HEPARD [Ademetionine] 500 mg Enteric-coated tablets
instructions for the medical use of
the medicinal product
HEPARD
Tradename:
Hepard, Хепард
International non-proprietary name
or generic name:
Ademethionine, Адеметионин
Composition
Each enteric-coated tablet contains:
active substance: ademetionine 1,4-butane disulfonate
500 mg;
excipients: Colloidal silicon dioxide, microcrystalline
cellulose, sodium starch glycolate, magnesium stearate, methacrylic acid-ethyl
acrylate copolymer, polyethylene glycol, polysorbate, dimethicone, sodium hydroxide,
talc.
Dosage form:
Enteric-coated
tablets.
Pharmacotherapeutic group:
Metabolic agent. Hepatoprotector.
Kode АТХ: А16А А02
Pharmacological
properties
Pharmacodynamics
Ademetionine belongs to the group of
hepatoprotectors and also has antidepressant activity. It has choleretic and
cholekinetic effects. It has detoxifying, regenerating, antioxidant,
antifibrotic, and neuroprotective properties.
It replenishes S-adenosyl-L-methionine
(ademetionine) deficiency and stimulates its production in the body. It is
found in all bodily fluids. The highest concentrations of ademetionine are
found in the liver and brain. It plays a key role in metabolic processes in the
body, participating in important biochemical reactions: transmethylation, transsulfuration,
and transamination. In transmethylation reactions, ademetionine donates a
methyl group for the synthesis of phospholipids in cell membranes,
neurotransmitters, nucleic acids, proteins, hormones, etc. In transsulfuration
reactions, ademetionine is a precursor of cysteine, taurine, glutathione
(providing a redox mechanism for cellular detoxification), and coenzyme A
(involved in biochemical reactions of the tricarboxylic acid cycle and
replenishing cellular energy potential).
It increases glutamine levels in the liver and
cysteine and taurine levels in plasma;
it reduces serum methionine levels, normalizing metabolic reactions in the
liver. After decarboxylation, it participates in aminopropylation processes as
a precursor of polyamines – putrescine (a stimulator of
cell regeneration and hepatocyte proliferation), spermidine, and spermine,
which are part of the ribosome structure, reducing 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 hepatocyte membrane-associated bile acid transport systems and promotes bile
acid passage into the biliary tract. It is effective in intralobular cholestasis
(impaired bile synthesis and flow). Ademetionine reduces the toxicity of bile
acids in hepatocytes by conjugating and sulfating them. Conjugation with
taurine increases the solubility of bile acids and their elimination from
hepatocytes. The process of bile acid sulfation facilitates their elimination
by the kidneys, facilitates their passage through the hepatocyte membrane, and
facilitates their excretion in bile. Furthermore, sulfated bile acids
themselves provide additional protection to liver cell membranes from the toxic
effects of non-sulfated bile acids (present in high concentrations in
hepatocytes during intrahepatic cholestasis). In patients with diffuse liver
diseases (cirrhosis, hepatitis) and intrahepatic cholestasis syndrome, ademetionine
reduces the severity of pruritus and changes in biochemical parameters,
including direct bilirubin concentrations, alkaline phosphatase activity,
aminotransferases, and others. The choleretic and hepatoprotective effect
persists for up to 3 months after discontinuation of treatment.
Efficacy has been demonstrated in hepatopathies
caused by various hepatotoxic drugs.
Antidepressant activity appears gradually,
beginning at the end of the first week of treatment, and stabilizes within 2
weeks of treatment.
Pharmacokinetics
The tablets are film-coated and dissolve only in the intestine, allowing
ademetionine to be released in the duodenum. Ademetionine peak plasma
concentrations are dose-dependent and range from 0.5-1 mg/L within 3-5 hours
after a single oral dose of 400 to 1000 mg. Ademetionine peak plasma
concentrations decrease to baseline within 24 hours. Oral bioavailability of
ademetionine increases when administered on an empty stomach.
Plasma protein binding is insignificant, ≤5%. It penetrates the blood-brain
barrier. A significant increase in cerebrospinal fluid concentrations is
observed.
It is metabolized in the liver. The process of formation, consumption, and
re-formation of ademetionine 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 hydrolase. Homocysteine, in turn, undergoes
reverse conversion to methionine via the transfer of a methyl group from
5-methyltetrahydrofolate. Finally, methionine can be converted to ademetionine,
completing the cycle.
T1/2 is 1.5 hours. It is excreted by the kidneys. In studies of healthy
volunteers receiving methyl-14C-labeled S-adenosyl-L-methionine, 15.5±1.5% of
the radioactivity was detected in the urine after 48 hours, and 23.5±3.5% in
the feces.
Indications for use
• Intrahepatic cholestasis in precirrhotic and
cirrhotic conditions, which can be observed in the following diseases:
• fatty liver;
• chronic hepatitis;
• toxic liver damage of various etiologies,
including alcohol-induced, viral, and drug-induced (antibiotics, antitumor,
antituberculosis, and antiviral drugs, tricyclic antidepressants, oral
contraceptives);
• chronic acalculous cholecystitis;
• cholangitis;
• liver cirrhosis;
• encephalopathy, including that associated with
liver failure (including alcohol-induced).
Contraindications
• Hypersensitivity to any component of the drug;
• Genetic disorders affecting the methionine
cycle and/or causing homocystinuria and/or hyperhomocysteinemia (cystathionine
beta-synthase deficiency, cyanocobalamin metabolism disorder);
• Bipolar disorder;
• Children and adolescents under 18 years of
age.
With caution
• Concomitant use with selective serotonin
reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine),
and medications containing tryptophan, including herbal ones.
• Elderly age;
• Renal insufficiency.
Method of
administration and dosage
The medication is taken orally. The
tablets should be swallowed whole, without chewing, preferably in the morning
between meals.
The recommended dose is 1-2 tablets
per day (500-1000 mg) and can be increased to 4 tablets per day (up to 2000
mg). The effect usually appears after 7-14 days of treatment and is maintained
with continued use.
If there is no positive effect after
2 weeks of treatment or if the patient's condition worsens, consult a doctor.
Special instructions and precautions
Consult a physician before use.
When using this medication in
patients with liver cirrhosis associated with hyperazotemia, regular monitoring
of blood nitrogen levels is necessary. During long-term therapy, serum urea and
creatinine levels should be measured.
Since cyanocobalamin and folic acid
deficiency can reduce ademetionine levels, plasma vitamin levels should be
monitored. If deficiency is detected, cyanocobalamin and folic acid
supplementation is recommended before initiating ademetionine treatment or
concomitant administration with ademetionine.
When using immunological testing,
ademetionine may falsely indicate elevated homocysteine levels in the blood. For patients taking ademetionine,
non-immunological assays are recommended to determine homocysteine levels.
Patients with depression or taking
antidepressants should consult a physician before starting Hepard. There have
been reports of sudden onset or worsening anxiety in patients taking
ademetionine. In most cases, discontinuing the drug is not required; in a few
cases, anxiety resolved after dose reduction or discontinuation of the drug.
Influence on the ability to drive vehicles and
mechanisms
Dizziness may occur. Driving or operating
machinery is not recommended while taking this medication until the patient is
confident that the therapy does not affect their ability to perform such
activities.
Use during
pregnancy and breastfeeding
The use of Hepard during pregnancy and breastfeeding
is not recommended without medical supervision.
Interaction
with other medicinal products
There are currently no known
interactions.
There is a report of serotonin
excess syndrome in a patient taking ademetionine and clomipramine. Such interactions
are considered possible, and caution should be exercised when prescribing
ademetionine with SSRIs, tricyclic antidepressants (such as clomipramine),
herbal remedies, and medications containing tryptophan.
Side
effect
Gastrointestinal: nausea, vomiting, diarrhea,
abdominal pain, dry mouth, dyspepsia, flatulence, bloating.
Nervous system: dizziness, headache, anxiety,
insomnia, or drowsiness.
Cardiovascular: decreased blood pressure, hot
flashes.
Allergic reactions: rash, itching, urticaria, increased
sweating.
Other: arthralgia, muscle spasms, swelling, fever, chills.
If any of the side effects listed in the instructions
worsen, or you notice any other side effects not listed in the instructions,
please notify your doctor.
Overdose
An overdose of Hepard is unlikely. In case of
overdose, patient observation and symptomatic treatment are recommended.
Storage conditions
Store at temperatures not exceeding 25°C.
Keep out of reach of children.
Shelf life
2 years. Do not use after the expiration date printed
on the package.
Vacation conditions
By prescription.
Release form
8 tablets in an aluminum-aluminum blister. 3 blisters with instructions for use in a cardboard box.