Ademetionine

INSTRUCTIONS for medical use of the medicinal product Ademetionine (Ademetionine)

Composition:

Active substance: ademetionine;

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

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

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties:

• vial with lyophilisate: lyophilized mass of white to yellowish color, free from foreign particles;
• vial with solvent: clear liquid from colorless to pale yellow, free from foreign particles;
• prepared solution: clear solution without visible particles, 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 (SAMe, ademetionine) is a natural amino acid present in virtually all tissues and body fluids. Ademetionine acts primarily as a coenzyme and a 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 able to cross the blood-brain barrier. Transmethylation reactions involving ademetionine play 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 compounds (cysteine, taurine, glutathione, coenzyme A, and others) via transsulfuration reactions. Glutathione, the most potent antioxidant in the liver, plays a crucial 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, following intravenous administration, the pharmacokinetic profile of ademetionine 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 of ademetionine achieved approximately 45 minutes after administration. After oral administration of enteric-coated tablets of ademetionine, peak plasma concentration is dose-dependent, ranging from 0.5 to 1 mg/L, and is reached within 3 to 5 hours after a single dose of 400 mg to 1000 mg. Plasma concentrations of ademetionine decline to baseline levels within 24 hours. Bioavailability following 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 100 mg and 500 mg doses of ademetionine, respectively. Plasma protein binding is negligible, at ≤ 5%.

Metabolism. The reactions responsible for the production, utilization, and regeneration of ademetionine are collectively known as the ademetionine cycle. In the first step of this cycle, an 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 is subsequently remethylated to methionine through transfer of a methyl group from 5-methyltetrahydrofolate. Finally, methionine can be converted back into ademetionine, thus completing the cycle.

Excretion. In radiolabeled studies, following oral administration of radiolabeled (methyl-14C) ademetionine 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 dose 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 (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal or herbal products 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 amounts to 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 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 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 the instructions for medical use of these medicinal products (see "Pharmacological properties. Metabolism").

Ademetionine is not recommended for use in patients with bipolar disorders. Cases have been reported in which depression turned into 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 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").

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 beyond 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 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 behaviours and therefore require careful monitoring and ongoing psychiatric support during ademetionine therapy to assess treatment effectiveness 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 required. Anxiety symptoms sometimes resolved after dose reduction or discontinuation of treatment.

Effect on immunochemical homocysteine assay.

Ademetionine interferes with immunochemical assays for homocysteine, potentially leading to falsely elevated plasma homocysteine levels in patients receiving ademetionine. Therefore, non-immunochemical 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 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 behaviour, 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, patients with depression should be closely monitored until improvement is evident.

Other psychiatric disorders for which this product is prescribed may also be associated with an increased risk of suicidal behaviour. In addition, 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 applied as in the treatment of patients with other psychiatric disorders.

Use during pregnancy or breastfeeding.

No adverse reactions have been 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 evaluation by the physician of the benefit-risk ratio for the pregnant woman and the foetus.

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 be initiated with parenteral administration of the drug followed by oral tablets, or treatment may start directly with tablets. The daily tablet dose can be divided into 2–3 doses. 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/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, ademetionine should be administered in the appropriate pharmaceutical form. 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 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 should 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 conducted 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 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 increased likelihood of decreased 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 case of overdose, physicians should contact local toxicology centers. Recommended management includes patient monitoring and supportive treatment.

Adverse Reactions

The most commonly reported adverse reactions during treatment with ademetionine are headache, diarrhoea, and nausea.

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 (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000).

Gastrointestinal disorders: common – abdominal pain, diarrhoea, nausea; uncommon – dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal haemorrhage, gastrointestinal disorders, vomiting, oesophagitis; rare – abdominal distension.

General disorders and administration site conditions: common – asthenia, oedema, hyperthermia, chills*, reactions at injection site*, necrosis at injection site*; rare – malaise.

Immune system disorders: uncommon – hypersensitivity*, anaphylactoid reactions* or anaphylactic reactions (e.g. hyperaemia, dyspnoea, 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, paraesthesia, dysgeusia*.

Psychiatric disorders: common – anxiety, insomnia; uncommon – agitation, confusion.

Respiratory, thoracic and mediastinal disorders: uncommon – laryngeal oedema*.

Skin and subcutaneous tissue disorders: common – pruritus; uncommon – hyperhidrosis, angioneurotic oedema*, allergic skin reactions (e.g. rash, pruritus, urticaria, erythema)*.

Vascular disorders: uncommon – flushing, hypotension, phlebitis.

Rare reports of suicidal thoughts/behaviour have been observed in patients with depressive syndromes (see section "Special precautions for use").

* Adverse reactions reported from spontaneous reports, not observed during clinical trials, classified as "uncommon" in frequency because the upper limit of the 95% confidence interval for the expected frequency does not exceed 3/X, where X=2115 (total number of patients in clinical trials).

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 via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Incompatibilities.

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

Packaging.

5 vials of lyophilisate and 5 vials of solvent (L-lysine monohydrate, sodium hydroxide, water for injections), 5 ml each, in a blister pack; 1 blister pack per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "FARMEX GROUP".

Manufacturer's address and place of business.

100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.

Marketing Authorisation Holder.

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVYA", Ukraine.

Address of the Marketing Authorisation Holder.

22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine