Heptral, lyophilizate 400 mg 5 pcs

Pharmacotherapeutic group: Other drugs for the gastrointestinal tract and metabolism, amino acids and their derivatives

ATC code: A16AA02

Pharmacological properties

Pharmacodynamics

Ademetionine belongs to the group of hepatoprotectors, also has antidepressant activity. It has choleretic and cholokinetic effect, has detoxifying, regenerating, antioxidant, antifibrotic and neuroprotective properties.

It replenishes the S-adenosyl-L-methionine (ademetionine) deficiency and stimulates its production in the body, contained in all body fluids. The highest concentration of ademetionine is found in the liver and brain. Ademetionine plays a key role in the metabolic processes of the body and takes part in major biochemical reactions: transmethylation, transsulfurization and transamination.

In transmethylation reactions ademetionine donates methyl groups for the synthesis of cell membrane phospholipids, neurotransmitters, nucleic acids, proteins, hormones and others. In transsulfurization reactions ademetionine is a precursor of cysteine, taurine, glutathione (providing redox mechanism of cellular detoxification), coenzyme A (is included into biochemical reactions of tricarboxylic acid cycle and fills the cell energy potential).

Increases glutamine content in the liver, plasma cysteine and taurine, decreases methionine content in the serum, normalizing metabolic reactions in the liver. After decarboxylation it participates in aminopropylation reactions, as precursor of polyamines – putrescine (stimulator of cell regeneration and hepatocyte proliferation), spermidine and spermine, which are part of the ribosome structure, which reduces the risk of fibrosis. It has a choleretic effect. Ademetionine normalizes the synthesis of endogenous phosphatidylcholine in hepatocytes, which increases membrane fluidity and polarization. This improves the function of bile acid transport systems associated with membranes of hepatocytes and contributes to bile acid passage to biliary tracts.

Effective with intradolocular variant of cholestasis (disorders of bile synthesis and flow). Ademetionine reduces the toxicity of bile acids in the hepatocyte by performing their conjugation and sulfation. Conjugation with taurine increases solubility of bile acids and their excretion from the hepatocyte. The process of sulfation of bile acids allows their elimination by kidneys and facilitates passing through hepatocyte membrane and excretion with bile.

In addition, sulfated bile acids additionally protect liver cell membranes from toxic effects of nonsulfated bile acids (in high concentrations present in hepatocytes with intrahepatic cholestasis). In patients with diffuse liver diseases (cirrhosis, hepatitis) with intrahepatic cholestasis syndrome, ademetionine reduces the severity of skin itching and changes in biochemical parameters, including direct bilirubin concentration, alkaline phosphatase activity, aminotransferases and others. Choleretic and hepatoprotective effect persists up to 3 months after discontinuation of treatment. It is shown to be effective in hepatopathies caused by various hepatotoxic drugs. Antidepressant activity appears gradually from the end of the first week of treatment and stabilizes during 2 weeks of treatment.

Several studies have confirmed the effectiveness of ademetionine in treatment of increased fatigability in patients with chronic liver disease. A pooled analysis of data from patients with pre-treatment symptoms of fatigue proved the effect of ademetionine treatment in reducing symptoms of fatigue in combination with a number of other symptoms, such as depression, hiccuria of the skin and mucous membranes, malaise and skin itching. Ademetionine treatment significantly improved mood in patients with alcoholic liver disease, who simultaneously achieved a positive response from symptoms of increased fatigability. In addition, in patients with alcoholic liver disease and nonalcoholic fatty liver disease with achieved response to ademetionine treatment on the side of symptoms of increased fatigability there was also observed a significant relief of such symptoms as hirsuteness of skin and mucous membranes, malaise and skin itching.

Pharmacokinetics

Tablets are covered with a film coating that dissolves only in the intestine, so that ademetionine is released in the duodenum.

Absorption

Bioavailability when ingested is 5%; it is increased when taken on an empty stomach. Maximal concentrations (Cmax) of ademetionine in plasma are dose-dependent – 0.5-1 mg/l 3-5 hours after a single oral dose from 400 to 1000 mg. Cmax of ademetionine in plasma decrease to the initial level within 24 hours.

Distribution

Binding with blood plasma proteins is insignificant – 5%.
It penetrates through the blood-brain barrier. There is a significant increase in concentration of ademetionine in cerebrospinal fluid.

Metabolism

Metabolized in the liver. The process of ademetionine formation, expenditure and reformation is called the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methylases use ademetionine as a substrate to produce S-adenosylhomocysteine, which is then hydrolyzed to homocysteine and adenosine by S-adenosylhomocysteine hydralase. Homocysteine, in turn, undergoes a reverse transformation to methionine by transferring the methyl group from 5-methyltetrahydrofolate. Eventually, methionine can be converted to ademethionine, completing the cycle.

Excretion

The half-life (T½) is 1.5 h. It is excreted by the kidneys. In studies in healthy volunteers, when ingested with labeled (methyl 14C) S-adenosyl-L-methionine, 15.5% ± 1.5% radioactivity was detected in the urine after 48 hours, and 23.5% ± 3.5% radioactivity in the feces after 72 hours. Thus, about 60% was deposited.

Indications

Heptral® is used in adults over 18 years of age for the following conditions:

• Intrahepatic cholestasis in pre-cirrhotic and cirrhotic conditions, which can be observed in the following diseases:

˗ fatty liver;
˗ chronic hepatitis;
˗ toxic liver damage of various etiologies, including alcohol, viruses, drugs (antibiotics; antitumor, antituberculosis and antiviral drugs, tricyclic antidepressants, oral contraceptives);
˗ chronic acalculous cholecystitis;
˗ cholangitis;
˗ liver cirrhosis;
˗ encephalopathy, including those associated with liver failure (alcoholic, etc.).

• Intrahepatic cholestasis in pregnant women.

• Symptoms of depression.

If there is no improvement or you feel worse, you should consult a doctor.

Special instructions

Children

The safety and effectiveness of Heptral® in children under 18 years of age have not yet been established. No data available.

Elderly patients

Clinical experience with the use of the drug Heptral® did not reveal any differences in its effectiveness in elderly patients and younger patients. However, given the high likelihood of existing impairment of liver, kidney or heart function, other concomitant pathology or concomitant therapy with other drugs, the dose of Heptral® in elderly patients should be selected with caution, starting the use of the drug from the lower limit of the dose range.

Patients with impaired renal function

There are limited clinical data on the use of Heptral® in patients with renal impairment, and therefore caution is recommended when using Heptral® in such patients.

Patients with liver dysfunction

The pharmacokinetic parameters of ademetionine are similar in healthy volunteers and in patients with chronic liver diseases.

Before taking Heptral®, consult your doctor or pharmacist.

This is especially important:

• if you are pregnant (first trimester) or breastfeeding your baby;
• if you are taking medicines called selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clopyramine), herbal medicines and medicines containing tryptophan;
• if you are an elderly person;
• if you suffer from kidney disease;

Be sure to tell your doctor:

• if you suffer from bipolar disorder, depression or other mental illness;
• if you have a decrease in the number of red blood cells (anemia);
• if you have a vitamin deficiency due to illness or dietary habits (for example, if you are a vegetarian).

Consult your doctor if during treatment:

• anxiety arises or intensifies – therapy may need to be reconsidered;
• an increased level of homocysteine ​​in the blood is determined, which can be caused by treatment with Heptral® (false increase).

Mental disorders

The drug is contraindicated in patients with bipolar disorder, as there have been reports of depression progressing to hypomania or mania during treatment with ademetionine.

Patients with depression are at increased risk of suicide and other serious adverse reactions, and such patients should be closely monitored by a physician during treatment with ademetionine to ensure adequate assessment and treatment of depressive symptoms. If you have been prescribed this drug to treat depression, tell your loved ones about it. Tell your doctor or loved ones if there are any changes in your mental status.

Cases of transient or worsening anxiety have been reported in patients treated with ademetionine. Contact your doctor if you experience these side effects, as in some cases the anxiety has gone away after reducing the dose or stopping treatment.
The drug has a tonic effect, so its use before bedtime is not recommended.

Laboratory indicators

During treatment of liver cirrhosis, it is necessary to control the concentration of nitrogen in the blood, and during long-term treatment, the concentration of urea and creatinine in the blood. Therefore, the attending physician may prescribe additional tests for you.

Deficiency of vitamin B12 and folic acid can lead to a decrease in ademetionine levels, so patients at risk (with anemia, liver disease, pregnancy, the possibility of vitamin deficiency, due to other diseases or diet, for example, vegetarians) require additional tests to assess the level of vitamins in the blood plasma.

The drug Heptral® may affect the results of homocysteine ​​determination. Consult your doctor if you are prescribed such a test.

Active ingredient

Ademetionine

Composition

The active ingredient is ademetionine.

Each lyophilisate vial contains ademetionine 1,4-butane disulfonate 760 mg (equivalent to 400 mg ademetionine ion).

Other excipients are (in the solvent): L-lysine, sodium hydroxide, water for injection.

Pregnancy

If you are pregnant or breastfeeding, think you may be pregnant, or are planning a pregnancy, consult your doctor before starting to use the drug.

During the first three months of pregnancy and during breastfeeding, the use of Heptral® is allowed only if the potential benefit to the woman outweighs the possible risk to the fetus or child.

Contraindications

Contraindications

Do not use Heptral®:

• if you are allergic to ademetionine or any other components of the drug listed in section 6 of the leaflet;
• if you have genetic disorders that affect the metabolism of methionine and/or cause homocystinuria and/or hyperhomocysteinemia (for example, deficiency of the enzyme cystathionine beta synthase, impaired metabolism of vitamin B12);
• if you have bipolar disorder;
• If you are under 18 years of age.

Side Effects

Like all medicines, Heptral® can cause side effects, although not everyone gets them.

Stop using Heptral® and seek immediate medical attention if you notice any of the following serious adverse reactions:

• allergic reactions, spotty or diffuse/widespread changes in skin color (rash, erythema), itching, urticaria, swelling (angioedema) of the face, eyes, lips and difficulty breathing (shortness of breath, bronchospasm), back pain or chest tightness, changes in blood pressure or increased, slow heart rate (tachycardia, bradycardia);
• difficulty breathing due to swelling of the throat (laryngeal edema).

Possible adverse reactions that may occur when using the drug Heptral

Common (may affect up to 1 in 10 people):

• headache;
• abdominal pain, diarrhea, nausea;
• anxiety;
• insomnia;
• fatigue (asthenia);
• skin itching.

Uncommon (may affect up to 1 in 100 people):

• dry mouth, upset stomach (dyspepsia), increased gas formation (flatulence), gastrointestinal pain, gastrointestinal bleeding, gastrointestinal upset, vomiting, inflammation of the esophageal mucosa (esophagitis);
• swelling at the injection site, increased temperature (fever), chills, reactions and tissue death at the injection site;
• allergic reactions (hypersensitivity reactions, anaphylactoid or anaphylactic reactions), patchy or diffuse/widespread changes in skin color (rash, erythema), skin itching, urticaria, swelling (angioedema) of the face, eyes, lips and difficulty breathing (shortness of breath, bronchospasm), back pain or tightness in the chest, changes in blood pressure (hypotension, arterial hypertension) or increased heart rate, slow heart rate (tachycardia, bradycardia), increased sweating;
• urinary tract infections;
• joint pain (arthralgia), muscle spasms;
• dizziness, changes in sensitivity (paresthesia), taste disturbance (dysgeusia);
• excitement, confusion;
• “hot flashes”, decreased blood pressure (hypotension), inflammation of the veins (phlebitis);
• difficulty breathing due to swelling of the throat (laryngeal edema).

Rare (may affect up to 1 in 1000 people):

• bloating;
• malaise.

Interaction

Tell your doctor or pharmacist if you are taking, have recently taken, or may start taking any other medications.

This is especially important if you are taking:

• anti-depression medications called selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (such as clomipramine).

• drugs and herbal remedies containing an amino acid (a component of protein) called tryptophan.

Overdose

An overdose of ademetionine is unlikely. In case of overdose, monitoring of the patient and symptomatic therapy is recommended.

Storage conditions

Store the drug at a temperature not exceeding 25 °C.

Manufacturer

Biologici Italia Laboratories S.r.L., Italy