Metacartin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MЕТАКАRTIN (METACARTIN)

Composition:

Active substance: levocarnitine;

1 ampoule (5 ml) of injection solution contains levocarnitine 1 g;

1 ml of injection solution contains levocarnitine 200 mg;

Excipients: hydrochloric acid diluted, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

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 addition, carnitine regulates the transport of energy produced by mitochondria into the cytoplasm by modulating the enzyme adenine nucleotide translocase.

The highest concentrations of carnitine are observed in skeletal muscles and myocardium. The myocardium, despite its ability to use various substrates for energy production, typically utilizes fatty acids. Therefore, carnitine plays an important role in cardiac metabolism, as fatty acid oxidation strictly depends on the availability of sufficient amounts of this substance. Experimental studies have shown that under various stress conditions—acute ischemia, diphtheritic myocarditis—carnitine levels in myocardial tissue may decrease. Studies using various animal models have confirmed the beneficial effects of carnitine on different experimentally induced cardiac dysfunctions: acute and chronic ischemia, heart failure, cardiac insufficiency associated with diphtheritic myocarditis, and drug-induced cardiotoxicity (propranolol, adriamycin).

Levocarnitine has demonstrated therapeutic efficacy in the following conditions:

• Primary carnitine deficiency, characterized by phenotypes such as lipid-storage myopathy, hepatic encephalopathy of Reye-like syndrome, and/or progressive dilated cardiomyopathy.
• Secondary carnitine deficiency in patients with genetically determined organic acidurias (propionic acidemia, methylmalonic aciduria, isovaleric acidemia) and in patients with genetic defects of β-oxidation. In these situations, secondary deficiency manifests as accumulation of fatty acid esters. Endogenous levocarnitine actually acts as a "buffer" for various fatty acids that cannot be metabolized.
• Secondary carnitine deficiency in patients undergoing intermittent hemodialysis. The reduction of levocarnitine in muscle tissue positively correlates with its loss into the dialysate.

Muscle symptoms commonly observed in such patients after hemodialysis sessions improve with levocarnitine therapy.

Pharmacokinetics.

After intravenous administration, levocarnitine is primarily excreted by the kidneys. Metabolic transformation is negligible, except for the reversible conversion of levocarnitine into its esters.

Clinical characteristics.

Indications.

Primary and secondary carnitine deficiency.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Interactions between levocarnitine and coumarin agents cannot be excluded. In very rare cases, an increased international normalized ratio (INR) has been reported when levocarnitine is used concomitantly with coumarin agents (see sections "Special precautions for use" and "Adverse reactions"). When these medicinal products are used concomitantly, INR should be monitored, or other coagulation tests performed weekly until stabilization, and monthly thereafter (see section "Special precautions for use").

Concomitant use of levocarnitine with medicinal products that induce hypocarnitinemia by enhancing renal excretion of carnitine (e.g., valproic acid, pivampicillin-containing prodrugs, cephalosporins, cisplatin, carboplatin, ifosfamide) may reduce its levels.

Special precautions for use

Administration of levocarnitine to patients with diabetes mellitus who are receiving insulin or oral hypoglycemic agents may cause hypoglycemia (due to improved glucose uptake). In such patients, plasma glucose levels should be monitored regularly to allow appropriate adjustment of hypoglycemic therapy.

Intravenous administration of the drug should be performed slowly (over 2–3 minutes).

During treatment with the drug, monitoring of water-electrolyte balance is required.

Administration of levocarnitine to patients with a history of seizure activity may increase the frequency and/or severity of seizures. In patients with predisposing factors, levocarnitine may also trigger seizures.

The safety and efficacy of oral 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 on hemodialysis may lead to accumulation in blood of potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), as these metabolites are normally excreted by the kidneys. This situation does not occur following intravenous administration of levocarnitine.

Levocarnitine is a physiological substance; therefore, there is no risk of habituation or dependence.

In very rare cases, an increase in INR has been reported with concomitant use of levocarnitine and coumarin derivatives. When these drugs are used concomitantly, INR should be monitored, or other coagulation tests performed weekly until stabilization, and monthly thereafter (see sections "Interaction with other medicinal products and other forms of interactions" and "Side effects").

Use during pregnancy or breastfeeding

Pregnancy

No teratogenic effects were observed with levocarnitine in preclinical studies. At the highest studied dose of 600 mg/kg body weight in animals, a statistically non-significant increase in post-implantation fetal loss was observed in early pregnancy. The significance of these findings for humans is unknown.

Adequate clinical studies in pregnant women have not been conducted. During pregnancy, the drug should be used only if the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding period

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

Fertility

No negative effects on fertility were observed in clinical studies.

Ability to affect reaction speed when driving or operating machinery

The drug does not affect the ability to drive or operate machinery.

Dosage and Administration.

Secondary carnitine deficiency in patients undergoing hemodialysis.

The medicinal product should be administered intravenously slowly at a dose of 2 g at the end of each dialysis session.

A dosage of 2.5 g may be indicated for patients undergoing dialysis for more than 1 year.

Intravenous administration of the medicinal product should be performed slowly (over 2–3 minutes).

Special patient categories

Elderly patients

These patients do not require dosage adjustment or other precautions. In clinical studies, the safety profile in younger and elderly patients was similar.

Patients with diabetes mellitus

Administration of levocarnitine to patients with diabetes mellitus who are receiving insulin or oral hypoglycemic therapy may cause hypoglycemia (due to improved glucose utilization). In such patients, plasma glucose levels should be monitored closely to adjust the hypoglycemic therapy regimen (see section "Special precautions for use").

Children.

The medicinal product may be used in children.

Overdose.

Overdose or prolonged use of levocarnitine may lead to diarrhea. Levocarnitine is readily removed from blood plasma by dialysis.

Adverse Reactions

Adverse reactions (based on clinical trials, literature, and post-marketing experience) are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA) and classified by frequency 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 (frequency cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

From the nervous system:

uncommon – headache; frequency not known – convulsions¹, dizziness.

From the cardiac disorders:

frequency not known – palpitations.

From the vascular disorders:

uncommon – arterial hypotension, arterial hypertension.

From the respiratory system, thoracic and mediastinal disorders:

frequency not known – dyspnea.

From the gastrointestinal disorders:

common – nausea, vomiting, diarrhea, abdominal pain; uncommon – dysgeusia, dyspepsia, dry mouth.

From the skin and subcutaneous tissue disorders:

frequency not known – pruritus, rash.

From the musculoskeletal and connective tissue disorders:

uncommon – muscle spasms; frequency not known – myasthenia², muscle tension.

General disorders and administration site conditions:

uncommon – chest pain, abnormal sensations, pyrexia, injection site reactions.

Investigations:

uncommon – increased blood pressure; very rare – increased INR³.

¹ Convulsions have been reported in patients with or without seizure activity who received levocarnitine orally or intravenously. Levocarnitine administration may increase the frequency and/or severity of seizures. In patients with predisposing factors, levocarnitine may also trigger seizures.

² Mild symptoms of myasthenia have been reported in patients with uremia.

³ Very rare cases of increased INR have been reported in patients receiving concomitant therapy with coumarin derivatives (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is very important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system.

Shelf life.

4 years.

Storage conditions.

Store at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities.

Do not mix with other medicinal products.

Packaging.

5 mL in brown glass ampoule; 5 ampoules in a blister pack; 1 or 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLID MEDITSIN ILAT SAN. VE TIDJ. A.SH./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

OPZCH, G.O. Pasha district, 6th street, No:30, Cerkezkoj/Tekirdag, Turkey /
COSB G.O. Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.

Marketing Authorization Holder.

LLC "UORLID MEDITSIN", Ukraine /
WORLD MEDICINE, LLC, Ukraine.