Heptral

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEPTRAL® (HEPTRAL®)

Composition:

Active substance: ademetionine;

1 tablet contains 949 mg of ademetionine 1,4-butanedisulfonate, corresponding to 500 mg of ademetionine cation;

Excipients: colloidal anhydrous silicon dioxide, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, methacrylic acid copolymer (type A), polyethylene glycol 6000, polysorbates, simethicone emulsion, sodium hydroxide, talc.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: film-coated oval tablets, white to yellowish in color, without cracks, "capping" effect or swelling.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolic processes. Amino acids and their derivatives. ATC code A16AA02.

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 present in virtually all tissues and body fluids. Ademetionine primarily acts as a coenzyme and methyl group donor in transmethylation reactions, which are essential metabolic processes in humans and animals. The transfer of methyl groups (transmethylation) is also essential for the formation of the bilayer phospholipid structure in cell membranes, promoting membrane fluidity. Ademetionine is capable of crossing the blood-brain barrier. Transmethylation processes involving ademetionine play a key role in the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin, and histamine.

Ademetionine also serves as a precursor in the formation of physiological sulfur-containing (thiol) compounds (cysteine, taurine, glutathione, coenzyme A, etc.) in transsulfuration reactions. Glutathione, the most potent antioxidant in the liver, plays a crucial role in hepatic detoxification. Ademetionine increases hepatic glutathione levels in patients with liver damage of both alcoholic and non-alcoholic etiology. Folic acid (folates) and vitamin B12 are essential cofactors in the metabolism and regeneration of ademetionine.

Intrahepatic cholestasis.

Intrahepatic cholestasis may be one of the complications of acute and chronic liver diseases and can occur independently of their etiology. This pathological condition is characterized by reduced bile secretion by hepatocytes, leading to the accumulation in blood of substances normally excreted via bile, such as bilirubin, bile salts, and enzymes.

Administration of ademetionine helps overcome the metabolic block (conversion of methionine to ademetionine) caused by reduced activity of the enzyme ademetionine synthetase. Thus, physiological mechanisms preventing the development of cholestasis are restored. Various experimental studies have demonstrated that the anticholestatic effect of ademetionine is achieved through: 1) restoration of microfluidity of cytoplasmic membranes via ademetionine-dependent synthesis of membrane phospholipids (reducing the cholesterol/phospholipid ratio), and 2) overcoming the metabolic block in the transsulfuration process, thereby restoring the synthesis of thiol groups involved in endogenous detoxification processes.

Pharmacokinetics.

Absorption. In humans, after intravenous administration, the pharmacokinetic profile of ademetionine is biexponential, consisting of a rapid distribution phase into tissues and a terminal elimination phase with a half-life of approximately 1.5 hours. Absorption after intramuscular administration is nearly complete (96%), with maximum plasma concentration reached about 45 minutes after administration. After oral administration of enteric-coated ademetionine tablets, maximum plasma concentration is dose-dependent, ranging from 0.5–1 mg/L, and is achieved within 3–5 hours after a single dose of 400 mg to 1000 mg. Plasma concentration declines to baseline levels within 24 hours. Bioavailability after oral administration increases when ademetionine is administered between meals. Following oral administration, tablets are absorbed in the intestinal tract and significantly increase plasma ademetionine concentration. Animal studies using isotopic methods have confirmed that oral administration of ademetionine stimulates the formation of methylated compounds in the liver. It has also been confirmed that ademetionine is metabolized via typical metabolic pathways characteristic of endogenous compounds (transmethylation, transsulfuration, decarboxylation, etc.).

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

Metabolism. The reactions producing, utilizing, and regenerating ademetionine are collectively known as the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methyltransferases 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 remethylation to methionine via transfer of a methyl group from 5-methyltetrahydrofolate. Finally, methionine can be converted back into ademetionine, completing the cycle.

Elimination. In radiolabeled studies, following oral administration of radioactively labeled (methyl-14C) ademetionine to healthy volunteers, urinary excretion of radioactivity was 15.5 ± 1.5% within 48 hours, and fecal excretion was 23.5 ± 3.5% within 72 hours, with approximately 60% of the administered substance incorporated into stable pools.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition").

Genetic defects affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia (e.g. cystathionine-beta-synthase deficiency, vitamin B12 metabolism defects).

Interaction with other medicinal products and other forms of interaction.

Cases of serotonin syndrome have been reported in a patient taking ademetionine concomitantly with clomipramine. Therefore, although the possibility of interaction is theoretically assumed, ademetionine should be used with caution when administered simultaneously with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products or herbal remedies containing tryptophan (see "Special precautions for use").

Special precautions for use.

Plasma ammonia levels should be monitored in patients with pre-cirrhotic or cirrhotic stage hyperammonemia who are receiving ademetionine tablets.

Since vitamin B12 and folic acid (folates) deficiency may lead to reduced concentrations of ademetionine, patients at risk (e.g., anemia, liver disease, pregnancy, or potential for vitamin deficiency due to other diseases or dietary habits such as veganism) should undergo regular blood tests to assess plasma levels of these substances. If deficiency is detected, treatment with vitamin B12 and/or folic acid (folates) is recommended prior to or during ademetionine therapy. In cases where such testing is not feasible, patients at risk should be given vitamin B12 and/or folic acid (folates) according to the instructions for medical use of these medicinal products (see "Pharmacological properties. Pharmacokinetics. Metabolism").

This medicinal product is not indicated for the treatment of depressive disorders, but may be used for the treatment of intrahepatic cholestasis in patients with depressive disorders. Therefore, the following warnings regarding patients receiving antidepressant therapy should be taken into account.

Ademetionine is not recommended for use in patients with bipolar disorders. Cases of transition from depression to hypomania or mania during ademetionine treatment have been reported.

One published case reported serotonin syndrome in a patient receiving ademetionine concomitantly with clomipramine. Although interaction is theoretically possible, ademetionine should be used with caution when administered together with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and medicinal products or herbal remedies containing tryptophan (see "Interaction with other medicinal products and other forms of interaction").

Patients with depression are generally at increased risk of suicide or other serious behaviors and therefore require careful monitoring and ongoing psychiatric support during antidepressant therapy to ensure timely identification and management of depressive symptoms. Patients with a history of suicidal behavior or ideation, or those exhibiting significant suicidal intent, are at higher risk of suicide attempts or ideation and should be under close supervision during treatment.

There have been reports of transient onset or worsening of anxiety in patients taking ademetionine. In most cases, discontinuation of therapy was not necessary. Anxiety symptoms sometimes resolved after dose reduction or discontinuation of treatment.

Effect on immunoassay of homocysteine.

Ademetionine affects immunoassay measurement of homocysteine, potentially leading to falsely elevated plasma homocysteine levels in patients receiving ademetionine. Therefore, non-immunoassay methods for determining plasma homocysteine levels are recommended in such patients.

Renal impairment. Clinical data on the use of ademetionine in patients with renal impairment are limited. Ademetionine should be used with caution in these patients.

Hepatic impairment. Pharmacokinetic characteristics do not differ between healthy volunteers and patients with chronic liver disease.

Elderly patients.

Clinical studies of ademetionine have not included sufficient numbers of patients aged 65 years and older to determine whether they respond differently compared to younger patients. Based on available clinical experience, no significant differences in response to treatment between elderly and younger patients have been observed. In general, dose selection for elderly patients should be cautious, usually starting with the lowest recommended dose, taking into account the greater frequency of decreased hepatic, renal, or cardiac function, presence of concomitant diseases, and use of other medicinal products.

Use during pregnancy or breastfeeding.

No adverse reactions have been observed in clinical studies involving women treated with ademetionine during the third trimester of pregnancy. Ademetionine should be used during the first two trimesters of pregnancy only if clearly needed.

During breastfeeding, ademetionine should be used only when the potential benefit justifies the potential risk to the infant.

Ability to influence reaction speed when driving or operating machinery.

Dizziness may occur in some patients during treatment with ademetionine. Patients should refrain from driving or operating machinery until they are fully certain that ademetionine therapy does not affect their ability to perform such activities.

Method of Administration and Dosage

Treatment may begin with parenteral administration of the drug (use Heptral**®** as a lyophilized powder for solution for injection in combination with the solvent), followed by transition to tablets, or treatment may start directly with tablets. The daily dose of tablets may be divided into 2–3 administrations.

Tablets should be swallowed whole, without chewing. Heptral**®** tablets are coated with a special enteric coating that dissolves only in the intestine, allowing ademetionine to be released in the duodenum. To ensure optimal absorption of the active ingredient and achieve full therapeutic effect, tablets should be taken between meals.

A Heptral**®** tablet should be removed from the blister pack immediately before administration. If the tablets have any color other than white to yellowish (due to damage to the aluminum packaging), their use is not recommended.

Initial Therapy

Oral administration: the recommended dose is 10–25 mg/kg body weight per day. The usual initial dose is 800 mg/day; the total daily dose should not exceed 1600 mg.

Maintenance Therapy

Oral administration: 800–1600 mg/day.

The individual initial and maintenance doses should be determined by a physician based on body weight, severity of the disease, and available dosage forms of the drug on the market.

Duration of therapy depends on the severity and course of the disease and is determined individually by the physician.

Children

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

Overdose

Cases of ademetionine overdose have been rarely observed. In the event of overdose, physicians should contact local toxicology centers. Generally, patient monitoring and supportive treatment are recommended.

Adverse Reactions

Ademetionine has been administered to approximately 2000 patients in clinical studies. The most commonly reported adverse reactions during treatment with ademetionine were headache, diarrhea, and nausea.

The adverse reactions listed below were reported at the specified frequencies during clinical studies of ademetionine (n=1922) and in spontaneous reports. Adverse reactions are classified by system organ class (according to MedDRA) and by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000).

Gastrointestinal disorders:
Common – abdominal pain, diarrhea, nausea;
Uncommon – dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal hemorrhage, gastrointestinal disorders, vomiting, esophagitis;
Rare – abdominal distension.

General disorders and administration site conditions:
Common – asthenia;
Uncommon – edema, hyperthermia, chills*, injection site reactions*1, necrosis at injection site*1;
Rare – malaise.

Immune system disorders:
Uncommon – hypersensitivity*, anaphylactoid reactions* or anaphylactic reactions (e.g., hyperemia, dyspnea, bronchospasm, back pain, chest discomfort, changes in blood pressure (hypotension, hypertension) or pulse rate (tachycardia, bradycardia))*.

Infections and infestations:
Uncommon – urinary tract infections.

Musculoskeletal and connective tissue disorders:
Uncommon – arthralgia, muscle cramps.

Nervous system disorders:
Common – headache;
Uncommon – dizziness, paresthesia, dysgeusia*.

Psychiatric disorders:
Common – anxiety, insomnia;
Uncommon – agitation, confusion.

Respiratory, thoracic and mediastinal disorders:
Uncommon – laryngeal edema*.

Skin and subcutaneous tissue disorders:
Common – pruritus;
Uncommon – hyperhidrosis, angioneurotic edema*, allergic skin reactions (e.g., rash, pruritus, urticaria, erythema)*.

Vascular disorders:
Uncommon – flushing, hypotension, phlebitis.

Rare cases of suicidal thoughts/behavior have been reported in patients with depressive disorders (see section "Special precautions").

*Adverse reactions from spontaneous reports, which are more frequently known from spontaneous reporting or were not observed during clinical studies, are classified as "uncommon" in frequency, considering that the upper limit of the 95% confidence interval for the expected frequency does not exceed 3/X, where X=1922 (total number of subjects in clinical studies).

1Applies to the injectable form of the medicinal product.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Store in the original blister pack in a place inaccessible to children.

Packaging. 10 tablets per blister. 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. AbbVie S.r.l., Italy.

Manufacturer's address and location of operations. C.R. 148 Pontina KM 52, SNC - Campoverde di Aprilia (loc. Aprilia) - 04011 Aprilia (LT), Italy.