Ademta

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

Composition:

Active substance: ademetionine;

1 vial contains ademetionine (as ademetionine 1,4-butanedisulfonate) 400 mg (761.52 mg);

Excipient: mannitol (E 421);

1 ampoule (5 ml) of solvent contains L-lysine monohydrochloride 324.40 mg, 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 metabolism. Amino acids and their derivatives. ATC code A16A A02.

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 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 in cell membranes and contributes to membrane fluidity. Ademetionine is able to cross the blood-brain barrier. The transmethylation process involving ademetionine is key 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 processes 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.

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

Distribution

The 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 minimal and does not exceed 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, 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.

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, 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 defect).

Interaction with other medicinal products and other forms of interaction.

Cases of serotonin syndrome have 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 in combination with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products, including herbal products, 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 of hyperammonemia who are taking ademetionine tablets.

Since vitamin B12 and folic acid (folates) deficiency may lead to reduced ademetionine concentration, 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 check plasma levels of these substances during treatment. If deficiency is detected, supplementation with vitamin B12 and/or folic acid (folates) is recommended either 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 have been reported in which patients switched from depression to hypomania or mania during ademetionine treatment.

One published case reported serotonin syndrome in a patient taking ademetionine concomitantly with 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 for longer than 6 weeks in 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 treatment.

Depression is associated with an increased risk of suicidal thoughts, suicidal behaviour, and suicide (suicidal events). 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 required until improvement is observed.

Other psychiatric disorders for which ademetionine is used 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 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 continuous psychiatric support during treatment with the medicinal product to monitor treatment efficacy 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 immunological assays for homocysteine, potentially leading to falsely elevated plasma homocysteine levels in patients taking ademetionine. Therefore, non-immunological methods for determining plasma homocysteine levels are recommended in 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. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

No adverse reactions were observed in clinical studies involving women who used 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 a physician of the benefit-risk ratio for the pregnant woman and the fetus.

Breastfeeding period

During breastfeeding, the medicinal product may be used only when the expected benefit to the mother outweighs the potential risk to the infant.

Ability to influence 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 further treatment with 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 a sufficient number of elderly patients (aged 65 years and older) to determine whether they respond differently to treatment compared to 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 performed cautiously, usually starting with the lowest recommended dose, taking into account the higher likelihood of reduced hepatic, renal, or cardiac function, the presence of concomitant pathological conditions, 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 dissolved in 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 administered by slow infusion over 1–2 hours. Any unused portion of the solution should 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, physicians should contact local toxicology centers. In case 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 adverse reactions listed below have been reported at the specified frequencies during clinical trials of ademetionine 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), frequency not known (frequency 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:

Common – asthenia; uncommon – oedema, hyperthermia, chills*, injection site reactions*, 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" in frequency because the upper limit of the 95% confidence interval for the expected frequency does not exceed 3/X, where X=1922 (total number of volunteers 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 marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 ºC in the original packaging and in a place inaccessible to children.

The reconstituted solution is stable for 6 hours at a temperature not exceeding 25 ºC or for 24 hours at 2–8 ºC.

Incompatibilities.

The reconstituted injection solution must 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.

UORLDMEDICINEILACSAN. VETIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operation.

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.