Likartin-n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LICARTIN-N (LICARTIN-N)

Composition:

Active substance: levocarnitine;

1 ml of solution contains 200 mg or 400 mg of levocarnitine;

Excipients: hydrochloric acid diluted, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless to slightly yellow liquid.

Pharmacotherapeutic group. Amino acids and their derivatives. Levocarnitine.

ATC code A16AA01.

Pharmacological properties.

Pharmacodynamics.

Carnitine is a natural component of cells, where it plays a fundamental role in energy synthesis and transport processes. It is essentially the only indispensable factor for the penetration of long-chain fatty acids into mitochondria and their participation in β-oxidation. In humans, physiological requirements for carnitine are met through dietary intake of carnitine-containing foods and via endogenous synthesis in the liver. Only the L-isomer of carnitine is biologically active. Levocarnitine plays an important role in lipid metabolism as well as in ketone body metabolism. Levocarnitine is necessary for the transport of long-chain fatty acids into mitochondria for subsequent beta-oxidation. By releasing coenzyme A from complex thioesters, levocarnitine enhances carbohydrate oxidation in the Krebs tricarboxylic acid cycle and stimulates the activity of the key glycolysis enzyme—pyruvate dehydrogenase—and, in skeletal muscles, the oxidation of branched-chain amino acids. Thus, levocarnitine directly or indirectly participates in most energy-producing processes, and its presence is essential for the oxidation of fatty acids, amino acids, glucose, and ketone bodies.

Pharmacokinetics.

Absorbed levocarnitine is transported via blood to various organs and systems. The presence of membrane-bound proteins in certain tissues of the body, including red blood cells, which bind carnitine, suggests that transport systems in blood and specific cellular uptake mechanisms are required for its active utilization in certain tissues.

The concentration of levocarnitine in blood serum and tissues depends on the activity of metabolic processes, the rate of levocarnitine biosynthesis, dietary characteristics, the movement of levocarnitine into and out of tissues, and the rate of its metabolism and excretion. All these factors may influence carnitine concentration in tissues.

Absorption

Levocarnitine is absorbed by the cells of the mucous membrane of the small intestine and enters the bloodstream relatively slowly; absorption is likely associated with an active trans-luminal mechanism. Absorption after oral administration is limited (< 10%) and variable.

Distribution

Absorbed levocarnitine is transported via blood to various organs; it is believed that the erythrocyte transport system is involved in this process.

Excretion

Levocarnitine is primarily excreted in urine. The excretion rate is directly proportional to the concentration of carnitine in the blood.

Metabolism

Levocarnitine is almost not metabolized in the body.

Clinical characteristics.

Indications.

Primary and secondary carnitine deficiency in adults and children, including newborns and infants.

Secondary carnitine deficiency in patients undergoing hemodialysis.

Suspected secondary carnitine deficiency in patients undergoing hemodialysis in the following cases:

• severe and persistent muscle cramps and/or hypotensive episodes during dialysis;
• energy deficit significantly impairing quality of life;
• muscle weakness and/or myopathy;
• cardiomyopathy;
• uremia-induced anemia unresponsive to erythropoietin treatment or requiring high doses of erythropoietin;
• loss of muscle mass.

Contraindications

Hypersensitivity to the active substance and/or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of glucocorticoids leads to accumulation of levocarnitine in body tissues (except liver). Other anabolic agents enhance the effect of levocarnitine.

In some cases, co-administration of levocarnitine with coumarin anticoagulants may lead to an increase in the international normalized ratio (INR); therefore, concomitant use requires caution. INR or other coagulation tests should be monitored weekly until stabilized, and monthly thereafter in patients receiving these anticoagulants together with levocarnitine.

Special precautions for use

Levocarnitine improves glucose utilization; therefore, its use in patients with diabetes mellitus who are receiving treatment with oral hypoglycemic agents may lead to hypoglycemia. In such cases, plasma glucose levels should be monitored regularly to allow timely adjustment of therapy.

The safety and efficacy of oral administration of levocarnitine in patients with renal insufficiency have not been studied. Prolonged oral administration of high doses of levocarnitine to patients with severe renal insufficiency or end-stage renal disease undergoing hemodialysis may lead to accumulation in the blood of potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), as these metabolites are normally excreted by the kidneys. This phenomenon is not observed after intravenous administration of levocarnitine.

In very rare cases, an increase in the international normalized ratio (INR) has been reported with concomitant use of levocarnitine and coumarin derivatives (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Seizures have been reported in patients with a history of seizure activity; however, it is unclear whether levocarnitine increases the incidence and/or severity of seizures. If levocarnitine is suspected as the cause of seizures, discontinuation of treatment should be considered.

High doses and prolonged use of levocarnitine may cause diarrhea.

Use during pregnancy or breastfeeding

Pregnancy

In rabbits, at the highest dose studied (600 mg/kg body weight), a statistically non-significant increase in post-implantation fetal loss was observed in early pregnancy. The relevance of these findings to humans is unknown. There is no experience with the use of levocarnitine in pregnant women with primary systemic carnitine deficiency.

Considering the serious consequences of carnitine deficiency for the pregnant woman, the risk of interrupting treatment is considered greater than the theoretical risk to the fetus if treatment is continued.

Period of breastfeeding

Levocarnitine is a natural component of human milk. The use of levocarnitine supplements in breastfeeding mothers has not been studied. During breastfeeding, the medicinal product should be used only if the expected benefit to the mother outweighs the potential risk to the infant due to excessive carnitine exposure.

Fertility

No negative effects on fertility have been observed in clinical studies.

Ability to influence reaction rate while driving or operating machinery

Unknown.

Method of Administration and Dosage

The medicinal product should be administered intravenously slowly over 2–3 minutes.

Adults, Children, Infants, and Newborns

During therapy, it is advisable to monitor levels of carnitine and acylcarnitine both in blood plasma and urine.

Use in Inborn Metabolic Disorders

The required dose depends on the specific type of inborn metabolic disorder and the severity of disease manifestations.

In cases of acute decompensation, the recommended dose may be up to 100 mg/kg per day administered in 3–4 doses. Higher doses may be used if necessary, although this may increase the risk of adverse reactions, particularly diarrhea.

Secondary Carnitine Deficiency in Patients Undergoing Hemodialysis

Prior to initiating therapy with Licartin-N, plasma carnitine levels must be monitored.

Secondary carnitine deficiency is diagnosed when the ratio of acylcarnitine to free carnitine in plasma exceeds 0.4 and/or when the concentration of free carnitine is less than 20 µmol/L.

A dose of 20 mg/kg should be administered intravenously as a bolus at the end of each dialysis session (allowing up to 3 sessions per week). The overall response should be assessed by monitoring plasma levels of acylcarnitine and free carnitine, as well as evaluating the patient's clinical condition. Normalization of carnitine content in muscle tissue and cardiomyocytes occurs approximately 3 months after achieving normal plasma carnitine concentration. If carnitine administration is discontinued, its levels will inevitably begin to decrease again. The need for a repeated loading course of treatment is determined by periodic quantitative measurement of plasma carnitine levels at regular intervals and by monitoring the patient's condition.

Hemodialysis — Maintenance Therapy

After completing the loading phase of intravenous levocarnitine administration, maintain therapy with a daily oral dose of 1 g of the drug. On dialysis days, administer 1 g of the drug orally immediately after completion of each dialysis session.

Elderly Patients

There is no need to adjust the dosage for these patients. In clinical studies, the safety profile in elderly patients was similar to that in younger patients.

Children

The medicinal product can be used in pediatric practice, including in newborns and infants.

Overdose

There have been no reports of levocarnitine toxicity in cases of overdose. In the event of overdose, supportive therapy should be administered. High doses of the drug may cause diarrhea. Levocarnitine is readily removed from plasma by dialysis. Treatment: take measures to remove the drug from the gastrointestinal tract if ingested orally; provide symptomatic and supportive therapy.

No cases of life-threatening overdose have been reported.

Side effects

The adverse reactions are listed by organ systems.

The frequency of adverse reactions is classified as follows: 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), frequency not known (cannot be estimated from available data).

Nervous system disorders: uncommon — headache.

Vascular disorders: uncommon — arterial hypotension, arterial hypertension.

Gastrointestinal disorders: common — nausea, vomiting, diarrhea³, abdominal pain.

Skin and subcutaneous tissue disorders: uncommon — body odor; frequency not known — pruritus, rash.

Musculoskeletal and connective tissue disorders: uncommon — muscle spasms; frequency not known — muscle tension.

General disorders and administration site conditions: uncommon — abnormal sensations, pyrexia.

Investigations: uncommon — increased blood pressure; very rare — increased INR².

1 Seizures have been reported in patients with or without a history of seizure activity who received levocarnitine orally or intravenously (see section "Special precautions").

2 Very rare cases of increased international normalized ratio (INR) have been reported when levocarnitine was used concomitantly with coumarin derivatives (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

3 High doses and prolonged use of levocarnitine may cause diarrhea. Reducing the dose often reduces or eliminates gastrointestinal symptoms. With long-term oral administration of levocarnitine, body odor should be monitored (reducing the dose may reduce or eliminate drug-induced odor). Tolerance to the drug should be carefully monitored during the first week of treatment and after any dose increase.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 5 ml in an ampoule. 5 ampoules per pack.

Prescription status. Prescription only.

Manufacturer. LLC "FARMASEL".

Manufacturer's address and place of business.
Ukraine, 07408, Kyiv region, Brovary district, village Kvitneve, Prorizna Street, 3.