Hepametion
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEPAMETION® (HEPAMETION)
Composition:
Active substance: ademetionine;
1 tablet contains 949 mg of S-adenosyl-L-methionine 1,4 butanedisulfonate, equivalent to
500 mg of ademetionine cation;
Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, coating mixture (containing: methacrylic acid copolymer (type A), talc, titanium dioxide (E 171), colloidal anhydrous silicon dioxide, sodium bicarbonate, sodium lauryl sulfate, polyethylene glycol (macrogol)).
Pharmaceutical form. Enteric-coated tablets.
Main physicochemical properties: film-coated tablets, oval-shaped, white to almost white.
Pharmacotherapeutic group. Agents affecting the digestive system and metabolic processes. Amino acids and their derivatives. ATC code A16AA02.
Pharmacological properties.
Pharmacodynamics.
Ademetionine, or S-adenosyl-L-methionine, is a derivative of the amino acid methionine. S-adenosyl-L-methionine (ademetionine) is a natural amino acid present in virtually 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. The transfer of methyl groups (transmethylation) is also essential for the formation of the bilayer phospholipid membrane in cell membranes, promoting membrane fluidity. Ademetionine is able to cross the blood-brain barrier. Transmethylation processes involving ademetionine play a key role in the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, norepinephrine, epinephrine), serotonin, melatonin, and histamine.
Ademetionine is also a precursor in the formation of physiological sulfur-containing (thiol) compounds (cysteine, taurine, glutathione, coenzyme A) in 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 processes of ademetionine.
Intrahepatic cholestasis.
Intrahepatic cholestasis may be one of the complications of acute and chronic liver diseases and may occur independently of their etiology. This pathological condition is characterized by reduced bile secretion by hepatocytes, leading to the accumulation in blood of substances normally excreted via bile, particularly bilirubin, bile salts, and enzymes.
The use of ademetionine helps overcome the metabolic block (conversion of methionine to ademetionine) caused by reduced activity of the enzyme ademetionine synthetase. Thus, physiological mechanisms preventing the development of cholestasis are restored. Various experimental studies have shown that the anti-cholestatic effect of ademetionine is achieved through: 1) restoration of microfluidity of cytoplasmic membranes via ademetionine-dependent synthesis of membrane phospholipids (reduction of the cholesterol/phospholipid ratio), and 2) overcoming the metabolic block in the transsulfuration process, thereby restoring the synthesis of thiol groups involved in endogenous detoxification processes.
Pharmacokinetics.
Absorption. In humans, after 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. Absorption after intramuscular administration is nearly complete (96%), with maximum plasma concentration reached approximately 45 minutes after administration. After oral administration of enteric-coated ademetionine tablets, the maximum plasma concentration is dose-dependent, ranging from 0.5–1 mg/L, and is achieved 3–5 hours after a single dose of 400 mg to 1000 mg. Plasma concentration decreases to baseline levels within 24 hours. Bioavailability after oral administration increases when ademetionine is administered between meals. Following oral administration, the tablets are absorbed in the intestinal tract and significantly increase plasma ademetionine concentration. Animal studies using isotopic methods have confirmed that oral administration of ademetionine stimulates the formation of methylated compounds in the liver. It has also been confirmed that the body's uptake of ademetionine occurs via typical metabolic pathways characteristic of endogenous compounds (transmethylation, transsulfuration, decarboxylation).
Distribution. The volume of distribution is 0.41 and 0.44 L/kg for ademetionine doses of 100 mg and 500 mg, respectively. Plasma protein binding is negligible, amounting to ≤ 5%.
Metabolism. The reactions that produce, utilize, and regenerate ademetionine are collectively known as the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methyltransferases use 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 to healthy volunteers, urinary excretion of the radioactive substance was 15.5 ± 1.5% within 48 hours, and fecal excretion was 23.5 ± 3.5% within 72 hours, with approximately 60% of the administered substance 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.
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.
Serotonin syndrome has been reported in a patient who was receiving ademetionine concomitantly with clomipramine. Therefore, although the possibility of interaction is theoretically assumed, ademetionine should be used with caution when administered simultaneously with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products or herbal preparations containing tryptophan (see section "Special precautions").
Special precautions for use
The level of ammonia should be monitored in patients with pre-cirrhotic or cirrhotic stage hyperammonemia who are taking ademetionine tablets.
Since vitamin B12 and folic acid (folate) deficiency may lead to reduced concentrations of ademetionine, patients at risk (e.g. those with anemia, liver disease, pregnancy, or potential vitamin deficiency due to other diseases or dietary habits such as veganism) 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 prescribing information for these medicinal products (see section "Pharmacological properties. Pharmacokinetics. Metabolism").
This medicinal product is not indicated for the treatment of depressive disorders, but may be used for the treatment of intrahepatic cholestasis in patients with depressive disorders. Therefore, the following warnings regarding patients receiving antidepressant therapy should be considered.
Ademetionine is not recommended for use in patients with bipolar disorders. Cases of transition from depression to hypomania or mania during ademetionine treatment have been reported.
One case of serotonin syndrome has been reported in a patient receiving ademetionine concomitantly with clomipramine. Although such an interaction is theoretically possible, ademetionine should be used with caution when administered together with SSRIs, tricyclic antidepressants (such as clomipramine), and medicinal or herbal products containing tryptophan (see section "Interaction with other medicinal products and other forms of interaction").
Patients with depression are generally at increased risk of suicide or other serious behaviors and therefore require careful monitoring and ongoing psychiatric support during antidepressant therapy to ensure timely identification and management of depressive symptoms. Patients with a history of suicidal behavior or ideation, or those exhibiting significant suicidal intent, are at higher risk of suicidal attempts or intentions and should be closely supervised during treatment.
There have been reports of transient onset or worsening of anxiety in patients taking ademetionine. In most cases, discontinuation of therapy was not necessary. Anxiety symptoms sometimes resolved after dose reduction or discontinuation of treatment.
Effect on immunological homocysteine assay
Ademetionine interferes with immunological assays for homocysteine, potentially leading to falsely elevated plasma homocysteine levels in patients taking ademetionine. Therefore, non-immunological methods for measuring plasma homocysteine levels are recommended in such patients.
Renal impairment. Clinical data on the use of ademetionine in patients with renal impairment are limited. Ademetionine should be used with caution in these patients.
Hepatic impairment. Pharmacokinetic characteristics do not differ between healthy volunteers and patients with chronic liver disease.
Elderly patients.
Clinical studies of ademetionine have not included sufficient numbers of patients aged 65 years and older to determine whether they respond differently compared to younger patients. Based on available clinical experience, no differences in responses to treatment between elderly and younger patients have been identified. In general, dose selection for elderly patients should be cautious, usually starting with the lowest recommended dose, taking into account the greater frequency of decreased hepatic, renal, or cardiac function, presence of concomitant diseases, and use of other medicinal products.
Excipients
This medicinal product contains 1.92 mg (0.08 mmol) of sodium per tablet, i.e., practically sodium-free.
Use during pregnancy or breastfeeding.
No adverse reactions were observed in women treated with ademetionine during the third trimester of pregnancy in clinical studies. Ademetionine should be used during the first two trimesters of pregnancy only if clearly needed.
During breastfeeding, ademetionine should be used only when the expected 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 treatment with ademetionine. Patients should refrain from driving vehicles or operating machinery until they are fully certain that ademetionine therapy does not impair their ability to perform such activities.
Dosage and Administration
Treatment may begin with parenteral administration of the drug (use the Hepametion**®** lyophilized powder for injection solution in combination with the solvent), followed by transition to tablet form, or treatment may start directly with tablets. The daily dose of tablets can be divided into 2–3 doses.
Tablets should be swallowed whole, without chewing. Hepametion**®** tablets are coated with a special enteric coating that dissolves only in the intestine, thereby releasing ademetionine in the duodenum. To ensure optimal absorption of the active substance and achieve full therapeutic effect, tablets should be taken between meals.
A Hepametion**®** tablet should be removed from the blister pack immediately before use. If the tablets have any color other than white to yellowish (due to damage of the aluminum packaging), their use is not recommended.
Initial Therapy
Oral administration: the recommended dose is 10–25 mg/kg body weight per day. The usual initial dose is 800 mg/day; the total daily dose should not exceed 1600 mg.
Maintenance Therapy
Oral administration: 800–1600 mg/day.
Individual initial and maintenance doses should be determined by a physician based on body weight, severity of the disease, and available dosage forms of the drug on the market.
Duration of therapy depends on the severity and course of the disease and is determined individually by the physician.
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. Generally, patient monitoring and supportive treatment are recommended.
Adverse Reactions
Ademetionine has been administered to approximately 2000 patients in clinical studies. The most commonly reported adverse reactions during treatment with ademetionine were headache, diarrhea, and nausea.
The adverse reactions listed below have been reported with the indicated frequency during clinical studies of ademetionine (n=1922) 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 (≥ 1/10000, < 1/1000), very rare (< 1/10000).
Gastrointestinal disorders:
Common – abdominal pain, diarrhea, nausea;
Uncommon – dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal hemorrhage, gastrointestinal disorders, vomiting, esophagitis;
Rare – abdominal distension.
General disorders and administration site conditions:
Common – asthenia;
Uncommon – edema, hyperthermia, chills*, injection site reactions*1, necrosis at injection site*1;
Rare – malaise.
Immune system disorders:
Uncommon – hypersensitivity*, anaphylactoid reactions*, or anaphylactic reactions (e.g., hyperemia, dyspnea, 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, paresthesia, dysgeusia*.
Psychiatric disorders:
Common – anxiety, insomnia;
Uncommon – agitation, confusion.
Respiratory, thoracic and mediastinal disorders:
Uncommon – laryngeal edema*.
Skin and subcutaneous tissue disorders:
Common – pruritus;
Uncommon – hyperhidrosis, angioneurotic edema*, allergic skin reactions (e.g., rash, pruritus, urticaria, erythema)*.
Vascular disorders:
Uncommon – flushing, hypotension, phlebitis.
Rare reports of suicidal thoughts/behaviour have been reported in patients with depressive disorders (see section "Special precautions").
*Adverse reactions from spontaneous reports, which are more frequently known from spontaneous reporting or were not observed in clinical studies, are classified with the frequency "uncommon", considering that the upper limit of the 95% confidence interval for the expected frequency does not exceed 3/X, where X=1922 (total number of subjects in clinical studies).
1Applies to the injectable form of the medicinal product.
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.
Packaging. 10 tablets in a blister. 2 blisters in a carton.
Prescription status. Prescription only.
Manufacturer. JSC "Kyivmedpreparat", Ukraine.
Manufacturer's address.
139 Saksaganskogo St., Kyiv, 01032, Ukraine.