Geptral time. liof. for solution for infection. 500 mg fl. + rastvo. 5 ml No. 5

Pharmacological properties

Pharmacodynamics. ademetionin, or s-adenozil-l-methionine, is derivative methionine amino acids. s-adenozil-l-methionine (ademetionin) — natural amino acid which is present practically at all fabrics and fluid mediums of an organism. ademetionin, first of all, also the donor of methyl group in transmethylation reactions which are the integral metabolic process at the person and animals acts as coenzyme. transfer of methyl groups (transmethylation) is also the integral metabolic process at construction of a double phospholipidic layer in cell membranes and promotes the fluidity of membranes. ademetionin it is capable to get through geb. process of transmethylation with participation of an ademetionin is key in formation of neurotransmitters of central nervous system, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin and a histamine.

Ademetionin is also a predecessor in formation of the physiological sulphurized (thiol) connections (cysteine, taurine, glutathione, coenzyme A, etc.) in transsulphonating reactions. Glutathione, powerful antioxidant in a liver, plays an important role in a hepatic detoxication. Ademetionin increases the level of hepatic glutathione at patients with damage of a liver of both alcoholic, and not alcoholic genesis. Folic acid (folate) and _{12 vitamin B} are the integral konutriyenta in processes of metabolism and restoration of an ademetionin.

Pharmacokinetics. Absorption. At the person later in/in introductions the pharmacokinetic profile of an ademetionin is biexponentsialny and consists of a phase of the fast significant distribution in fabrics and a final phase of elimination with T _½ about 1.5 h. Absorption at in in introduction is almost full (96%), the maximum plasma concentration is reached in 45 min. after use. After oral administration of kishechnorastvorimy tablets of an ademetionin the maximum plasma concentration is dose-dependent, makes 0.5-1 mg/l and is reached in 3–5 h after reception of a single dose from 400 mg to 1000 mg. Plasma concentration decreases to initial value during 24 h. The bioavailability after oral administration increases if ademetionin it is applied between meals. At oral administration of a tablet are absorbed in an intestinal path and considerably increase plasma concentration of an ademetionin. Researches on animals by means of isotope methods confirmed that oral administration of an ademetionin stimulates formation of metilirovanny connections in a liver. Also it was confirmed that assimilation of an ademetionin an organism happens in the typical metabolic ways characteristic of endogenous connection (transmethylation, transsulphonating, decarboxylation, etc.).

Distribution. The volume of distribution is 0.41 and 0.44 l/kg for doses of an ademetionin of 100 mg and 500 mg respectively. Linking with proteins of blood plasma insignificant also makes ≤5%.

Metabolism. Reactions which make acquire and regenerate ademetionin, are called a cycle of an ademetionin. At the first stage of this cycle the ademetioninzavisimy metilaza uses ademetionin as substrate for products S-adenozil-gomotsisteina which then is hydrolyzed to a gomotsistein and adenosine by means of S-adenozilgomotsisteingidrolazy. Gomotsistein, in turn, is exposed to the return transformation in methionine by transfer of methyl group from 5 methyltetrahydrofolates. After all, methionine can turn in ademetionin, finishing a cycle.

Removal. In radio isotope researches at oral administration it is radioactive marked ( ^{14 methyl} C) an ademetionina at healthy volunteers the removal with urine of radioactive material made 15.5±1.5% in 48 h and removal with a stake made 23.5±3.5% in 72 h, at the same time in steady pools remained about 60% of substance are incorporated.

Indication

Intra hepatic cholestasia at adults, including at patients with chronic hepatitis of various etiology and cirrhosis; an intra hepatic cholestasia at pregnant women.

Treatment can begin

with parenteral administration of medicament with the subsequent use of medicament in the form of tablets or at once from use of tablets. the daily dose of tablets can be divided into 2–3 receptions.

should swallow of

Tablet entirely, without chewing. Tablets of the medicament Geptral ^® are covered with a special cover which is dissolved only in intestines thanks to what ademetionin it is released in a duodenum. And for full therapeutic effect of a tablet it is necessary to apply to the best absorption of active agent between meals.

® should take the Tablet of the medicament Geptral ^{from the blister just before reception. If tablets have other color, except from white to yellowish (because of disturbance of integrity of an aluminum wrapper), it is recommended to refrain from their use.}

Initial therapy.

Orally (inside) the recommended dose makes 10–25 mg/kg of body weight a day. The initial dose makes 800 mg/days, the general daily dose should not exceed 1600 mg.

In/in or in the oil recommended dose makes 5–12 mg/kg of body weight a day during 2 weeks. The initial dose makes 500 mg/days, the general daily dose should not exceed 1000 mg (for parenteral administration to use the medicament Geptral ^® in the form of powder of the solution lyophilized for preparation for injections complete with solvent).

Maintenance therapy.

to Apply orally (inside) 800–1600 mg/days

Duration of therapy depends on weight of a course of the disease and is defined by the doctor individually.

Contraindication

Hypersensitivity to active ingredient or any excipient of medicament (see structure).

Genetic defects influencing a metioninovy cycle and/or a defiant homocystinuria and/or a gipergomotsisteinemiya (for example insufficiency цистатионин-β-синтазы, defect of metabolism of _{12 vitamin B} ).

Side effects

during clinical trials ademetionin applied more than 2100 patients. most often at treatment ademetioniny it was reported about a headache, diarrhea and nausea.

About the following side reactions it was reported with the specified frequency during clinical trials of use of an ademetionin (n=2115) and also in spontaneous messages. Side reactions are classified by the systems of bodies (according to MedDRA) and by emergence frequency: very often (≥1/10), it is frequent (≥1/100, 1/10), infrequently (≥1/1000, 1/100), is rare (≥1/10,000, 1/1000), is very rare (1/10,000).

from a GIT: often — an abdominal pain, diarrhea, nausea; infrequently — dryness in a mouth, dyspepsia, a meteorism, gastrointestinal pain, gastrointestinal bleeding, gastrointestinal disturbances, vomiting; seldom — an abdominal distension, an esophagitis.

General disturbances and reactions in the injection site: infrequently — an asthenia, hypostasis, a hyperthermia, a fever *, reactions in the injection site * ¹ ; necrosis in the injection site * ¹ ; seldom — an indisposition.

from the immune system: infrequently — hypersensitivity, anaphylactoid reactions or anaphylactic reactions (for example hyperaemia, short wind, a bronchospasm, a dorsodynia, discomfort in a thorax, changes of the ABP (arterial hypotension, AG) or pulse rate (tachycardia, bradycardia)) *.

Infection and invasion: infrequently — infections of urinary tract.

from the musculoskeletal system and connective tissue: infrequently — an arthralgia, muscular spasms.

from nervous system: often — a headache; infrequently — dizziness, paresthesias.

Mental disorders: often — alarm, insomnia; infrequently — agitation, confusion of consciousness.

from the respiratory system, bodies of a thorax and mediastinum: infrequently — hypostasis gortani*.

from skin and hypodermic cellulose: often — an itching; infrequently — a hyperhidrosis, a Quincke's disease *, allergic skin reactions (for example rash, an itching, urticaria, an erythema) *.

from vessels: infrequently — inflows, arterial hypotension, phlebitis.

* Side reactions from spontaneous messages which were not observed during clinical trials the emergence classified by frequency "rare" in view of the fact that the upper bound of 95% of a confidence interval for the expected frequency does not exceed 3/X where X =2115 (total number of volunteers in clinical trials).

¹ Concerns an injection form of drug.

Special instructions

Drug in the form of the lyophilized powder contains sodium less than 1 mmol (23 mg) on a dose, that is almost free from sodium. one medicament dose contains 8.28 mg of sodium (it is equivalent to sodium content in 21.04 mg of table salt). it is equivalent to 0.4% of the maximum daily intake of sodium recommended a cart for adults (5 g of table salt).

In To administration of solution of an ademetionin very slowly (see USE).

Should control ammonia level at patients with a pretsirrotichesky or cirrhotic stage of a giperammoniyemiya who apply tablets of an ademetionin.

to reduction of concentration of an ademetionin, patients from risk group (anemia, liver diseases, pregnancy or a possibility of development of a vitamin deficiency because of other disease or a way of food, such as vegetarianism) it is regularly necessary to carry out blood test for check of plasma levels of these substances. If it is revealed insufficiency, treatment by _{12 vitamin B} and/or folic acid (folates) to is recommended or during use of an ademetionin. In case of impossibility of carrying out the specified researches the use of _{12 vitamin B} and/or folic acid (folates) according to instructions for use of these medicines is recommended to patients from risk group (see. Pharmacological PROPERTIES. Metabolism).

for use for patients with bipolar psychoses. It was reported about patients who had a transition from a depression to a hypomania or a mania at treatment ademetioniny.

published one message about development of a serotoninovy syndrome in the patient who applied ademetionin against the background of reception of a klomipramin. Though the possibility of interaction is supposed theoretically, it is necessary to apply with care ademetionin along with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as klomipramin), the medicaments and vegetable means containing tryptophane (see INTERACTIONS).

Patients with a depression usually are in risk group of commission of a suicide or other serious acts therefore demand careful observation and continuous mental health services at treatment ademetioniny for the purpose of appropriate detection and treatment of symptoms of a depression.

patients accepting ademetionin Had messages about short-term emergence or strengthening of feeling of alarm. In most cases in interruption of therapy there was no need. Sometimes the feeling of alarm disappeared after reduction of a dose or the termination of therapy.

Influence on immunoassay of a gomotsistein.

Ademetionin influences immunoassay of a gomotsistein which results can mistakenly indicate the increased level of a gomotsistein in blood plasma at the patients accepting ademetionin. In this regard such patients are recommended to apply not immunological methods of determination of level of a gomotsistein in blood plasma.

Renal failure. There are limited clinical data on use of an ademetionin to patients with a renal failure. Such patients ademetionin should apply with care.

Liver failure. Pharmacokinetic characteristics do not differ at healthy volunteers and patients with a chronic disease of a liver.

Patients of advanced age.

Clinical trials of an ademetionin did not include enough patients aged from 65 years to establish whether the difference on treatment in comparison with young patients is responsible. On the basis of the available clinical experience, differences in treatment responses at patients of advanced age and young patients are not revealed. Generally, selection of a dose for patients of advanced age needs to be carried out carefully, usually since the minimum recommended dose, considering the increased frequency of decrease in hepatic, renal or warm function, existence of the accompanying morbid conditions and use of medicines.

Use during pregnancy and feeding by a breast.

during clinical trials at women who were treated ademetioniny in the III trimester of pregnancy did not observe any side reactions. Ademetionin it is necessary to apply only in urgent cases in the first two trimesters of pregnancy.

during feeding by a breast ademetionin is applied only when the potential advantage of its use exceeds potential risk for the baby.

Children. Safety and efficiency of use of an ademetionin are not established to children.

Ability to influence speed of response at control of vehicles or other mechanisms. Some patients at use of an ademetionin can have a dizziness. Patients should refrain from control of vehicles or work with other mechanisms until is full confidence that therapy ademetioniny does not affect their ability to carry out the specified types of activity.

Interaction

It was reported about development of a serotoninovy syndrome in the patient who applied ademetionin against the background of reception of a klomipramin. because of it though the possibility of interaction is supposed theoretically, it is necessary to apply with care ademetionin along with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as klomipramin), the medicaments and vegetable means containing tryptophane (see special instructions).

Incompatibility. Ademetionin (solution for injections) should not be mixed with the alkaline solutions or solutions containing calcium ions.

overdose Cases ademetioniny were observed by

seldom. at overdose the doctors have to address to local poison control center. generally, observation of the patient and use of maintenance therapy is recommended.

Storage conditions

Drug in the form of tablets does not demand special storage conditions.

Drug in the form of the lyophilized powder — at a temperature not above 25 °C.

UAHEP170339