Instructions for use Heptral enteric-coated tablets 500 mg blister No. 20
Composition
active ingredient: ademetionine;
1 tablet contains 949 mg of ademethionine 1,4-butanedisulfonate, which corresponds to 500 mg of ademethionine cation;
excipients: colloidal anhydrous silicon dioxide, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, methacrylate copolymer (type A), polyethylene glycol 6000, polysorbates, simethicone emulsion, sodium hydroxide, talc.
Dosage form
Enteric-coated tablets.
Main physicochemical properties: film-coated tablets, oval-shaped, white to yellowish in color, without cracks, "cap" effect and swelling.
Pharmacotherapeutic group
Drugs affecting the digestive system and metabolic processes. Amino acids and their derivatives. ATX code A16A A02.
Pharmacological properties
Pharmacodynamics.
Ademethionine, or S-adenosyl-L-methionine, is a derivative of the amino acid methionine. S-adenosyl-L-methionine (ademethionine) is a natural amino acid that is present in almost all tissues and body fluids. Ademethionine primarily acts as a coenzyme and methyl group donor in transmethylation reactions, which is an integral metabolic process in humans and animals. The transfer of methyl groups (transmethylation) is also an integral 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 of the central nervous system, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin, and histamine.
Ademethionine is also a precursor in the formation of physiological sulfur (thiol) 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 the level of hepatic glutathione in patients with liver damage of both alcoholic and non-alcoholic genesis. Folic acid (folate) and vitamin B12 are essential co-nutrients in the processes of metabolism and recovery of ademethionine.
Pharmacokinetics.
Absorption. In humans, the pharmacokinetic profile of ademetionine after intravenous administration is biexponential and consists of a phase of rapid, pronounced distribution in tissues and a terminal elimination phase with a half-life of about 1.5 hours. Absorption after intramuscular administration is almost complete (96%), the maximum plasma concentration is reached approximately 45 minutes after administration. After oral 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 mg to 1000 mg. Plasma concentration decreases to the initial value within 24 hours. Bioavailability after oral administration increases if ademetionine is used between meals. When administered orally, the tablets are absorbed in the intestinal tract and significantly increase the plasma concentration of ademetionine. 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 absorption of ademetionine by the body occurs through typical metabolic pathways characteristic of an endogenous compound (transmethylation, transsulfuration, decarboxylation, etc.).
Distribution: The volume of distribution is 0.41 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 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.
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.
Clinical characteristics.
Indication
– Intrahepatic cholestasis in adults, including patients with chronic hepatitis of various etiologies and cirrhosis of the liver;
– intrahepatic cholestasis in pregnant women.
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 unlikely,
Theoretically, caution should be exercised when ademetionine is used concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and drugs and herbal remedies containing tryptophan (see Precautions).
Application features
Ammonia levels should be monitored in patients with pre-cirrhotic or cirrhotic stages of 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 "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 (SSRIs), tricyclic antidepressants (such as clomipramine), and drugs and herbal remedies containing tryptophan (see Interactions with other medicinal products and other forms of interaction).
Patients with depression are generally at risk for suicide or other serious acts and therefore require close monitoring and ongoing psychiatric care during treatment with ademetionine to appropriately identify and treat symptoms of depression.
There have been reports of transient onset or increased anxiety in patients taking ademetionine. In most cases, discontinuation of therapy was not necessary. Sometimes, anxiety resolved after dose reduction or discontinuation of therapy.
Effect 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.
Renal impairment: There are limited clinical data on the use of ademetionine in patients with renal impairment. Ademetionine should be used with caution in such patients.
Hepatic impairment: Pharmacokinetic characteristics do not differ between healthy volunteers and patients with chronic liver disease.
Elderly patients.
Clinical studies of ademetionine did not include sufficient numbers of patients aged 65 years and over to determine whether there is a difference in response to treatment compared with younger patients. Based on available clinical experience, no differences in response to treatment have been identified between elderly patients and younger patients. In general, dose selection for an elderly patient should be made with caution, usually starting at the lowest recommended dose, taking into account the increased frequency of decreased hepatic, renal, or cardiac function, the presence of concomitant pathological conditions, and the use of other medications.
Use during pregnancy or breastfeeding
In clinical studies, no adverse reactions were observed in women treated with ademetionine during the third trimester of pregnancy. Ademetionine should be used only if clearly needed during the first two trimesters of pregnancy.
During breastfeeding, ademetionine should 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 when taking ademetionine. Patients should refrain from driving or operating machinery until they are certain that ademetionine therapy does not affect their ability to perform these activities.
Method of administration and doses
The tablets should be swallowed whole, without chewing. Heptral® 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 Heptral® 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), it is recommended to refrain from using them.
Initial therapy
Oral (internal): The recommended dose is 10–25 mg/kg body weight per day. The usual starting dose is 800 mg/day, the total daily dose should not exceed 1600 mg.
Intravenous or intramuscular: the recommended dose is 5–12 mg/kg body weight per day for 2 weeks. The usual initial dose is 500 mg/day, the total daily dose should not exceed 800 mg (for parenteral administration, use Heptral® in the form of a lyophilized powder for solution for injection complete with solvent).
Supportive therapy
Administer orally (internally) 800–1600 mg/day.
The duration of therapy depends on the severity and course of the disease and is determined by the doctor individually.
Children.
The safety and effectiveness of ademetionine in children have not been established.
Overdose
Cases of overdose with ademetionine have been observed rarely. In case of overdose, physicians should contact local poison control centers. In general, patient monitoring and supportive treatment are recommended.
Adverse reactions
In clinical trials, ademetionine was used in more than 2,100 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 during
clinical studies of ademetionine (n=2115), as well as in spontaneous reports. Adverse reactions are classified by system organ class (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, <1/1,000), very rare (<1/10,000).
Gastrointestinal disorders: common - abdominal pain, diarrhea, nausea; uncommon - dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal bleeding, gastrointestinal disorders, vomiting; rare - bloating, esophagitis.
General disorders and administration site conditions: uncommon – asthenia, oedema, 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: uncommon – arthralgia, muscle cramps.
Nervous system disorders: common – headache; uncommon – dizziness, paresthesia.
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, angioedema*, allergic skin reactions (e.g. rash, pruritus, urticaria, erythema)*.
Vascular disorders: uncommon – hot flashes, hypotension, phlebitis.
Adverse reactions
from spontaneous reports not observed in clinical trials, classified by frequency of occurrence as "uncommon" given that the upper limit of the 95% confidence interval for the expected frequency does not exceed 3/X, where X=2115 (total number of volunteers in clinical trials).
1 Refers to the injectable form of the drug.
Expiration date
3 years.
Storage conditions
Does not require special storage conditions.
Store in the original blister out of the reach of children.
Packaging
10 tablets in a blister.
2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
AbbVie Srl, Italy.
Location of the manufacturer and address of its place of business
SR 148 Pontina KM 52, SNC - Campoverde di Aprilia (loc. Aprilia) - 04011 Aprilia (LT), Italy/SR 148 Pontina KM 52, SNC - Campoverde di Aprilia (loc. Aprilia) - 04011 Aprilia (LT), Italy.
