Adecicol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADECYCOL

Composition:

Active substance: ademetionine;

1 vial of powder contains 760 mg of ademetionine (S-adenosyl-L-methionine 1,4-butanedisulfonate), equivalent to 400 mg of ademetionine cation;

Excipients: none.

1 ampoule of solvent contains L-lysine (50 % aqueous solution), calculated as L-lysine, sodium hydroxide, water for injections.

Pharmaceutical form. Powder and solvent for solution for injection.

Main physicochemical characteristics:

Powder: hygroscopic white or almost white powder;

Solvent: light yellow liquid;

Reconstituted solution: clear light yellow solution.

Pharmacotherapeutic group. Agents acting on the digestive system and metabolism. Amino acids and their derivatives. Ademetionine. ATC code A16AA02.

Pharmacological properties.

Pharmacodynamics.

S-adenosyl-L-methionine (adenosylmethionine) is a natural amino acid present in almost 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 for the formation of the bilayer phospholipid membrane in cell membranes, promoting membrane fluidity. Adenosylmethionine is able to cross the blood-brain barrier. Transmethylation processes involving adenosylmethionine are key in the synthesis of central nervous system neurotransmitters, including catecholamines (dopamine, noradrenaline, adrenaline), 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 processes 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.

After intramuscular administration, the drug is almost completely absorbed (96%); maximum plasma concentration of adenosylmethionine is reached approximately 45 minutes after administration.

Following oral administration of enteric-coated tablets of adenosylmethionine, maximum plasma concentration is dose-dependent, ranging from 0.5 to 1 mg/L, and is achieved within 3 to 5 hours after a single dose of 400 mg to 1000 mg. Plasma concentration decreases to baseline levels within 24 hours. Bioavailability after oral administration increases when adenosylmethionine is administered between meals.

Distribution

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

Metabolism

The reactions that produce, utilize, and regenerate adenosylmethionine are 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. Finally, methionine can be converted back into adenosylmethionine, thus completing the cycle.

Excretion

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

Contraindications.

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

Hypersensitivity to any of the components of the drug (see section "Composition").

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 section "Special precautions").

Special precautions for use.

Intravenous administration should be performed very slowly (see section "Dosage and administration").

Suicide/suicidal thoughts

Depression is associated with an increased risk of suicidal thoughts, suicidal behaviour, and suicide (suicidal events). The risk persists until remission occurs during treatment of depression. Since significant improvement may not occur during the first weeks of treatment or for several weeks after initiation of initial therapy, patients with depression require careful monitoring until improvement is observed.

Other psychiatric disorders for which this medicinal product is prescribed may also be associated with an increased risk of suicidal behaviour. 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 taken as for patients with other psychiatric disorders.

Since vitamin B12 and folic acid (folates) deficiency may lead to reduced concentrations of ademetionine, patients at risk (anaemia, liver disease, pregnancy, potential for vitamin deficiency due to other diseases or dietary habits such as vegetarianism) should undergo regular blood tests to check 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 use. In cases where such testing cannot be performed, 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 section "Pharmacological properties").

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

One case report describes the development of serotonin syndrome in a patient taking ademetionine concomitantly with clomipramine. Although interaction is theoretically possible, ademetionine should be used cautiously when administered simultaneously with SSRIs, tricyclic antidepressants (such as clomipramine), and medicinal products or herbal preparations containing tryptophan (see section "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. There are many approaches to treating depression; therefore, patients should consult their physician to determine optimal therapy. Patients should be advised to inform their physician if symptoms of their illness (depression) do not improve or worsen during ademetionine therapy.

Patients with depression are generally at increased risk of suicide or other serious acts and therefore require careful monitoring and ongoing psychiatric support during treatment with ademetionine to monitor treatment effectiveness 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. In some instances, anxiety resolved after dose reduction or discontinuation of treatment.

Effect on immunological homocysteine assay

Ademetionine affects the immunological assay for homocysteine, potentially leading to falsely elevated plasma homocysteine levels in patients taking ademetionine. Therefore, non-immunological methods for determining plasma homocysteine levels are recommended for 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 such patients.

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

Elderly patients

Clinical studies of ademetionine did not include 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 differences in treatment response between elderly and younger patients have been observed. In general, dose selection for elderly patients should be cautious, starting with the lowest recommended dose, taking into account the increased likelihood of reduced hepatic, renal, or cardiac function, the presence of concomitant pathological conditions, and use of other medicinal products.

Ammonia levels should be monitored in patients with pre-cirrhotic or cirrhotic stages of hyperammonaemia who are taking ademetionine in tablet form.

Excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

In clinical studies, no adverse reactions were observed in women treated with ademetionine during the third trimester of pregnancy.

Ademetionine should be used during the first and second trimesters of pregnancy only after careful benefit-risk assessment by the physician (benefit to the pregnant woman versus risk to the foetus).

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

Treatment usually begins with parenteral administration of the drug, followed by the use of ademetionine in tablet form, or treatment may start directly with tablets.

The powder must be dissolved in the special solvent provided, immediately before use.

Ademetionine should not be mixed with alkaline solutions or solutions containing calcium ions.

If the lyophilized powder has a color other than white to yellowish (due to cracks in the vial or exposure to elevated temperature), its use should be avoided.

Initial Therapy

Intravenous or intramuscular administration: the recommended dose is 5–12 mg/kg body weight per day. The usual initial dose is 400 mg/day; the total daily dose should not exceed 1000 mg. The duration of initial parenteral therapy is 15–20 days for treatment of depressive disorders and 2 weeks for treatment of liver diseases.

Oral (per os): for oral administration, ademetionine should be used in the form of enteric-coated tablets. The recommended dose is 10–25 mg/kg body weight per day. The usual initial dose is 800 mg/day (2 tablets); the total daily dose should not exceed 1600 mg (4 tablets).

Maintenance Therapy

Oral administration of 2–4 tablets per day (800–1600 mg/day).

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

For intramuscular or intravenous administration, the lyophilized powder should be dissolved in the special solvent provided, immediately before use. For intravenous infusion, the required dose of ademetionine should be further diluted in 250 mL of physiological saline or 5% dextrose (glucose) solution and infused slowly over 1–2 hours. Any unused portion of the solution should be discarded.

Elderly Patients

Clinical studies of ademetionine have not included sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, based on available clinical experience, no differences in responses to treatment have been observed between elderly and younger patients. Therapy in elderly patients should be initiated at the lowest recommended dose, considering reduced hepatic, renal, or cardiac function, presence of concomitant diseases, and use of other medicinal products.

Children

Safety and efficacy of ademetionine in children have not been established.

Overdose

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

Adverse Reactions

The most commonly reported adverse reactions during treatment with ademetionine are headache, diarrhoea, and nausea.

The adverse reactions listed below have been reported with the specified frequency during clinical trials with ademetionine, as well as in spontaneous reports. Adverse reactions are classified by system organ class (according to MedDRA) and by frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000).

Gastrointestinal disorders:
Common – abdominal pain, diarrhoea, nausea;
Uncommon – dry mouth, dyspepsia, flatulence, gastrointestinal pain, gastrointestinal haemorrhage, gastrointestinal disorder, vomiting, oesophagitis;
Rare – abdominal distension.

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

Immune system disorders:
Uncommon – hypersensitivity*, anaphylactoid reactions*, or anaphylactic reactions (e.g., flushing, dyspnoea, 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, paraesthesia, dysgeusia*.

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

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

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

Cardiovascular disorders:
Uncommon – flushing, hypotension, phlebitis.

Rare cases of suicidal thoughts/behaviour have been reported in patients with depressive syndromes (see section "Special Warnings and Precautions for Use").

* Adverse reactions from spontaneous reports, observed more frequently in spontaneous reports or not observed during clinical trials, classified as "uncommon" in frequency since 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 ademetionine clinical trials).

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

The solution obtained after reconstitution with solvent should be stored for no more than 6 hours at 2 °C to 8 °C and for no more than 2 hours at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities.

Ademetionine must not be mixed with alkaline solutions or with preparations containing calcium ions.

Packaging.
5 vials of powder and 5 ampoules of solvent, 5 ml each, in a blister pack. One blister pack per carton.

Prescription status.
Prescription only.

Manufacturer.

BIOMEDICA FOSCAMA INDUSTRIA CHIMICO FARMACEUTICA SPA.

Manufacturer's address.
Via Morolense 87, Ferentino (FR), 03013, Italy.