Heptral

INSTRUCTIONS for medical use of the medicinal product HEPTRAL® (HEPTRAL®)

Composition:

Active substance: ademetionine;

One vial of lyophilized powder contains 949 mg of ademetionine 1,4-butandisulfonate, equivalent to 500 mg of ademetionine cation;

Excipients: none.

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

Pharmaceutical form. Lyophilized powder for solution for injection.

Main physicochemical properties: lyophilized powder – lyophilized compacted mass ranging from practically white to yellowish in color, free from foreign particles; solvent – clear liquid from colorless to pale yellow, free from foreign particles; reconstituted solution – clear solution from colorless to yellow, without visible precipitate.

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. Transfer of methyl groups (transmethylation) is also a crucial metabolic process involved in 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 critical 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 processes of ademetionine.

Intrahepatic cholestasis.

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

The use of ademetionine helps overcome the metabolic block (conversion of methionine to ademetionine) caused by reduced activity of the enzyme ademetionine synthetase. Thus, physiological mechanisms preventing the development of cholestasis are restored. Various experimental studies have shown 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 the metabolic block in the transsulfuration process, thereby restoring the synthesis of thiol groups involved in endogenous detoxification processes.

Pharmacokinetics.

Absorption. In humans, after intravenous administration, the pharmacokinetic profile of ademetionine is biexponential and consists of a rapid distribution phase in 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 ademetionine tablets, maximum plasma concentration is dose-dependent, ranging from 0.5 to 1 mg/L, and is achieved within 3 to 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 ademetionine is administered between meals. Following oral administration, 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 metabolized via typical metabolic pathways characteristic of endogenous compounds (transmethylation, transsulfuration, decarboxylation, etc.).

Distribution. Volume of distribution is 0.41 and 0.44 L/kg for ademetionine doses of 100 mg and 500 mg, respectively. Plasma protein binding is negligible, 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 methyltransferases use 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 to ademetionine, completing the cycle.

Elimination. In radiolabeled studies, following oral administration of radiolabeled (methyl-14C) ademetionine to 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 dose incorporated into stable body 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 defect).

Interaction with other medicinal products and other forms of interaction.

Serotonin syndrome has been reported in a patient receiving ademetionine concomitantly with clomipramine. Therefore, although the possibility of interaction is theoretically assumed, ademetionine should be used with caution when administered simultaneously with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products or herbal preparations containing tryptophan (see "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. One dose of the medicinal product contains 8.28 mg of sodium (equivalent to the sodium content in 21.04 mg of table salt). This corresponds to 0.4% of the WHO recommended maximum daily intake of sodium for adults (5 g of table salt).

Intravenous administration of ademetionine solution must be performed very slowly (see "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 decreased ademetionine concentrations, patients at risk (e.g. anaemia, liver disease, pregnancy, or potential for vitamin deficiency due to other diseases or dietary habits such as veganism) should have 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 "Pharmacological properties. Pharmacokinetics. Metabolism").

This preparation is not indicated 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 must be considered.

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

One published case reported 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 concomitantly 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").

Patients with depression are generally at increased 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 thoughts, or those exhibiting a high degree of suicidal intent, are at increased risk of suicidal ideation or attempts and should be closely supervised 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. In some instances, anxiety 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-immunoassay methods for determining plasma homocysteine levels are recommended for such patients.

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.

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 responses to treatment have been observed between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting with the lowest recommended dose, taking into account the greater frequency of decreased hepatic, renal, or cardiac function, presence of concomitant diseases, and use of other medicinal products.

Use during pregnancy or breastfeeding.

In clinical studies, no adverse reactions were observed in women treated with ademetionine during the third trimester of pregnancy. Ademetionine should be used during the first two trimesters of pregnancy only if clearly needed.

During breastfeeding, ademetionine may be used only when 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 impair their ability to perform such activities.

Method of Administration and Dosage

Treatment may be initiated with parenteral administration of the drug, followed by transition to tablet form, or may start directly with tablets.

For intramuscular or intravenous use, the lyophilized powder must be dissolved in the solvent provided, immediately before administration. For intravenous administration, the required dose of dissolved 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.

Initial Therapy

Intravenously or intramuscularly: 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 according to the instructions for medical use of Heptral**®** tablets in enteric-coated form.

The 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 reported. In the event 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 treatment with ademetionine were headache, diarrhea, and nausea.

The adverse reactions listed below were reported with the specified frequency during clinical studies of ademetionine (n=1922) and in spontaneous reports. Adverse reactions are classified by organ systems (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 disorders, 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 during clinical studies, are classified as "uncommon" based on the fact that 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).

Shelf life. Lyophilized powder in vials – 3 years. Solvent in ampoules – 3 years. On the secondary packaging (cardboard box), the manufacturing date of the medicinal product refers to the lyophilized powder. The shelf life of the final medicinal product (kit) is determined by the component (lyophilized powder or solvent) with the earlier expiry date.

Storage conditions. Store at temperatures not exceeding 25 °C in a place inaccessible to children.

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

Packaging. 5 glass vials with lyophilized powder and 5 ampoules with solvent (5 ml each) in a blister pack sealed with aluminum foil. One blister pack per cardboard box.

Prescription status. Prescription only.

Manufacturer. Biologici Italia Laboratories S.R.L., Italy or Delpharm Saint Remy, France.

Manufacturer's address and site of operations. Via Filippo Serpero, 2 - 20060 Masate (MI), Italy or Rue de l’Isle, Saint Remy Sur Avre, 28380, France.