Heptral, lyophilized powder for preparation of solution for injection 5ml x 5 pcs — Made in Italy — Free Delivery

Pharmacological properties

Pharmacodynamics. Ademetionine, or s-adenosyl-l-methionine, is a derivative of the amino acid methionine. s-adenosyl-l-methionine (ademetionine) is a natural amino acid that is present in almost all tissues and body fluids. ademetionine primarily acts as a coenzyme and methyl group donor in transmethylation reactions, which are an integral metabolic process in humans and animals. the transfer of methyl groups (transmethylation) is also an integral metabolic process during the construction of a double phospholipid layer in cell membranes and contributes to membrane fluidity. ademetionine is able to penetrate the geb. the process of transmethylation involving ademetionine is key in the formation of CNS neurotransmitters, including catecholamines (dopamine, norepinephrine, adrenaline), serotonin, melatonin, and histamine.

Ademetionine is also a precursor in the formation of physiological sulfonated (thiol) compounds (cysteine, taurine, glutathione, coenzyme A, etc.) in transsulfurization reactions. Glutathione, a powerful antioxidant in the liver, plays an important role in liver detoxification. Ademetionine increases the level of hepatic glutathione in patients with liver damage of both alcoholic and non-alcoholic genesis. Folic acid (folate) and vitamin B12 are essential contributors to the metabolism and recovery of ademetionine.

Pharmacokinetics. Absorption. In humans, after intravenous administration, the pharmacokinetic profile of ademetionine is biexponential and consists of a phase of rapid pronounced distribution in tissues and the final phase of elimination with a T½ of about 1.5 hours. Absorption with intravenous administration is almost complete (96%), the maximum plasma concentration achieved 45 minutes after application. After oral administration of enteric tablets of ademetionine, the maximum plasma concentration is dose-dependent, it is 0.5-1 mg / l and is reached 3-5 hours after taking a single dose of 400 mg to 1000 mg. Plasma concentration decreases to the initial value within 24 hours. Bioavailability after oral administration is increased if ademetionine is used between meals. When administered orally, the tablets are absorbed in the intestinal tract and significantly increase the plasma concentration of ademetionine. Animal studies using isotope methods have confirmed that oral administration of ademetionine stimulates the formation of methylated compounds in the liver. It was also confirmed that the assimilation of ademetionine by the body occurs by typical metabolic pathways characteristic of an endogenous compound (transmethylation, transsulfurization, decarboxylation, etc.).

Distribution. The volume of distribution is 0.41 and 0.44 l / kg for doses of ademetionine 100 mg and 500 mg, respectively. Plasma protein binding is insignificant and is ≤5%.

Metabolism. The reactions that produce, metabolize, and regenerate ademetionine are called the ademetionine cycle. At the first stage of this cycle, ademetionine-dependent methylase uses ademetionine 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 transfer of a methyl group from 5-methyltetrahydrofolate. Eventually, methionine can be converted to ademetionine, completing the cycle.

Excretion. In radioisotope studies with oral administration of radioactively labeled (methyl 14C) ademetionine in healthy volunteers, urinary excretion of the radioactive substance was 15.5 ± 1.5% after 48 hours and excretion with feces was 23.5 ± 3.5% after 72 hours. at the same time, about 60% of the substance remained incorporated in the stable pools.

Indications

Intrahepatic cholestasis in adults, including in patients with chronic hepatitis of various etiologies and liver cirrhosis; intrahepatic cholestasis in pregnant women.

Application

Treatment can begin with parenteral administration of the preparation followed by the use of the preparation in the form of tablets or immediately with the use of tablets. the daily dose of tablets can be divided into 2-3 doses.

The tablets should be swallowed whole without chewing. The tablets of the Heptral® preparation are covered with a special membrane that dissolves only in the intestine, due to which ademetionine is released in the duodenum. For better absorption of the active substance and for the full therapeutic effect, the tablets should be used between meals.

The tablet of the preparation Heptral® should be removed from the blister immediately before taking. If the tablets have a color other than white to yellowish (due to the violation of the integrity of the aluminum wrapper), it is recommended to refrain from using them.

Initial therapy.

Orally (by mouth) the recommended dose is 10–25 mg / kg of body weight per day. The initial dose is 800 mg / day, the total daily dose should not exceed 1600 mg.

In / in or in / m the recommended dose is 5-12 mg / kg of body weight per day for 2 weeks. The initial dose is 500 mg / day, the total daily dose should not exceed 1000 mg (for parenteral administration, use Heptral® in the form of a lyophilized powder for the preparation of an injection solution complete with a solvent).

Supportive therapy.

Apply orally (inside) 800-1600 mg / day.

The duration of therapy depends on the severity of the course of the disease and is determined by the doctor individually.

Contraindications

Hypersensitivity to the active substance or any excipient of the preparation (see composition).

Genetic defects affecting the methionine cycle and / or causing homocystinuria and / or hyperhomocysteinemia (eg, cystathionine β-synthase deficiency, defect in vitamin B12 metabolism).

Side effects

In clinical trials, ademetionine was used by more than 2,100 patients. headache, diarrhea, and nausea were reported most frequently with ademetionine treatment.

The following adverse reactions were reported with the specified frequency in clinical studies of ademetionine (n = 2115), as well as in spontaneous reports. Adverse reactions are classified by organ systems (according to MedDRA) and by frequency of occurrence: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely ( ≥1 / 10,000, 1/1000), very rare (1/10,000).

From the gastrointestinal tract: often - abdominal pain, diarrhea, nausea; infrequently - dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal bleeding, gastrointestinal disturbances, vomiting; rarely - bloating, esophagitis.

General disorders and reactions at the injection site: infrequently - asthenia, edema, hyperthermia, chills *, reactions at the injection site * 1; necrosis at the injection site * 1; rarely - malaise.

From the immune system: infrequently - hypersensitivity, anaphylactoid reactions or anaphylactic reactions (for example, hyperemia, shortness of breath, bronchospasm, back pain, chest discomfort, changes in blood pressure (arterial hypotension, AH) or pulse rate (tachycardia, bradycardia)) *.

Infections and invasions: infrequently - urinary tract infections.

From the side of the musculoskeletal system and connective tissue: infrequently - arthralgia, muscle cramps.

From the nervous system: often - headache; infrequently - dizziness, paresthesia.

Mental disorders: often - anxiety, insomnia; infrequently - agitation, confusion.

From the respiratory system, chest and mediastinal organs: infrequently - laryngeal edema *.

On the part of the skin and subcutaneous tissue: often - itching; infrequently - hyperhidrosis, angioedema *, allergic skin reactions (for example, rash, pruritus, urticaria, erythema) *.

From the side of the vessels: infrequently - hot flashes, arterial hypotension, phlebitis.

* Adverse reactions from spontaneous reports that were not observed in clinical trials, classified according to the frequency of occurrence of "rare" due to the fact that the upper limit of the 95% confidence interval for the expected frequency does not exceed 3 / X, where X = 2115 (total number of volunteers in clinical trials).

1 Refers to the injectable form of the preparation.

Special instructions

The preparation in the form of a lyophilized powder contains sodium less than 1 mmol (23 mg) per dose, that is, it is practically free of sodium. one dose of the preparation contains 8.28 mg of sodium (equivalent to the sodium content of 21.04 mg of table salt). this is equivalent to 0.4% of the recommended maximum daily sodium intake for adults (5 g table salt).

The intravenous administration of ademetionine solution must be carried out very slowly (see APPLICATION).

Ammonia levels should be monitored in patients with pre-cirrhotic or cirrhotic hyperammonemia who are using ademetionine tablets.

Since vitamin B12 and folate (folate) deficiencies can lead to a decrease in ademetionine concentration, patients at risk (anemia, liver disease, pregnancy, or the possibility of vitamin deficiency due to another medical condition or diet, such as vegetarianism) should be tested regularly. blood to check the plasma levels of these substances. If deficiency is found, treatment with vitamin B12 and / or folic acid (folate) is recommended before or during the use of ademetionine. If it is impossible to carry out these studies, patients from the risk group are recommended to use vitamin B12 and / or folic acid (folates) in accordance with the instructions for the use of these preparation (see PHARMACOLOGICAL PROPERTIES. Metabolism).

Ademetionine is not recommended for use in patients with bipolar psychosis. There have been reports of patients who transitioned from depression to hypomania or mania while treated with ademetionine.

One report was published on the development of serotonin syndrome in a patient who used ademetionine while taking clomipramine. Although the potential for interactions is theoretically expected, caution should be exercised when using ademetionine with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), preparations and herbal remedies containing tryptophan (see INTERACTIONS).

Patients with depression are usually at risk of committing suicide or other serious misconduct, and therefore require close monitoring and ongoing psychiatric care while treating ademetionine in order to properly identify and treat symptoms of depression.

There have been reports of a short-term appearance or increased feelings of anxiety in patients taking ademetionine. In most cases, interruption of therapy was not necessary. Sometimes the feeling of anxiety disappeared after dose reduction or discontinuation of therapy.

Effect on homocysteine ​​immunoassay.

Ademetionine interferes with the homocysteine ​​immunoassay, the results of which may erroneously indicate elevated plasma homocysteine ​​levels in patients taking ademetionine. In this regard, such patients are recommended to use non-immunological methods for determining the level of homocysteine ​​in blood plasma.

Renal failure There are limited clinical data on the use of ademetionine in patients with renal insufficiency. Ademetionine should be used with caution in such patients.

Liver failure. Pharmacokinetic characteristics did not differ between healthy volunteers and patients with chronic liver disease.

Elderly patients.

Clinical trials of ademetionine did not include enough patients 65 years of age or older to determine if there is a difference in response to treatment compared with younger patients. Based on available clinical experience, no differences were found in response to treatment in elderly and younger patients. In general, dose selection for elderly patients should be done with caution, usually starting with the minimum recommended dose, given the increased frequency of decreased hepatic, renal or cardiac function, the presence of concomitant pathological conditions and the use of preparations.

Use during pregnancy and lactation.

In the course of clinical studies in women who were treated with ademetionine in the third trimester of pregnancy, no adverse reactions were observed. Ademetionine should be used only if absolutely necessary in the first two trimesters of pregnancy.

During lactation, ademetionine is used only when the potential benefit from its use outweighs the potential risk to the infant.

Children. The safety and efficacy of using ademetionine in children have not been established.

The ability to influence the reaction rate when driving vehicles or other mechanisms. In some patients, dizziness may occur when using ademetionine. Patients should refrain from driving vehicles or working with other mechanisms until it is completely certain that ademetionine therapy does not affect their ability to perform these activities.

Interactions

It was reported about the development of serotonin syndrome in a patient who used ademetionine while taking clomipramine. because of this, although the possibility of interaction is theoretically assumed, caution should be exercised when using ademetionine simultaneously with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as clomipramine), preparations and herbal remedies containing tryptophan (see special instructions).

Incompatibility. Ademetionine (injection solution) should not be mixed with alkaline solutions or solutions containing calcium ions.

Overdose

Cases of ademetionine overdose were observed rarely. in case of overdose, doctors should contact the local poison control center. in general, patient observation and supportive care are recommended.

Storage conditions

The preparation in the form of tablets does not require special storage conditions.

The preparation is in the form of a lyophilized powder - at a temperature not exceeding 25 ° C.