Active substanceAdemethionineAdemethionine
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  • Dosage form: & nbsplyophilizate for the preparation of solution for intravenous and intramuscular administration
    Composition:

    Composition of lyophilizate per bottle:

    Active substance: ademethionine 1,4-butanedisulfonate 760.0 mg (in terms of cation ademetionina 400.0 mg).

    The composition of the solvent per ampoule;

    Excipients: Llysine 342.4 mg; sodium hydroxide 11.5 mg; water for injection up to 5 ml.

    Description:

    Lyophilizate: White or almost white lyophilized mass, compacted into a tablet.

    Solvent: Transparent colorless or with a yellowish tinge liquid with a characteristic odor.

    Pharmacotherapeutic group:Hepatoprotective agent
    ATX: & nbsp

    A.16.A.A.02   Ademethionine

    Pharmacodynamics:

    Ademetionine belongs to the group of hepatoprotectors, it also has antidepressant activity. It has choleretic and cholekinetic effect, detoxification, regenerating, antioxidant, antifibrozing and neuroprotective properties. Replenishes the deficit S-adenosyl-L-metionine (ademethionine) and stimulates its production in the body, is contained in all media of the body. The highest concentration of ademetionine is found in the liver and brain. Performs a key role in the metabolic processes of the body, takes part in important biochemical reactions: transmethylation, transulfurization, transamination. In the reactions of transmethylation ademethionine donates a methyl group for the synthesis of phospholipids of cell membranes, neurotransmitters, nucleic acids, proteins, hormones, etc. In the transsulfation reactions ademethionine is the precursor of cysteine, taurine, glutathione (providing the oxidation-reduction mechanism of cellular detoxification), coenzyme acetylation (included in biochemical reactions of the tricarboxylic acid cycle and replenishes the energy potential of the cell).Increases the glutamine content in the liver, cysteine ​​and taurine in plasma; reduces the content of methionine in the serum, normalizing metabolic reactions in the liver. After decarboxylation, it participates in aminopropylation reactions, like the predecessor of polyamines-putrescine (the stimulator of cell regeneration and proliferation of hepatocytes), spermidine and spermine, which are part of the ribosome structure, which reduces the risk of fibrosis. Has a choleretic effect. Ademethionine normalizes the synthesis of endogenous phosphatidylcholine in hepatocytes, which increases the fluidity and polarization of membranes. This improves the function of hepatocyte-associated transport systems of bile acids and promotes the passage of bile acids into the biliary system. Effective with intrahepatic (intralobular and interlobular) variant of cholestasis (violation of synthesis and current of bile). Ademethionine reduces the toxicity of bile acids in the hepatocyte, carrying out their conjugation and sulfation. Conjugation with taurine increases the solubility of bile acids and their removal from the hepatocyte. The process of sulphation of bile acids contributes to the possibility of their elimination by the kidneys, facilitates the passage through the membrane of the hepatocyte and excretion with bile.In addition, the sulfated bile acids themselves additionally protect the liver cell membranes from the toxic effect of non-sulphated bile acids (in high concentrations present in hepatocytes with intrahepatic cholestasis). In patients with diffuse liver disease (cirrhosis, hepatitis) with intrahepatic cholestasis syndrome ademethionine reduces the severity of skin itching and changes in biochemical parameters, incl. the level of direct bilirubin, the activity of alkaline phosphatase, aminotransferases, etc. Choleretic and hepatoprotective effects persist up to 3 months after discontinuation of treatment. Efficacy is shown for hepatopathies caused by various hepatotoxic drugs. The appointment of patients with opioid addiction, accompanied by liver damage, leads to regression of clinical manifestations of abstinence, improvement of the functional state of the liver and the processes of microsomal oxidation. Antidepressant activity manifests itself gradually, beginning with the end of the first week of treatment, and stabilized within 2 weeks of treatment.Effective in recurrent endogenous and neurotic depressions resistant to amitriptyline. Has the ability to interrupt recurrence of depression. The appointment in osteoarthritis reduces the severity of the pain syndrome, increases the synthesis of proteoglycans and leads to partial regeneration of the cartilaginous tissue.

    Pharmacokinetics:

    Suction

    Bioavailability at parenteral introduction - 96%, concentration in plasma reaches maximum values ​​in 45 minutes.

    Distribution

    Linkage to blood plasma proteins is insignificant, ≤ 5%. Penetrates through the blood-brain barrier. There is a significant increase in the concentration of ademetionine in the cerebrospinal fluid.

    Metabolism

    Metabolised in the liver. The process of formation, expenditure and re-formation of ademethionine is called the ademethionine cycle. At the first stage of this cycle, ademethionine-dependent methylases are used ademethionine as a substrate for products Sadenosyl homocysteine, which is then hydrolyzed to homocysteine ​​and adenosine by Sadenosylhomocysteinehydralase. Homocysteine, in turn,is reverse-converted to methionine by transferring the methyl group from 5-methyltetrahydrofolate. Eventually methionine can be transformed into ademethionine, completing the cycle.

    Excretion

    The half-life (T1 / 2) is 1.5 hours. It is excreted by the kidneys.

    Indications:

    Intrahepatic cholestasis with precirrotic and cirrhotic conditions, which can be observed in the following diseases:

    - fatty degeneration of the liver;

    - chronic hepatitis;

    - toxic liver damage of various etiologies, including alcoholic, viral, medicinal (antibiotics, antitumor, antituberculosis and antiviral drugs, tricyclic antidepressants, oral contraceptives);

    - chronic acalculous cholecystitis;

    - cholangitis;

    - cirrhosis of the liver;

    - encephalopathy, incl. associated with hepatic insufficiency (alcohol and etc).

    Intrahepatic cholestasis in pregnant women.

    Symptoms of depression.

    Contraindications:

    - Genetic disorders affecting the methionine cycle and / or causing homocystinuria and / or hyperhomocysteinemia (cystathionine beta-synthase deficiency, cyanocobalamin metabolism disorder);

    - hypersensitivity to any of the components of the drug;

    - age to 18 years (experience of medical use in children is limited).

    Carefully:

    Bipolar disorders (see section "Special instructions").

    Pregnancy (I trimester) and the period of breastfeeding (use is possible only if the potential benefit to the mother exceeds the possible risk to the fetus or the baby).

    Simultaneous administration with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), as well as preparations of plant origin and preparations containing tryptophan (see the section "Interaction with other medicinal products").

    Elderly age.

    Renal failure.

    Pregnancy and lactation:

    The use of high doses of ademethionine in III trimester of pregnancy did not cause any undesirable effects. The use of the drug in pregnant women in the first trimester and during breastfeeding is possible only if the potential benefit to the mother exceeds the possible risk to the fetus or child.

    Dosing and Administration:

    Intravenous and intramuscular.

    The lyophilizate must be dissolved in a specially applied solvent immediately before administration. The rest of the drug must be disposed of. The drug should not be mixed with alkaline solutions and solutions containing calcium ions. If the lyophilizate has a color different from white to almost white (due to a crack in the vial or heat exposure), the Geparett® preparation should not be used. The drug Geparett® with intravenous administration is very slow.

    Initial therapy:

    Intravenous or intramuscular administration: the recommended dose is 5-12 mg / kg / day intravenously or intramuscularly.

    Intrahepatic cholestasis

    From 400 mg / day to 800 mg / day (1-2 vials a day) for 2 weeks.

    Depression

    From 400 mg / day to 800 mg / day (1-2 vials a day) for 15-20 days.

    If necessary, maintenance therapy is recommended to continue taking ademethionine in the form of tablets at a dose of 800-1600 mg / day for 2-4 weeks.

    Therapy with Geparett® can be started with intravenous or intramuscular injection followed by the use of ademethionine in the form of tablets or immediately with the use of the drug in the form of tablets.

    Elderly patients

    Clinical experience with ademethionine has not revealed any difference in its efficacy in elderly patients and younger patients. However, given the high likelihood of existing violations of the liver, kidney or heart, other concomitant pathologies, or simultaneous therapy with other drugs, the dose of Geparett® should be selected with caution in elderly patients starting with the lower limit of the dose range.

    Renal insufficiency

    There are limited clinical data on the use of ademetionine in patients with renal insufficiency, and therefore caution should be exercised when using Geparett® in these patients.

    Liver failure

    The pharmacokinetics of ademetionin are similar in healthy volunteers and in patients with chronic liver disease.

    Children

    The use of Geparett® in children is contraindicated (efficacy and safety not established).

    Side effects:

    All adverse reactions are distributed according to organ systems. The incidence of adverse reactions is given according to the classification of the World Health Organization (WHO): very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10000,<1/1000); very rarely (<1/10000).

    System of organs

    Frequency

    Undesirable effects

    Infectious and parasitic diseases

    Infrequently

    Urinary tract infections

    Immune system disorders

    Infrequently

    Reactions

    hypersensitivity Anaphylactoid or anaphylactic reactions (including hyperemia of the skin, dyspnea, bronchospasm, back pain, a feeling of discomfort in the chest, changes in blood pressure (arterial hypotension, arterial hypertension) or heart rate (tachycardia, bradycardia))

    Disorders of the psyche

    Often

    Anxiety

    Insomnia

    Infrequently

    Agitation

    Confusion of consciousness

    Disturbances from the nervous system

    Often

    Headache

    Infrequently

    Dizziness

    Paresthesia

    Vascular disorders

    Infrequently

    "Tides"

    Arterial hypotension Phlebitis

    Disturbances from the respiratory system, chest and mediastinal organs

    Infrequently

    Laryngeal edema

    Disorders from the gastrointestinal tract

    Often

    Abdominal pain

    Diarrhea

    Nausea

    Infrequently

    Dry mouth

    Dyspepsia

    Flatulence

    Gastrointestinal pain

    Gastrointestinal

    bleeding

    Gastrointestinal

    disorders

    Vomiting

    Bloating

    Esophagitis

    Disturbances from the skin and subcutaneous tissues

    Often

    Itchy skin

    Infrequently

    Increased sweating Angioedema Swelling and allergic reactions (including rash, itching, urticaria, erythema)

    Disturbances from musculoskeletal and connective tissue

    Infrequently

    Arthralgia

    Muscle spasms

    General disorders and disorders at the site of administration

    Infrequently

    Asthenia

    Edema

    Fever

    Chills

    Reactions at the site of administration

    Necrosis of the skin at the site of administration

    Rarely

    Malaise

    If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

    Overdose:

    Overdosage of the drug Heparetta® is unlikely. In case of an overdose, it is recommended that you follow the patient and perform symptomatic therapy.

    Interaction:It should be used with caution ademethionine simultaneously with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), as well as with herbs and preparations containing tryptophan.
    Special instructions:

    Given the tonic effect of the drug, it is not recommended to apply it before bedtime. When using Geparett® with patients with cirrhosis of the liver against a background of hyperaemia, systematic monitoring of the nitrogen content in the blood is necessary. During prolonged therapy, it is necessary to determine the content of urea and creatinine in the blood serum. It is not recommended to apply ademethionine patients with bipolar disorders. There are reports of the transition of depression to hypomania or mania in patients taking ademethionine.

    Patients with depression have an increased risk of suicide and other serious adverse events, so during treatment with ademethionine, such patients should be under constant medical supervision to evaluate and treat the symptoms of depression. Patients should inform the doctor if their symptoms of depression do not decrease or worsen with ademethionine therapy.

    There is a probability of sudden occurrence or increase of anxiety in patients taking ademethionine. In most cases, cancellation of therapy is not required, in several cases, anxiety disappeared after a dose reduction or drug withdrawal.Since the deficiency of cyanocobalamin and folic acid can reduce ademetionin in patients at risk (with anemia, liver disease, pregnancy, or the likelihood of vitamin deficiency, due to other diseases or diet, for example, in vegetarians), you should control the vitamin levels in the blood plasma. If insufficiency is detected, the administration of cyanocobalamin and folic acid is recommended before treatment with ademethionine or simultaneous administration with ademethionine.

    In immunoassay, the use of ademetionine may contribute to a false determination of the high homocysteine ​​content in the blood. For patients receiving ademethionine, it is recommended to use non-immunological assays to determine the content of homocysteine.

    Heparetta® lyophilizate for the preparation of a solution for intravenous and intramuscular administration, 400 mg / 5 ml contains less than 1 mmol sodium (23 mg) per dose, i.e. practically does not contain sodium.

    Effect on the ability to drive transp. cf. and fur:

    Some patients may experience dizziness when using Geparett®.It is not recommended to operate the transport and work with the mechanisms during the application of the drug until the patients are sure that the therapy does not affect the ability to engage in this type of activity.

    Form release / dosage:

    Lyophilizate for the preparation of solution for intravenous and intramuscular injection, 400 mg.

    Packaging:

    760 mg of lyophilizate in a vial of colorless neutral glass type I, sealed with a rubber stopper with an aluminum cap with a plastic lid or without a plastic lid.

    5 ml solvent in ampoules of colorless neutral glass of type I with a break ring or with a break point, or without a kink ring and without a break point.

    5 vials with lyophilizate and 5 vials with a solvent in a total of 10 cells or in two separate out of 5 cells contour mesh packages of polymer material or 5 vials with lyophilizate and 5 vials with a solvent in a total of 10 cells or in two separate of 5 cells contour mesh packaging of polymeric material, coated with aluminum foil with printing or without printing.

    One common contour cell package or two separate contiguous cell packs with lyophilizate and solventtogether with instructions for the use of a medicinal product for medical use in a pack of cardboard.

    For 30 or 50 vials of lyophilizate with an equivalent amount of ampoules with a solvent together with an equal number of instructions for the use of medicinal products for medical use in a cardboard box or a cardboard box with partitions (for hospitals).

    In addition, ampoule or scarifier knives are placed in packs or boxes with ampoules without a kink ring and break points.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years (for lyophilizate).

    3 years (for solvent).

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004212
    Date of registration:27.03.2017
    Expiration Date:27.03.2022
    The owner of the registration certificate:TRIVIUM-XXI, LLC TRIVIUM-XXI, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp19.04.2017
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