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

Excipients: silicon dioxide colloid - 5.50 mg, microcrystalline cellulose - 118.00 mg, sodium carboxymethyl starch (type A) - 22.00 mg, magnesium stearate - 5.50 mg; tablet shell: methacrylic acid and ethyl acrylate copolymer (1: 1) - 32.63 mg, macrogol-6000 - 9.56 mg, polysorbate-80 - 0.52 mg, simethicone emulsion (30%) - 0.40 mg, sodium hydroxide - 0 , 44 mg, talc - 21.77 mg.

Description:

The tablets are oval in shape, biconvex, smooth, from white to light yellow, covered with a film membrane.

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 In the reactions of transulfurization, ademetionine is a precursor of cysteine, taurine, glutathione (providing an oxidation-reduction mechanism of cellular detoxification), coenzyme A (involved in biochemical reactions of the tricarbonate cycle acids 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 putrescine polyamines (the cell regeneration and proliferation hepatocyte stimulant), spermidine and spermine, which are part of the ribosome structure, which reduces the risk 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, incl. 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. 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. Ademethionine increases the synthesis of proteoglycans and leads to partial regeneration of cartilaginous tissue.

Pharmacokinetics:

Suction

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

Distribution

When using ademetionine at a dose of 500 mg volume of distribution (V_d) is 0.44 l / kg. The degree of binding to plasma proteins is negligible and amounts to ≤ 5%.

Metabolism

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, undergoes reverse transformation to methionine by transferring the methyl group from 5-methyltetrahydrofolate. Eventually methionine can be converted by methionine-adenosyl transferase type I into ademethionine, completing the cycle.

Excretion

In studies in healthy volunteers with oral administration of labeled (methyl ¹⁴FROM) S-adenosyl-L-methionine in urine, 15.5 ± 1.5% of radioactivity was detected 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 states that 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 (alcoholic, etc.).

- Intrahepatic cholestasis in pregnant women.

- Symptoms of depression.

Contraindications:

Genetic disorders affecting the methionine cycle and / or causing homocystinuria and / or hyperhomocysteinemia (eg, cystathionine beta-synthase deficiency, cyanocobal amine metabolism disorder).

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 trimester) and the period of breastfeeding (see the section on "Application during pregnancy and during breastfeeding").

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

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 Heptral® in pregnant women in I and II trimesters, as well as 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, between meals.

Tablets of the preparation Heptral® should be removed from the blister immediately before ingestion. In case the tablets have a color different from white to light yellow (due to leakage of aluminum foil), the preparation of Heptral® is not recommended.

Initial therapy:

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

Depression

The usual initial dose is 500-800 mg / day, the total daily dose should not exceed 1600 mg.

Intrahepatic cholestasis

The usual initial dose is 500-800 mg / day, the total daily dose should not exceed 1600 mg.

Supportive therapy:

500 or 800-1600 mg / day.

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

Clinical experience with the use of Heptral® did not reveal 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 medicines, the dose of Heptral® 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 Heptral® in patients with renal insufficiency, and therefore caution should be exercised when using Heptral® 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 Heptral ® in children is contraindicated (efficacy and safety not established).

Side effects:

Among the most frequent 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 heart rate (tachycardia, bradycardia)) *
Disorders of the psyche	Often	Anxiety Insomnia
Disorders of the psyche	Infrequently	Agitation Confusion of consciousness
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 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
	Rarely	Vomiting 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, skin itching, 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* Reactions at the site of administration * Necrosis of the skin at the injection site *
	Rarely	Malaise

* - undesirable effects revealed in post-marketing application of ademetionine ("spontaneous" reports), not observed in clinical trials, were attributed to the number of undesirable effects with the incidence of "infrequently" on the grounds that the upper limit 95 % The confidence interval for assessing the occurrence does not exceed 3 / X, where X = 2115 (the total number of subjects observed in clinical trials).

Overdose:

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

Interaction:

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 used with caution ademethionine together with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), as well as herbs and preparations containing tryptophan.

Special instructions:

Given the tonic effect of the drug, it is not recommended to take it before bedtime. When using Heptral® in patients with cirrhosis of the liver against a background of hyperaemia, systematic monitoring of the nitrogen content of 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 in the event that their symptoms of depression are not diminished or aggravated by ademethionine therapy.

There are also reports of sudden onset or worsening of anxiety in patients taking ademethionine. In most cases, no treatment was required, in a few 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.

Ademetionine intake can affect the result of homocysteine detection in blood plasma, obtained by immunological methods.

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

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

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

Form release / dosage:

Tablets, coated with enteric coating, 500 mg.

Packaging:

10 tablets per blister of PA / PVC/AL and aluminum foil. 1 or 2 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children!

Shelf life:

3 years.The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004269

Date of registration:28.04.2017

Expiration Date:28.04.2022

The owner of the registration certificate:Abbott Laboratories, GmbHAbbott Laboratories, GmbH Germany

Manufacturer: & nbsp

AbbVie S.r.L. Italy

Representation: & nbspABBOTT LABORATORIES LLC ABBOTT LABORATORIES LLC Russia

Information update date: & nbsp02.06.2017

Illustrated instructions

Instructions

Heptral® (Heptral®)