Heptral

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

Composition:

Active substance: ademetionine;

1 vial of lyophilized powder contains 760 mg of ademetionine 1,4-butandisulfonate, corresponding to 400 mg of ademetionine cation;

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

Pharmaceutical form. Lyophilized powder for preparation of a solution for injection.

Main physicochemical properties: Lyophilized powder – lyophilized mass ranging from practically white to yellowish, free from foreign particles; solvent – clear liquid ranging from colorless to pale yellow, free from foreign particles; prepared solution – clear solution without visible particles, ranging from 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 primarily 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 a crucial metabolic process in the formation of the bilayer phospholipid membrane of cells, promoting membrane fluidity. Adenosylmethionine is able to cross the blood-brain barrier. Transmethylation involving adenosylmethionine plays a key role in the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin, and histamine.

Adenosylmethionine also serves as 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 vital 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, 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 approximately 45 minutes after administration. Following oral administration of enteric-coated tablets of adenosylmethionine, maximum 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. Oral bioavailability increases when adenosylmethionine is administered between meals.

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

Metabolism. The reactions responsible for the production, utilization, and regeneration of 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 radiolabeled (methyl-14C) adenosylmethionine in healthy volunteers, urinary excretion of radioactivity accounted for 15.5 ± 1.5% within 48 hours, and fecal excretion accounted for 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 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, tricyclic antidepressants (such as clomipramine), and medicinal products or herbal remedies containing tryptophan (see "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 "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 (anemia, liver disease, pregnancy, or potential vitamin deficiency due to other diseases or dietary habits such as vegetarianism) should undergo regular blood tests to assess 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 instructions for medical use of these medicinal products (see "Pharmacological properties. Metabolism").

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 case report describes the development of serotonin syndrome in a patient receiving ademetionine while on clomipramine. Although 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 remedies containing tryptophan (see "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 assess treatment efficacy for depressive symptoms.

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

Effect on immunological homocysteine assay.

Ademetionine affects the immunological assay for homocysteine, potentially leading to falsely elevated plasma homocysteine levels in patients receiving ademetionine. Therefore, non-immunological methods for determining plasma homocysteine levels are recommended in 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 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 events). The risk persists until remission occurs during antidepressant treatment. Significant improvement may not occur during the first weeks of treatment or 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, these disorders may be associated with major depressive disorder. When treating patients with major depressive disorder, great caution should be exercised, 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 ratio for the pregnant woman and 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.

Administration and Dosage

Treatment may begin with parenteral administration of the drug followed by oral tablets, or 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 1000 mg. The duration of initial parenteral therapy is 15–20 days when treating depressive syndromes and 2 weeks when treating liver diseases.

Oral administration: for oral use, Heptral**®** enteric-coated tablets 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

Oral administration of 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 administration, the lyophilized powder should be dissolved in the special solvent provided, immediately before use. 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 must 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 compared to younger patients. However, 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 frequency of impaired hepatic, renal, or cardiac function, the presence of concomitant diseases, and the 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 at the specified frequencies during clinical studies of ademetionine (n=1922) and in spontaneous reports. Adverse reactions are classified by system organ classes (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*, reactions at injection site*, 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 ideation/behaviour have been reported in patients with depressive syndromes (see section "Special Warnings and Precautions for Use").

* Adverse reactions from spontaneous reports, observed more frequently in spontaneous reports or 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).

Shelf life. Lyophilized powder in vials – 3 years. Solvent in ampoules – 3 years.

On the secondary packaging (carton box), the manufacturing date of the medicinal product refers to the lyophilized powder. The shelf life of the final medicinal product is determined by the component (lyophilized powder or solvent) with the earlier expiry date.

Storage conditions. Store out of reach and sight of children, at a temperature not exceeding 25 °C.

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

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

Prescription category. Prescription only.

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

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