Metacartin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METACARTIN (METACARTIN)

Composition:

Active substance: levocarnitine;

1 vial (10 ml) of the medicinal product contains 1 g of levocarnitine;

Excipients: malic acid, sodium benzoate (E 211), sodium saccharin, orange flavoring, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colorless or slightly yellow 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 reduced levels of carnitine in myocardial tissues may occur under various stress conditions, acute ischemia, and diphtheritic myocarditis. Studies using various animal models have confirmed the beneficial effects of carnitine on different artificially induced cardiac function impairments: acute and chronic ischemia, heart failure, heart failure associated with diphtheritic myocarditis, and drug-induced cardiotoxicity (e.g., propranolol, adriamycin).

Levocarnitine has demonstrated therapeutic efficacy in the following conditions:

• Primary carnitine deficiency, characterized by phenotypes such as lipid-storage myopathy, hepatic encephalopathy resembling Reye’s 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 effectively acts as a buffer for various fatty acids that cannot be metabolized;
• Secondary carnitine deficiency in patients undergoing intermittent hemodialysis. Reduced muscle levels of levocarnitine positively correlate with its loss into dialysate fluid.

Muscular symptoms commonly observed in these patients after hemodialysis sessions improve with levocarnitine therapy.

Pharmacokinetics.

Following oral administration, levocarnitine undergoes degradation by intestinal bacteria, leading to the formation of trimethylamine (TMA) and γ-butyrobetaine. Since only about 10–20% of the administered dose reaches systemic circulation unchanged, intestinal metabolism is considered responsible for the elimination of approximately 80–90% of the oral dose.

Following absorption, γ-butyrobetaine is excreted unchanged in urine, whereas TMA is metabolized to trimethylamine-N-oxide (TMAO), which is found in urine along with a small amount of unchanged TMA.

Long-term oral administration of levocarnitine to patients with severe renal insufficiency or to patients undergoing hemodialysis may lead to accumulation of TMA and TMAO in blood plasma and, consequently, may cause trimethylaminuria—a pathological condition characterized by a strong fish-like odor of urine, exhaled breath, and sweat in patients.

Clinical characteristics.

Indications.

Primary and secondary carnitine deficiency.

Contraindications.

Hypersensitivity to the active substance 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 derivatives cannot be excluded. In very rare cases, an increased international normalized ratio (INR) has been reported when levocarnitine is used concomitantly with coumarin derivatives (see sections "Special instructions", "Adverse reactions"). When these agents are used concomitantly, INR monitoring or other coagulation tests should be performed weekly until stabilization, and monthly thereafter (see section "Special instructions").

Concomitant use of levocarnitine with agents 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

The use of levocarnitine in patients with diabetes mellitus who are receiving insulin or oral hypoglycemic agents that enhance glucose utilization may cause hypoglycemia. In such patients, plasma glucose levels should be monitored regularly to allow timely adjustment of hypoglycemic therapy.

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

The safety and efficacy of oral levocarnitine in patients with renal insufficiency have not been studied. Long-term oral administration of high doses of levocarnitine in 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 is not observed after intravenous administration of levocarnitine.

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

Very rarely, increased INR has been reported with concomitant use of levocarnitine and coumarin derivatives (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions"). When these agents are used concomitantly, INR monitoring or other coagulation tests should be performed weekly until stabilization, and monthly thereafter.

Use during pregnancy or breastfeeding

Pregnancy

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

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

Breastfeeding period

Levocarnitine is a normal component of human milk. The use of levocarnitine 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 exposure to carnitine.

Fertility

Clinical studies have not shown any negative effect on fertility.

Ability to influence reaction rate while driving or operating machinery

Levocarnitine does not affect the ability to drive or operate machinery.

Dosage and Administration

Route of Administration

The medicinal product is intended for oral use. Before administration, the solution should be diluted in a glass of water and taken 30 minutes before meals. For accurate dosing, use the provided dosing syringe or measuring cup.

During treatment, it is advisable to monitor free carnitine and acyl-carnitine levels both in blood plasma and urine.

Dosage

The dosage and duration of levocarnitine treatment are determined individually by a physician based on the patient's age, body weight, and the specific nosological form of the disease.

Adults

Primary and Secondary Carnitine Deficiency

Dosage depends on the specific inherited metabolic disorder and the severity of the patient's condition at the time of treatment.

Generally, the recommended oral dose ranges from 100 to 200 mg/kg/day, administered in 2–4 divided doses. For less severe conditions, a lower dose (50–100 mg/kg/day) may be sufficient.

If clinical and biochemical parameters do not improve, the dose may be temporarily increased.

In acute metabolic decompensation, higher doses (up to 400 mg/kg/day) or intravenous administration of levocarnitine at a daily dose of 100 mg/kg may be required.

Secondary Carnitine Deficiency in Patients Undergoing Hemodialysis

If significant clinical improvement is achieved after an initial course of intravenous levocarnitine, maintenance therapy may be administered orally at a dose of 1 g per day. On dialysis days, the oral dose should be taken after the dialysis procedure.

The maximum daily dose for adults is 6 g (60 mL).

The average treatment course for adults and children lasts 1–3 months. If necessary, the course may be repeated. In cases of primary and secondary carnitine deficiency, the medicinal product should be administered continuously or until the underlying cause is resolved.

Children

The medicinal product may be administered to children from the first day of life, including preterm infants. Treatment should begin with a dose of 50 mg/kg/day. The usual pediatric dose is 50–100 mg/kg/day (see table).

The maximum daily dose for children is 3 g (30 ml).

Special patient groups

Patients with renal impairment

The medicinal product should not be used for prolonged periods at high doses in patients with severe renal function impairment due to accumulation of potentially toxic metabolites TMA and TMAO (see section "Special precautions for use").

Elderly patients

No dosage adjustment or additional precautions are required for elderly patients. In clinical studies, the safety profile was similar in younger and elderly patients.

Patients with diabetes mellitus

Administration of levocarnitine to patients with diabetes mellitus who are receiving insulin or oral hypoglycemic agents that enhance glucose utilization may cause hypoglycemia. In such patients, plasma glucose levels should be monitored regularly to allow timely adjustment of hypoglycemic therapy (see section "Special precautions for use").

Children

The medicinal product can be administered to children from the first day of life.

Overdose

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

Adverse Reactions

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

Central and peripheral nervous system:

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

Cardiac disorders:

Frequency not known – palpitations.

Vascular disorders:

Uncommon – arterial hypotension, arterial hypertension.

Respiratory, thoracic and mediastinal disorders:

Frequency not known – dyspnea.

Gastrointestinal disorders:

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

Skin and subcutaneous tissue disorders:

Uncommon – abnormal body odor²; frequency not known – pruritus, rash.

Musculoskeletal and connective tissue disorders:

Uncommon – muscle spasms; frequency not known – myasthenia³, muscle tension.

General disorders and administration site conditions:

Uncommon – chest pain, abnormal sensations, pyrexia.

Investigations:

Uncommon – increased blood pressure; very rare – increased INR⁴.

¹ Seizures have been reported in patients with or without a history of 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 Long-term oral administration of levocarnitine to patients with severe renal insufficiency or patients undergoing hemodialysis may lead to accumulation of TMA and TMAO in blood plasma, resulting in trimethylaminuria—a pathological condition characterized by a strong fish-like odor of urine, exhaled air, and sweat (see section "Pharmacological properties. Pharmacodynamics").

³ Mild symptoms of myasthenia have been reported in patients with uremia.

⁴ 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", "Special warnings and precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

4 years.

Storage conditions

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging

10 ml in vials; 10 vials in a cardboard box.

Prescription status

Over-the-counter (without prescription).

Manufacturer

WORLD MEDICINE ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar / Istanbul, Turkey.

Marketing Authorization Holder

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.