Instructions for Ademta lyophilisate for solution for injection 400 mg in a vial + ampoules of solvent No. 5
Composition
active ingredient: ademetionine;
1 vial contains ademetionine (in the form of ademetionine 1,4-butanedisulfonate) 400 mg;
excipient: mannitol (E 421).
1 ampoule (5 ml) with solvent contains L-lysine monohydrochloride, sodium hydroxide, water for injection.
Dosage form
Lyophilisate for solution for injection.
Main physicochemical properties:
powder: white lyophilized powder;
Solution for injection: clear solution from colorless to yellow.
Pharmacotherapeutic group
Drugs affecting the digestive system and metabolic processes. Amino acids and their derivatives. ATC code A16A A02.
Pharmacological properties
Pharmacodynamics.
Ademethionine (S-adenosyl-L-methionine) is a natural amino acid found in almost all tissues and body fluids. Ademethionine 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 an essential metabolic process in the construction of the phospholipid bilayer in cell membranes and contributes to membrane fluidity. Ademethionine is able to penetrate the blood-brain barrier. The transmethylation process involving ademethionine is key in the formation of neurotransmitters in the central nervous system, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin, and histamine.
Ademethionine is also a precursor in the formation of physiological sulfur compounds (cysteine, taurine, glutathione, coenzyme A) in transsulfuration reactions. Glutathione, the most powerful antioxidant in the liver, plays an important role in hepatic detoxification. Ademethionine increases hepatic glutathione levels in patients with liver damage of both alcoholic and non-alcoholic genesis. Folic acid (folate) and vitamin B12 are necessary co-nutrients in the processes of metabolism and recovery of ademethionine.
Pharmacokinetics.
Absorption
When administered intravenously, the pharmacokinetic profile of ademetionine is biexponential and consists of a phase of rapid, pronounced tissue distribution and a terminal elimination phase with a half-life of about 1.5 hours.
When administered intramuscularly, the absorption of ademetionine is almost complete (96%), with maximum plasma concentration achieved approximately 45 minutes after administration.
Distribution
The volume of distribution is 0.41 and 0.44 l/kg for doses of ademetionine 100 and 500 mg, respectively. Plasma protein binding is negligible and is ≤ 5%.
Metabolism
The reactions that produce, utilize, and regenerate ademethionine are called the ademethionine cycle. In the first step of this cycle, ademethionine-dependent methylase uses ademethionine as a substrate to produce S-adenosyl-homocysteine, which is then hydrolyzed to homocysteine and adenosine by S-adenosyl-homocysteine hydrolase. Homocysteine, in turn, undergoes reverse transformation to methionine by transfer of a methyl group from 5-methyltetrahydrofolate. Ultimately, methionine can be converted to ademethionine, completing the cycle.
Breeding
In radioisotope studies with oral administration of radiolabeled (methyl 14C) ademetionine in healthy volunteers, urinary excretion of radioactive substance was 15.5 ± 1.5% after 48 hours, fecal excretion was 23.5 ± 3.5% after 72 hours, with approximately 60% of the substance remaining incorporated in stable pools.
Indication
Intrahepatic cholestasis in adults, including patients with chronic hepatitis of various etiologies and cirrhosis of the liver;
intrahepatic cholestasis in pregnant women;
depressive syndromes.
Contraindication
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 types of interactions
Serotonin syndrome has been reported in a patient taking ademetionine while taking clomipramine. Therefore, although the possibility of interaction is theoretically possible, caution should be exercised when using ademetionine concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products, including herbal remedies, containing tryptophan (see section 4.4).
Application features
Intravenous administration of the drug should be carried out very slowly (see section "Method of administration and dosage").
Since vitamin B12 and folic acid (folate) deficiency may lead to decreased ademetionine concentrations, patients at risk (anemia, liver disease, pregnancy, or the possibility of vitamin deficiency due to other diseases or dietary habits such as vegetarianism) should have regular blood tests to check plasma levels of these substances while taking the drug. If deficiency is detected, treatment with vitamin B12 and/or folic acid (folate) is recommended before or during use of the drug. If these tests are not possible, patients at risk are recommended to use vitamin B12 and/or folic acid (folate) according to the instructions for medical use of these drugs (see section "Pharmacological properties").
The drug is not recommended for use in patients with bipolar psychosis. There have been reports of patients who have experienced a transition from depression to hypomania or mania while taking ademetionine.
There has been one published report of serotonin syndrome in a patient taking ademetionine while taking clomipramine. Although the possibility of interaction is theoretically possible, caution should be exercised when the drug is used concomitantly with SSRIs, tricyclic antidepressants (such as clomipramine), and medicinal products, including herbal remedies, containing tryptophan (see section 4.5).
The efficacy of ademetionine in the treatment of depression has been demonstrated in short-term clinical trials (3–6 weeks). The efficacy of ademetionine for longer than 6 weeks in the treatment of depression is unknown. There are many treatments for depression, so patients should consult with their doctor to determine the optimal therapy. Patients should be advised to inform their doctor if their symptoms (depression) persist or worsen while taking the drug.
Depression is associated with an increased risk of suicidal thoughts, suicidal behaviour and suicide (suicidal events). The risk persists until remission occurs in the treatment of depression. Significant improvement may not occur during the first weeks of treatment or for several weeks after the initial course of therapy, therefore, during the use of the drug, patients with depression should be carefully monitored until improvement is observed.
Other psychiatric conditions for which ademetionine is used may also be associated with an increased risk of suicidal behaviour. In addition, such conditions may be associated with major depressive disorder. When treating patients with major depressive disorder, great caution should be exercised and the same precautions should be taken as when treating patients with other psychiatric conditions.
Patients with depression are usually at increased risk of committing suicide or other serious acts, and therefore require close supervision and ongoing psychiatric care while using the drug to monitor the effectiveness of treatment for depressive symptoms.
There have been reports of transient onset or increased anxiety in patients taking ademetionine. In most cases, treatment discontinuation was not necessary. Sometimes the anxiety disappeared after dose reduction or discontinuation of therapy.
Ademetionine interferes with the immunoassay for homocysteine, which may falsely indicate 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 insufficiency. The drug should be used with caution in such patients.
This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Pregnancy
During clinical studies in women who used ademetionine in the third trimester of pregnancy, no adverse reactions were observed. During the first and second trimesters of pregnancy, the drug should be used only after a careful assessment by the doctor of the benefit-risk ratio for the pregnant woman.
Breastfeeding period
During breastfeeding, the drug can be used only if the expected benefit to the mother outweighs the potential risk to the infant.
Ability to influence reaction speed when driving vehicles or other mechanisms
Some patients may experience dizziness while taking ademetionine. In such cases, you should refrain from driving or operating machinery until the symptoms have completely disappeared, as they may affect your reaction time during these activities.
Method of administration and doses
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 drug is 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 in the treatment of depressive syndromes and 14 days in the treatment of liver diseases.
Elderly patients
Clinical studies with ademetionine did not include sufficient numbers of elderly patients (aged 65 years and over) to determine whether there are differences in response to treatment between elderly and younger patients. However, clinical experience has not identified differences in response to treatment between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the lowest recommended dose, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, the presence of concomitant medical conditions, and the use of other medications.
Method of application
The drug 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 saline or 5% dextrose (glucose) solution and infused slowly over 1–2 hours. Any unused portion of the solution should be discarded.
The solution for injection 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 temperature), it should be avoided.
Children.
The safety and effectiveness of ademetionine in children have not been established.
Overdose
Cases of overdose with ademetionine have been reported rarely. In the event of overdose, monitoring of the patient's condition and supportive treatment are recommended.
Side effects
The most commonly reported side effects with ademetionine were headache, diarrhea, and nausea.
The following adverse reactions have been reported with the following frequencies in clinical trials with ademetionine and in spontaneous reports. Adverse reactions are classified by system organ class (MedDRA) and frequency: 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), not known (frequency cannot be estimated from the available data).
From the digestive tract:
often - abdominal pain, diarrhea, nausea; infrequently - dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal bleeding, gastrointestinal disorders, vomiting, esophagitis; rarely - abdominal distension.
General disorders and administration site conditions:
infrequently - asthenia, edema, hyperthermia, chills*, injection site reactions*, injection site necrosis*; rarely - malaise.
Immune system disorders: uncommon: hypersensitivity*, anaphylactoid reactions* or anaphylactic reactions (e.g. flushing, 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:
infrequently - arthralgia, muscle cramps.
From the nervous system:
often - headache; infrequently - dizziness, paresthesia, dysgeusia*.
From the psyche:
often - anxiety, insomnia; infrequently - agitation, confusion.
From the respiratory system, chest organs and mediastinum:
uncommon – laryngeal edema*.
Skin and subcutaneous tissue disorders:
common - itching; uncommon - hyperhidrosis, angioedema*, allergic skin reactions (e.g. rash, itching, urticaria, erythema)*.
From the vascular side:
infrequently - hot flashes, hypotension, phlebitis.
* Adverse reactions from spontaneous reports that were observed more frequently in spontaneous reports or not observed in clinical trials 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 volunteers in clinical trials).
There have been rare reports of suicidal thoughts/behavior in patients with depressive syndromes (see section "Special warnings and precautions for use").
Reporting of suspected adverse reactions
Reporting suspected adverse reactions that occur after the marketing authorisation of a medicinal product is very important. This allows the benefit/risk balance of the medicinal product to be continuously monitored. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
Lyophilisate for solution for injection – 3 years.
Solvent – 4 years.
Storage conditions
Store at a temperature not exceeding 25 ºС in a place inaccessible to children.
The prepared solution is stable for 6 hours at a temperature not exceeding 25 °C or for 24 hours at a temperature of 2-8 °C.
Incompatibility
The prepared solution for injection should not be mixed with alkaline solutions or solutions containing calcium ions.
Packaging
400 mg of lyophilisate for solution for injection in a vial complete with 5 ml of solvent in an ampoule; 5 vials of lyophilisate for solution for injection and 5 ampoules of solvent in a contour blister pack; 1 contour blister pack in a cardboard box.
Vacation category
According to the recipe.
Producer
Mefar Ilach San. A.Sh./ Mefar Ilac San. AS
Address
Ramazanoglu Mach. Ansar Jad. No. 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey/
Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.
Applicant
WORLD MEDICINE, LLC, Ukraine.
