Heptral

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

Composition:

Active ingredient: ademetionine;

1 tablet contains 760 mg of ademetionine 1,4-butanedisulfonate, corresponding to 400 mg of ademetionine cation;

Excipients: colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, methacrylic acid copolymer dispersion, polyethylene glycol 6000, talc, simethicone emulsion, polysorbate 80, sodium hydroxide.

Pharmaceutical form. Enteric-coated tablets.

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

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

Pharmacological Properties

Pharmacodynamics

S-adenosyl-L-methionine (adenosylmethionine) is a natural amino acid present in virtually all tissues and body fluids. Adenosylmethionine acts primarily 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 a necessary metabolic process in the formation of the bilayer phospholipid structure of cell membranes, contributing to membrane fluidity. Adenosylmethionine is able to cross the blood-brain barrier. Transmethylation involving adenosylmethionine is key in the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, norepinephrine, epinephrine), serotonin, melatonin, and histamine.

Adenosylmethionine is also a precursor in the formation of physiological sulfur-containing 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. Adenosylmethionine 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 adenosylmethionine.

Pharmacokinetics

Absorption. In humans, after intravenous administration, the pharmacokinetic profile of adenosylmethionine is biexponential and consists 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 peak plasma concentration reached about 45 minutes after administration. Following oral administration of enteric-coated tablets of adenosylmethionine, peak plasma concentration is dose-dependent, ranging from 0.5 to 1 mg/L, and is achieved 3 to 5 hours after a single dose of 400 mg to 1000 mg. Plasma concentration decreases to baseline levels within 24 hours. Oral bioavailability increases when adenosylmethionine is administered between meals.

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

Metabolism. The reactions responsible for the production, utilization, and regeneration of adenosylmethionine are collectively known as the adenosylmethionine cycle. In the first step of this cycle, adenosylmethionine-dependent methyltransferase uses adenosylmethionine 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. Ultimately, methionine can be converted back into adenosylmethionine, thus completing the cycle.

Excretion. In radiolabeled studies, following oral administration of radiolabeled (methyl-14C) adenosylmethionine in 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;
• depressive syndromes.

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 disorders).

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, 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 taking 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 vegetarianism) 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 before 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. Metabolism").

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

One case report has been published describing the development of serotonin syndrome in a patient receiving ademetionine concurrently with clomipramine. Although such an interaction is theoretically possible, ademetionine should be used with caution when administered concomitantly 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").

The efficacy of ademetionine in the treatment of depression has been demonstrated in short-term clinical studies (3–6 weeks). The efficacy of ademetionine treatment lasting longer than 6 weeks for depression is unknown. Since there are many treatment options for depression, patients should consult their physician to determine optimal therapy. Patients should be advised to inform their physician if symptoms of their condition (depression) do not improve or worsen during ademetionine therapy.

Patients with depression are generally at increased risk of suicide or other serious behaviors and therefore require careful monitoring and ongoing psychiatric support during ademetionine treatment to monitor treatment efficacy for depressive symptoms.

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.

Impact on immunoassay of homocysteine.

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

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

Renal impairment. Limited clinical data are available on the use of ademetionine in patients with renal impairment. Ademetionine should be used with caution in such patients.

Suicide/suicidal thoughts.

Depression is associated with an increased risk of suicidal thoughts, suicidal behavior, and suicide (suicidal events). This risk persists until remission occurs during treatment of depression. Significant improvement may not occur during the first few weeks of treatment or several weeks after initiation of therapy; therefore, close monitoring of patients with depression is necessary until improvement is observed.

Other psychiatric disorders for which this drug is prescribed may also be associated with an increased risk of suicidal behavior. Moreover, such disorders may be associated with major depressive disorder. When treating patients with major depressive disorder, particular caution should be exercised, and the same safety measures should be applied as in the treatment of patients with other psychiatric disorders.

Use during pregnancy or breastfeeding.

No adverse reactions were observed in women treated with ademetionine during the third trimester of pregnancy in clinical studies. Ademetionine should be used during the first and second trimesters of pregnancy only after careful evaluation by a physician of the benefit-risk ratio for the pregnant woman and the fetus.

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

Ability to affect reaction speed when driving or operating machinery.

Dizziness may occur in some patients during ademetionine therapy. In such cases, patients should refrain from driving or operating machinery until symptoms that may affect reaction speed during these activities have completely resolved.

Method of administration and dosage.

Treatment may begin with parenteral administration of the drug followed by oral tablets, or may start directly with tablets. The daily tablet dose may be divided into 2–3 administrations.

Initial therapy

Oral (by mouth): The recommended dose is 10–25 mg/kg body weight per day. The usual initial dose is 800 mg/day (2 tablets), and the total daily dose should not exceed 1600 mg (4 tablets).

Intravenous or intramuscular: The recommended dose is 5–12 mg/kg body weight per day. The usual initial dose is 400 mg/day, and the total daily dose should not exceed 1000 mg. The duration of initial parenteral therapy is 15–20 days for treatment of depressive syndromes and 2 weeks for treatment of liver diseases (for parenteral administration, use Heptral**®** lyophilized powder for solution for injection).

Maintenance therapy

Oral administration: 2–4 tablets daily (800–1600 mg/day).

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

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

Heptral**®** tablets should be removed from the blister pack immediately before use. Tablets showing any color other than white to yellowish (due to damage to the aluminum packaging) should not be used.

Elderly patients.

Clinical studies with ademetionine have not included a sufficient number of elderly patients (i.e., patients aged 65 years and older) to determine whether they respond differently from younger patients. However, based on available clinical experience, no 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, considering the greater frequency of decreased hepatic, renal, or cardiac function, presence of concomitant diseases, and use of other medicinal products.

Children.

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

Overdose.

Cases of ademetionine overdose have been rarely reported. In case of overdose, physicians should contact local toxicology centers. In general, 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 following adverse reactions have been reported with the specified frequencies during clinical studies of ademetionine (n=1922) and in spontaneous reports. Adverse reactions are classified by system organ classes (according to MedDRA) and by frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).

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/behaviour have been reported in patients with depressive syndromes (see section "Special precautions").

* Adverse reactions from spontaneous reports, observed more frequently in spontaneous reports or not observed during clinical studies, are classified with the frequency "uncommon" because 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).

1 Applies to the injectable form of the medicinal product.

Shelf life. 3 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C.

Packaging. 10 tablets per blister. 1 or 2 blisters per cardboard package.

Prescription status. Prescription only.

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

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