Ademta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADEMTA (ADEMTA)

Composition:

active substance: ademetionine;

1 vial contains ademetionine (in the form of ademetionine 1,4-butanedisulfonate) 400 mg;

excipient: mannite (E 421).

1 ampoule (5 ml) of solvent contains L-lysine monohydrochloride, sodium hydroxide, water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties:

powder: lyophilized white powder;

solution for injection: clear solution 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.

Ademetionine (S-adenosyl-L-methionine) 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. Transfer of methyl groups (transmethylation) is also a necessary metabolic process in the formation of the bilayer phospholipid membrane in cell membranes and promotes membrane fluidity. Ademetionine is able to cross the blood-brain barrier. The transmethylation process involving ademetionine plays a key role in 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) 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

Following 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.

After intramuscular administration, absorption of ademetionine is nearly complete (96%), and maximum plasma concentration is reached approximately 45 minutes after administration.

Distribution

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

Excretion

In radiolabeled studies, following oral administration of radioactively labeled (methyl-14C) ademetionine to healthy volunteers, urinary excretion of radioactivity was 15.5 ± 1.5% within 48 hours, fecal excretion was 23.5 ± 3.5% within 72 hours, while approximately 60% of the administered substance remained 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.
• 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.

Serotonin syndrome has been reported in a patient taking ademetionine concomitantly with clomipramine. Therefore, although the possibility of interaction is theoretically assumed, ademetionine should be used with caution in combination with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products, including herbal ones, containing tryptophan (see section "Special precautions").

Special precautions for use.

Intravenous administration of the medicinal product should be performed very slowly (see section "Dosage and administration").

During treatment with the medicinal product, 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 a decrease in ademetionine concentration, patients at risk (e.g., anemia, liver disease, pregnancy, or potential vitamin deficiency due to other diseases or dietary habits such as vegetarianism) should undergo regular blood tests to check plasma levels of these substances during treatment. If deficiency is detected, supplementation with vitamin B12 and/or folic acid (folates) is recommended before or during treatment with the medicinal product. 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 section "Pharmacological properties").

The medicinal product is not recommended for use in patients with bipolar disorders. Cases of transition from depression to hypomania or mania have been reported during ademetionine therapy.

One published case of serotonin syndrome has been reported in a patient receiving ademetionine while taking clomipramine. Although such interaction is theoretically possible, caution should be exercised when using the medicinal product concomitantly with SSRIs, tricyclic antidepressants (such as clomipramine), and other medicinal products, including 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 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 treatment.

Depression is associated with an increased risk of suicidal thoughts, suicidal behavior, and suicide (suicidal events). This risk may persist until remission occurs during treatment of depression. 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 required until improvement is observed.

Other psychiatric disorders for which ademetionine is used may also be associated with an increased risk of suicidal behavior. Moreover, such disorders may be associated with major depressive disorder. Particular caution should be exercised when treating patients with major depressive disorder, and the same safety measures should be applied as in the treatment of patients with other psychiatric disorders.

Patients with depression are generally at increased risk of suicide or other serious acts and therefore require close monitoring and ongoing psychiatric support during treatment with the medicinal product to monitor the effectiveness of therapy for depressive symptoms.

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

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.

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

There are limited clinical data on the use of ademetionine in patients with renal impairment. The medicinal product should be used with caution in such patients.

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

Use during pregnancy or breastfeeding.

Pregnancy

No adverse reactions were observed in clinical studies involving women who received ademetionine during the third trimester of pregnancy. During the first and second trimesters of pregnancy, the medicinal product should be used only after careful assessment by the physician of the benefit-risk ratio for the pregnant woman and the fetus.

Breastfeeding period

The medicinal product may be used during breastfeeding only when the expected 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 treatment with ademetionine. 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

The medicinal product is intended for parenteral administration.

Treatment may begin with parenteral administration followed by the use of ademetionine in tablet form.

The injection solution should be prepared immediately before use.

Dosage

The medicinal product should be administered intravenously or intramuscularly at a dose of 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 14 days when treating liver diseases.

Elderly Patients

Clinical studies conducted with ademetionine have not included sufficient numbers of elderly patients (aged 65 years and older) to determine whether they 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, dose selection for elderly patients should be cautious, usually starting with the lowest recommended dose, taking into account the increased likelihood of impaired hepatic, renal, or cardiac function, the presence of concomitant diseases, and the use of other medicinal products.

Method of Administration

The medicinal product is intended for intravenous or intramuscular administration. The lyophilized powder should be reconstituted with the special solvent provided, immediately before use. 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.

The injection solution 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.

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, patient monitoring and supportive treatment are recommended.

Adverse Reactions

The most commonly reported adverse reactions during administration of ademetionine are headache, diarrhoea, and nausea.

The following adverse reactions have been reported at the specified frequencies during clinical trials with ademetionine, as well as 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), frequency not known (cannot be estimated from available data).

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:

uncommon – 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.

* Adverse reactions from spontaneous reports observed more frequently in spontaneous reports or not observed during clinical trials, classified as "uncommon" based on 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 trials).

Rare cases of suicidal thoughts/behaviour have been reported in patients with depressive syndromes (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life

Lyophilisate for injection solution – 3 years.

Solvent – 4 years.

Storage conditions

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

The reconstituted solution is stable for 6 hours at temperatures not exceeding 25 °C or for 24 hours at 2–8 °C.

Incompatibilities

The reconstituted injection solution should not be mixed with alkaline solutions or solutions containing calcium ions.

Packaging

400 mg of lyophilisate for injection solution in a vial, supplied with 5 mL of solvent in an ampoule; 5 vials of lyophilisate for injection solution and 5 ampoules of solvent in a blister pack; 1 blister pack in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Mefar Ilac San. A.S. / Mefar Ilac San. A.S.

Manufacturer's address and location of operations

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey / Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorisation Holder

WORLD MEDICINE, LLC, Ukraine / WORLD MEDICINE, LLC, Ukraine.