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

Excipients: silicon colloidal dioxide - 4.4 mg, microcrystalline cellulose - 93.6 mg, sodium carboxymethyl starch (type A) - 17.6 mg, magnesium stearate - 4.4 mg;

tablet shell: methacrylic acid and ethyl acrylate copolymer (1: 1) - 27.6 mg, macrogol-6000 - 8.07 mg, polysorbate-80 - 0.44 mg, simethicone (emulsion 30%) - 0.13 mg, sodium hydroxide - 0 , 36 mg, talc - 18.4 mg, water - Q.S.

Description:

Tablets are oval in shape, biconvex, from white to white with a yellowish tint of color, 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. Has choleretic and cholekinetic effect, has 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 (incorporated into the 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 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, 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 liver and microsomal oxidation processes. 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. 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:

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

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, ademethionine-dependent methylases are used ademethionine as a substrate for the production of S-adenosyl homocysteine, which is then hydrolyzed to homocysteine and adenosine by S-adenosyl homocysteine hydrolase. 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) - 1.5 hours. It is excreted by the kidneys. In studies in healthy volunteers with the ingestion of labeled (methyl 14C) 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 conditions, which can observed with 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 (cystathionine beta-synthase deficiency, vitamin B12 metabolism disorder);

Hypersensitivity to any of the components of the drug;

Age under 18. (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 ademetionine in the III trimester of pregnancy did not cause any undesirable effects. The use of Heptral® 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:

Inside. Tablets should be taken whole, not liquid, preferably in the morning 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 white with a yellowish can opener (due to leaks in the aluminum foil), the Heptral® preparation is not recommended.

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 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 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 liver function, nights or heart, other concomitant pathologies or simultaneous therapy with other drugs, the dose of Heptral® to elderly patients should be selected with caution, starting with the use of the drug from the lower limit of the dose range.

Renal insufficiency

There are limited clinical data on the use of the drug Heptral ® in patients with renal insufficiency, in this regard, it is recommended to use caution when using the drug Heptral® 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 Heptral ® 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.Below are the data on adverse reactions observed during clinical trials (n = 2115) and in post-marketing application 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, pain In the back, 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
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, 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 , reactions at the injection site , skin necrosis at the injection site *
	Rarely	Malaise

* - undesirable effects revealed during 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 basis of,that the upper limit of the 95% confidence interval of the detection threshold does not exceed 3 / X, where X = 2115 (the total number of subjects observed in clinical trials).

Overdose:Overdose of the drug Heptral® 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 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 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 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 immunological analysis, 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.

Effect on the ability to drive transp. cf. and fur:Some patients may experience dizziness when taking Heptral®. 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:The tablets are covered with an enteric coating, 400 mg.

Packaging:

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

Storage conditions:

In the dark place at a temperature of 15 ° C to 25 ° C. Keep out of the reach of children.

Shelf life:3 years.Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N011968 / 01

Date of registration:11.08.2011

The owner of the registration certificate:Abbott Sr.L.Abbott Sr.L. Italy

Manufacturer: & nbsp

ABBOTT SRL Italy

HOSPIRA, S.p.A. Italy

Representation: & nbspABBOTT LABORATORIES LLC ABBOTT LABORATORIES LLC Russia

Information update date: & nbsp10.03.2015

Illustrated instructions

Instructions

Heptral® (Heptral®)