Instructions for Hep-art tablets 400mg No. 20
Composition
active ingredient: ademetionine;
1 tablet contains: ademethionine 1,4-butanedisulfonate – 760.0 mg (corresponding to ademethionine cation – 400 mg);
excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;
film coating excipients: acrylis yellow 93A220018 (methacrylic acid copolymer, talc, titanium dioxide, silicon dioxide, sodium lauryl sulfate, sodium bicarbonate, iron oxide yellow), dimethicone, polyethylene glycol.
Dosage form
Enteric-coated tablets.
Main physicochemical properties: film-coated tablets from light yellow to yellow, oval in shape, without cracks, damage or swelling.
Pharmacotherapeutic group
Drugs affecting the digestive system and metabolic processes. Amino acids and their derivatives. ATC code A16A A02.
Pharmacological properties
Pharmacodynamics
S-adenosyl-L-methionine (ademethionine) 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. Methyl group transfer (transmethylation) is also an essential metabolic process in the formation of the phospholipid bilayer in cell membranes and contributes to membrane fluidity. Ademethionine is able to cross 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, etc.) 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. In humans, after intravenous administration, the pharmacokinetic profile of ademetionine is biexponential and consists of a phase of rapid, pronounced distribution in tissues and a terminal elimination phase with a half-life of approximately 1.5 hours. Absorption after intramuscular administration is almost complete (96%), the maximum plasma concentration is reached approximately 45 minutes after administration. After internal administration of enteric-coated ademetionine tablets, the maximum plasma concentration is dose-dependent, is 0.5-1 mg/l and is reached 3-5 hours after taking a single dose of 400 to 1000 mg. Plasma concentration decreases to the initial value within 24 hours. Bioavailability after oral administration increases if ademetionine is taken between meals.
Distribution: The volume of distribution is 0.41 L/kg and 0.44 L/kg for ademetionine doses of 100 mg and 500 mg, respectively. Serum protein binding is negligible and is ≤ 5%.
Metabolism. The reactions that produce, utilize, and recycle 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.
Excretion: In radioisotope studies with oral administration of radiolabeled (methyl 14C) ademetionine in healthy volunteers, urinary excretion of radioactive material was 15.5 ± 1.5% after 48 hours and faecal excretion was 23.5 ± 3.5% after 72 hours, with approximately 60% of the material 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 drug (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 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 an interaction is theoretically possible, caution should be exercised when using ademetionine concomitantly with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), and drugs and herbal remedies containing tryptophan (see section 4.4).
Application features
Ammonia levels should be monitored in patients with pre-cirrhotic or cirrhotic hyperammonemia who are taking ademetionine tablets.
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. If deficiency is detected, treatment with vitamin B12 and/or folic acid (folate) is recommended before or during the use of ademetionine. If these studies cannot be performed, patients at risk are recommended to use vitamin B12 and/or folic acid (folate) in accordance with the instructions for medical use of these drugs (see section "Pharmacological properties. Metabolism").
Ademetionine is not recommended for use in patients with bipolar psychosis. There have been reports of patients transitioning from depression to hypomania or mania while treated with ademetionine.
There has been one published report of serotonin syndrome in a patient taking ademetionine while taking clomipramine. Although the possibility of an interaction is theoretically possible, caution should be exercised when ademetionine is used concomitantly with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), and drugs and 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) do not improve or worsen during treatment with ademetionine.
Patients with depression are usually at increased risk of committing suicide or other serious acts, therefore they require close supervision and ongoing psychiatric care during treatment with ademetionine in order to monitor the effectiveness of treatment of depressive symptoms.
There have been reports of transient onset or increased anxiety in patients taking ademetionine. In most cases, discontinuation of therapy was not necessary. Sometimes the anxiety disappeared after dose reduction or discontinuation of therapy.
Impact on homocysteine immunoassay
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.
Liver failure
Pharmacokinetic characteristics do not differ between healthy volunteers and patients with chronic liver disease.
Kidney failure
There are limited clinical data on the use of ademetionine in patients with renal insufficiency. 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 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, patients with depression should be closely monitored until improvement is observed.
Other psychiatric conditions for which this drug is prescribed may also be associated with an increased risk of suicidal behavior. 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.
Use during pregnancy or breastfeeding
During breastfeeding, ademetionine can be used only if the potential benefit from its use outweighs the potential risk to the infant.
Ability to influence reaction speed when driving vehicles or other mechanisms
Some patients may experience dizziness during ademetionine therapy. In such cases, you should refrain from driving or operating other mechanisms until the symptoms disappear, which may affect the speed of reaction during these activities.
Method of administration and doses
Treatment can be started with parenteral administration of the drug followed by the use of the drug in tablet form or immediately with the use of tablets. The daily dose of tablets can be divided into 2-3 doses.
Initial therapy
Oral (internal): The recommended dose is 10-25 mg/kg body weight per day. The usual starting dose is 800 mg/day (2 tablets), the total daily dose should not exceed 1600 mg (4 tablets).
Intravenously or intramuscularly: 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 in the treatment of depressive syndromes and 2 weeks in the treatment of liver diseases (for parenteral administration, use the drug Hep-Art® in the form of a lyophilized powder for the preparation of a solution for injection).
Supportive therapy
Administer orally 2-4 tablets per day (800-1600 mg/day).
The duration of therapy depends on the severity and course of the disease and is determined by the doctor individually.
The tablets should be swallowed without chewing. Hep-Art® tablets are coated with a special coating that dissolves only in the intestine, due to which ademetionine is released in the duodenum. For better absorption of the active substance and for the full therapeutic effect, the tablets should be taken between meals.
The Hep-Art® tablet should be removed from the blister immediately before taking it. If the tablets are any color other than white to yellowish (due to a violation of the integrity of the aluminum wrapper), you should refrain from using them.
Elderly patients
Clinical studies with ademetionine did not include sufficient numbers of elderly patients (i.e., 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 made with caution, 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.
Children
The safety and effectiveness of ademetionine in children have not been established.
Overdose
Cases of overdose with ademetionine have been reported rarely. In case of overdose, physicians should contact local poison control centers. In general, patient observation and supportive treatment are recommended.
Side effects
Ademetionine was used in clinical trials in approximately 2000 patients. The most commonly reported adverse reactions during treatment with ademetionine were headache, diarrhea, and nausea.
The following adverse reactions have been reported with the following frequencies in clinical trials with ademetionine (n=1922) and in spontaneous reports. Adverse reactions are classified by system organ class (MedDRA) and frequency of occurrence: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), rare (<1/10000).
Gastrointestinal: often - abdominal pain, diarrhea, nausea; infrequently - dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal bleeding, gastrointestinal disorders, vomiting, esophagitis; rarely - abdominal bloating.
General disorders and administration site conditions: common – asthenia; uncommon – edema, hyperthermia, chills*, injection site reactions*1, injection site necrosis*1; rare – 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.
Nervous system disorders: often – headache; infrequently – dizziness, paresthesia, dysgeusia*.
Mental disorders: often - anxiety, insomnia; infrequently - agitation, confusion.
Respiratory, thoracic and mediastinal disorders: uncommon – laryngeal edema*.
Skin and subcutaneous tissue disorders: common: pruritus; uncommon: hyperhidrosis, angioedema*, allergic skin reactions (e.g. rash, pruritus, urticaria, erythema)*.
There have been rare reports of suicidal thoughts/behavior in patients with depressive syndromes (see section "Special warnings and precautions for use").
* Adverse reactions from spontaneous reports that were observed more frequently in spontaneous reports or not observed in clinical trials are classified as “uncommon” since 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).
1 Refers to the injectable form of the drug.
Expiration date
2 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
4 tablets in a blister. 5 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "Farmak".
Address
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
