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

Auxiliary substances (shell): 88.0 mg (methacrylic acid and ethyl acrylate copolymer [1: 1] - 52.8 mg, talc 28.336 mg, macrogol 4.4 mg, silicon colloidal dioxide 1.1 mg, sodium bicarbonate 0.924 mg, sodium lauryl sulfate - 0.44 mg, simethicone emulsion 30% (in terms of simethicone) - 0.202 mg).

Description:

Oval biconvex tablets covered with a film coating of white or almost white color. The core is from white to almost white.

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-methionine (ademethionine) and stimulates its production in the body, is contained in all the environments 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 transsulfurization reactions ademethionine is the precursor of cysteine, taurine, glutathione (providing the redox mechanism of cellular detoxification),coenzyme A (is included in the 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 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. Purpose for patients with opioid drug 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 stabilizing within 2 weeks of treatment. Effective in recurrent endogenous and neurotic depressions resistant to amitriptyline. Has the ability to interrupt recurrence of depression. Ademethionine increases the synthesis of proteoglycans and leads to partial regeneration of cartilaginous tissue.

Pharmacokinetics:

The tablets are covered with a film membrane that dissolves only in the intestine, so ademethionine is released in the duodenum.

Suction

Bioavailability with oral administration - 5%, increases with fasting. The maximum concentrations (Cmah) ademetionine in plasma are dose-dependent and amount to 0.5-1 ml / l 3-5 hours after a single oral intake at doses of 400 to 1000 mg. FROMmadhemetionine in plasma are reduced to the baseline within 24 hours.

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 S-adenosyl 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. In studies in healthy volunteers with oral administration of labeled (methyl ¹⁴FROM) S-adenosyl-L-methionine in urine was found 15.5 ± 1.5% of radioactivity after 48 hours, and in feces - 23.5 ± 3.5% of radioactivity after 72 hours. Thus, about 60% was deposited.

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 (alcoholic, 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, B12 metabolism disorders).

- Hypersensitivity to any of the components of the drug.

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

Carefully:

Bipolar disorders (see section "Special instructions").

Pregnancy (I, II trimester) and the period of breastfeeding (use is possible only if the potential benefit to the mother exceeds the possible risk to the fetus and 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 section "Interaction with other drugs").

Elderly age.

Renal failure.

Pregnancy and lactation:

In clinical studies, it was shown that the use of ademetionine in the III trimester of pregnancy did not cause any undesirable effects. The use of Heptrazan in pregnant women in the I and II 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:

Inside. Tablets should be taken whole, not liquid, preferably in the morning between meals.

Tablets of the drug Heptrazan should be removed from the blister immediately before ingestion. In case the tablets have a color different from white to white with a yellowish tinge (due to leaks in the aluminum foil), the Heptrazan preparation should not be used.

Initial therapy

The recommended dose is 10-25 mg / kg / day.

Intrahepatic cholestasis

The dose is from 800 mg / day to 1600 mg / day.

Depression

The dose is from 800 mg / day to 1600 mg / day.

The duration of therapy is determined by the doctor.

Therapy can be started with intravenous or intramuscular administration of preparations of ademetionine from other manufacturers 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 simultaneous 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 data on the use of Heptrazan in patients with renal failure, therefore, it is recommended that caution be application of 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, shortness of breath, bronchospasm, back pain, 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 skin rash, skin 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 , 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 = 21 15 (the total number of subjects observed in clinical trials).

Overdose:

Overdose of the drug Heptrazan is unlikely. In case of an overdose it is recommended to monitor 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 prescribing Heptrazan to 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 are also reports of sudden onset or worsening 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 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 level in the blood.

For patients receiving ademethionine, it is recommended to use non-immunological assays to determine the level of homocysteine.

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:

Intestinal soluble tablets 400 mg.

Packaging:

10 tablets into a contour mesh box of aluminum foil, laminated oriented polyamide and polyvinyl chloride film, and foil of aluminum printed lacquered or of a polyvinyl chloride / polyvinylidene chloride film and aluminum foil printed lacquer.

20, 40 or 50 tablets in a jar of polypropylene or low pressure polyethylene, sealed with a lid for medicines with a control of the first opening of high-pressure polyethylene. Free space in the bank is filled with cotton hygroscopic cotton. The label is self-adhesive on the can.

1 or 2 contour squares or 1 jar along with instructions for use in a pack of cardboard.

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-004430

Date of registration:24.08.2017

Expiration Date:24.08.2022

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

Manufacturer: & nbsp

ZIO-HEALTH, JSC Russia

Information update date: & nbsp13.09.2017

Illustrated instructions

Instructions

Heptransan (Heptrasan)