Heptrazan - instructions for use, dose, side effects, contraindications

1 ml of solvent contains: Llysine monohydrate 76.92 mg (in terms of Llysine 68.48 mg), sodium hydroxide up to 2.3 mg, water for injection up to 1.0 ml.

Description:

Lyophilizate: lyophilized-dried mass from white to almost white. Reconstituted solution: Clear solution from colorless to yellowish color. Solvent for Heptrazan: transparent liquid from colorless to light yellow color.

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, gransulfurization, transamination. In the reactions of transmethylation ademethionine donates a methyl group to the synthesis of cell membrane phospholipids, neurotransmitters, nucleic acids, proteins, hormones, and others. In the reactions transsulfuration ademethionine is a precursor of cysteine, taurine, glutathione (providing redox mechanism cellular detoxification), coenzyme A (included in the biochemical reactions of the tricarboxylic acid cycle and replenishes the energy potential of the cells).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 passage of bile acids into the biliary tract. Effective with intraloble variant of cholestasis (a 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, including the concentration 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.

Pharmacokinetics:

Suction

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

Distribution

The connection with blood plasma proteins is insignificant, is <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, ademetioin-dependent methylases are used ademethionine as a substrate for products S-adenesyl homocysteine, which is then hydrolyzed to homocysteine and adenosine by Sadenosylhomocysteinehydralase. Homocysteine, in turn, undergoes reverse transformation 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, including associated with hepatic insufficiency (alcohol and etc).

Intrahepatic cholestasis in pregnant women.

Symptomatic therapy 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.

- Bipolar disorders (see section "Special instructions").

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

Carefully:

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:

In clinical studies, it has been shown that the use of ademethionine in III trimester of pregnancy did not cause any undesirable effects. The use of heptrazan 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 that is different from almost white to white with a yellowish tint (due to a crack in the vial or heat exposure), the drug should not be used.

The drug Heptrasan with intravenous administration is administered very slowly.

Initial therapy

Intramuscular or intravenous 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 Heptrazan in the form of tablets at a dose of 800-1600 mg / day for 2-4 weeks. Therapy with Heptrazan can be started with intravenous or intramuscular injection followed by the use of Heptrazan in the form of tablets or immediately with the use of Heptrazan in the form of tablets.

Elderly patients

The clinical experience of using the drug Heptrazan did not reveal any difference in its effectiveness in elderly patients and younger patients. However, given the high likelihood of existing violations of the liver, kidney or heart, other concomitant pathologies or concomitant therapy with other drugs, the dose of Heptrazan should be selected with caution for elderly patients starting with the lower limit of the dose range.

Renal insufficiency

There are limited clinical data on the use of the drug Heptrazan in patients with renal insufficiency, therefore it is recommended to use caution when using the drug Heptrazan in such patients.

Liver failure

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

Children

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

Side effects:

Among the most common adverse reactions identified in clinical trials involving more than 2,100 patients were: headache, nausea and diarrhea. The following are data on adverse reactions observed during clinical trials (n= 2115) and in the postmarketing use of ademetionine ("spontaneous" reports). All reactions are distributed according to organ systems and the frequency of development: 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	Hypersensitivity reactions 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 pulse rate (tachycardia bradycardia)) *
Disorders of the psyche	Often	Anxiety, insomnia
Disorders of the psyche	Infrequently	Agitation, confusion
Disturbances from the nervous system	Often	Headache
Disturbances from the nervous system	Infrequently	Dizziness, paresthesia
Vascular disorders	Infrequently	"Tides", arterial hypotension, phlebitis
Disturbances from the respiratory system, chest, mediastinum	Infrequently	Laryngeal edema *
Disorders from the gastrointestinal tract	Often	Abdominal pain, diarrhea, dry mouth, nausea
	Infrequently	Dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal bleeding, gastrointestinal disorders, vomiting
	Rarely	Bloating, esophagitis
Disturbances from the skin and subcutaneous tissues	Often	Itchy skin
Disturbances from the skin and subcutaneous tissues	Infrequently	Increased sweating, angioedema, * skin-allergic reactions (including rash, itchy skin, hives, 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 , reaction at the injection site , skin necrosis at the injection site. *
	Rarely	Malaise

* - the undesirable effects revealed in the postmarketing use of ademetionine ("spontaneous" reports), not observed in clinical trials, were classified as undesirable effects with a frequency of "infrequent" on the grounds that the upper limit of the 95% exceeds 3 / X, where X = 2115 (the total number of subjects observed in clinical trials).

Overdose:Overdosage of Heptrazan is unlikely. In case of an overdose, it is recommended that you follow the patient and perform symptomatic therapy.

Interaction:

No known interactions with other drugs have been observed.

There is a report on the syndrome of excess serotonin in the patient who took ademethionine and clomipramine. It is believed that such interaction is possible, and should be cautiously appointed ademethionine together with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), as well as preparations of plant origin and preparations containing tryptophan.

Special instructions:

Given the tonic effect of the drug, it is not recommended to take it before bedtime. When using the drug Heptrazan, patients with cirrhosis on a background of hyperaemia require a systematic control of the nitrogen content in the blood. 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.

In patients with depression, there is 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 depression. Patients should inform the doctor if their symptoms of depression do not decrease or worsen with ademethionine therapy.

There are also reports of a sudden occurrence or increase in 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 the ademetionin content in patients at risk (with anemia, liver disease, pregnancy, or with a potential for 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 methods of analysis to determine the level of homocysteine.

The drug Heptransan 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 one ampoule with a solvent, i.e., practically free of sodium.

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

Some patients may experience dizziness when taking Heptrazan.

It is not recommended to drive the car and work with the machines during 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:

Lyophilizate: 400 mg of active ingredient in terms of ademethionine ion in bottles of colorless neutral glass, sealed with rubber stoppers, with aluminum caps and plastic caps.

Solvent: 5.0 ml of solvent into ampoules of colorless neutral glass with a break point or without it.

5 vials with lyophilizate and 5 vials with a solvent or 5 vials with lyophilizate or 5 vials with a solvent in a contour cell pack of film polyvinyl chloride.

1 circuit cell pack containing 5 vials of lyophilizate and 5 vials of solvent or 1 circuit cell package containing 5 vials of lyophilizate and 1 circuit cell package containing 5 vials of solvent together with instructions for use in a pack of cardboard.

6 or 10 contour cell packs containing 5 vials of lyophilizate and 5 ampoules with a solvent or 6 or 10 contiguous cell packs containing 5 vials of lyophilizate and 6 or 10 cell contiguous packs containing 5 vials of solvent together with instructions for use in a box of cardboard (for hospitals).

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004418

Date of registration:16.08.2017

Expiration Date:16.08.2022

The owner of the registration certificate:IRVIN 2, LLC IRVIN 2, LLC Russia

Manufacturer: & nbsp

RKNPK of the Ministry of Health of Russia, FGBU Russia

Information update date: & nbsp06.09.2017

Illustrated instructions

Instructions

Heptransan (Heptrasan)