine 1,4-butandisulfonate — 760.0 mg (corresponding to ademetionine cation — 400 mg);

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

Excipients for film coating: acrylic yellow 93A220018 (copolymer of methacrylic acid, talc, titanium dioxide, silicon dioxide, sodium lauryl sulfate, sodium bicarbonate, yellow iron oxide), dimethicone, polyethylene glycol.

Pharmaceutical form. Enteric-coated tablets.

Main physico-chemical properties: film-coated tablets from light yellow to yellow, oval-shaped, without cracks, damage or swelling.

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 almost all tissues and body fluids. Ademetionine 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 of cells, promoting membrane fluidity. Ademetionine is capable of crossing the blood-brain barrier. Transmethylation involving ademetionine is crucial for the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin, and histamine.

Ademetionine 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 an important 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.

Pharmacokinetics.

Absorption. In humans, after intravenous administration, the pharmacokinetic profile of ademetionine 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 ademetionine, 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 to 1000 mg. Plasma concentration decreases to baseline levels within 24 hours. Bioavailability after oral administration increases when ademetionine is administered between meals.

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

Metabolism. The reactions responsible for the production, utilization, and regeneration of ademetionine are 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 via transfer of a methyl group from 5-methyltetrahydrofolate. Finally, methionine can be converted back into ademetionine, completing the cycle.

Elimination. 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 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.

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 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 taking ademetionine while on clomipramine. Although the possibility of interaction is theoretically assumed, ademetionine should be used with caution concomitantly with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), and medicinal products or herbal remedies containing tryptophan (see section "Special precautions for use").

Special precautions for use.

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

Since vitamin B12 and folic acid (folates) deficiency may lead to decreased concentrations of ademetionine, patients at risk (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 given 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 disorders. Cases of transition from depression to hypomania or mania during treatment with ademetionine have been reported.

One published case reported the development of serotonin syndrome in a patient taking ademetionine concomitantly with clomipramine. Although such interaction is theoretically possible, ademetionine should be used with caution when administered simultaneously with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), and drugs or herbal products 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 trials (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 the optimal therapy. Patients should be advised to inform their doctor 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 treatment with ademetionine to assess the effectiveness of therapy in alleviating 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 immunological homocysteine assay

Ademetionine affects the results of immunological homocysteine assays, which may falsely indicate elevated plasma homocysteine levels. Therefore, for patients taking ademetionine, non-immunological methods are recommended for determining plasma homocysteine levels.

Hepatic impairment

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

Renal impairment

Limited clinical data are available on 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 phenomena). The risk persists until remission occurs during treatment of depression. 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 drug is prescribed may also be associated with an increased risk of suicidal behavior. In addition, such 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 taken as for patients with other psychiatric disorders.

Use during pregnancy or breastfeeding

No adverse reactions were observed in women treated with ademetionine during the third trimester of pregnancy in clinical studies. Ademetionine should be used during the first and second trimesters of pregnancy only after careful evaluation by a physician of the benefit-risk ratio 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 influence reaction speed when driving or operating machinery

Some patients may experience dizziness 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 (for parenteral use, the medicinal product Hep-Art® in the form of lyophilized powder for preparation of injection solution) followed by administration of the tablet form, or treatment may start directly with tablets. The daily dose of tablets may be divided into 2–3 doses.

Initial Therapy

Oral (internal) administration: 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 per day (800–1600 mg/day).

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

Tablets should be swallowed whole without chewing. Hep-Art® tablets are coated with a special enteric coating that dissolves only in the intestine, allowing ademetionine to be released in the duodenum. To ensure better absorption of the active substance and achieve full therapeutic effect, tablets should be taken between meals.

Hep-Art® tablets should be removed from the blister pack immediately before use. If the tablets have any color other than white to yellowish (due to damage to the integrity of the aluminum packaging), their 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 elderly patients respond differently to treatment compared to younger patients. However, based on available clinical experience, no differences in treatment responses 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. 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 have been reported with the specified frequency during clinical studies of ademetionine (n = 1922) and in spontaneous reports. Adverse reactions are classified by system organ class (according to MedDRA [Medical Dictionary for Regulatory Activities]) 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 disorders, vomiting, esophagitis;
Rare — abdominal distension.

General disorders and administration site conditions:
Common — asthenia;
Uncommon — edema, hyperthermia, chills*, reactions at the injection site*1, necrosis at the injection site*1;
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 ideation/behavior have been reported in patients with depressive disorders (see section "Special Warnings and Precautions for Use").

* Frequency of adverse reactions based on spontaneous reports, observed more frequently than in clinical studies or not observed at all during clinical studies, classified as "uncommon" because the upper limit of the 95% confidence interval for the expected frequency does not exceed 3/X, where X = 1,922 (total number of subjects in clinical studies).

1 Applies to the injectable form of the medicinal product.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

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.

Keep out of reach and sight of children.

Packaging.

4 tablets in a blister. 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.