CARDONAT L-CARNITINE

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDONAT L-CARNITINE (CARDONAT L-CARNITINE)

Composition:

active substance: levocarnitine;

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

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 through modulation of the adenine nucleotide translocase enzyme.

The highest concentrations of carnitine are observed in skeletal muscles and myocardium. Despite its ability to use various substrates for energy production, the myocardium 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, and diphtheritic myocarditis, a decrease in carnitine levels in myocardial tissue may occur. Studies using various animal models have confirmed the beneficial effects of carnitine on different experimentally induced cardiac functional 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 of Reye-like syndrome, and/or progressive dilated cardiomyopathy;
• Secondary carnitine deficiency in patients with genetically determined organic acidurias (e.g., 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 acts as a "buffer" for various fatty acids that cannot be metabolized;
• Secondary carnitine deficiency in patients undergoing intermittent hemodialysis. Decreased levocarnitine levels in muscles positively correlate with its loss into the dialysate.

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

Pharmacokinetics

Following 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 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. There have been very rare reports of increased international normalized ratio (INR) with concomitant use of levocarnitine and coumarin agents (see sections "Special precautions for use" and "Adverse reactions"). Patients receiving concomitant therapy with anticoagulants and the medicinal product CARDONAT L-CARNITINE should be monitored for INR or other coagulation tests weekly until parameters stabilize, and monthly thereafter (see section "Special precautions for use").

Concomitant administration of levocarnitine with medicinal products that induce hypocarnitinemia by enhancing renal excretion of carnitine (e.g., valproic acid, pivampicillin-containing preparations, cephalosporins, cisplatin, carboplatin, and 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 uptake may lead to hypoglycemia. Therefore, in such patients, regular monitoring of plasma glucose levels is required to allow timely adjustment of hypoglycemic therapy.

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

During administration of the medicinal product, monitoring of water-electrolyte balance is necessary.

The use of levocarnitine in patients with a history of seizure activity may increase the frequency and/or severity of seizures. In patients with predisposing factors, levocarnitine administration 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 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, the risk of habituation or dependence is absent.

Very rare cases of increased INR have been reported with concomitant use of levocarnitine and coumarin derivatives. Patients receiving concomitant anticoagulant therapy and the medicinal product CARDONAT L-CARNITINE should be monitored for INR or other coagulation tests weekly until parameters stabilize, and monthly thereafter (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Use during pregnancy or breastfeeding

Pregnancy

Reproductive function studies were conducted in rats and rabbits. No signs of teratogenic effects were observed in either species. In rabbits, unlike rats, a statistically non-significant increase in post-implantation fetal loss was observed at the maximum studied dose (600 mg/kg per day) compared to the control group. The significance of these findings for humans is unknown. Adequate clinical studies in pregnant women have not been conducted.

During pregnancy, the medicinal product CARDONAT L-CARNITINE 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 in breastfeeding mothers has not been studied.

During breastfeeding, the medicinal product CARDONAT L-CARNITINE should be used only if the expected benefit to the woman outweighs the potential risk to the infant due to excessive carnitine exposure.

Fertility

During clinical fertility studies, positive effects were observed and no safety-related risks were identified.

Ability to influence reaction speed when driving or operating machinery

The medicinal product 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 at a dose of 2 g slowly at the end of the dialysis session.

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

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

Special Patient Populations

Elderly Patients

No dosage adjustment or other precautions are required for elderly patients receiving CARDONAT L-CARNITINE. In clinical studies, the safety profile was similar in younger and elderly patients.

Diabetic Patients

Administration of levocarnitine to patients with diabetes mellitus who are receiving insulin or oral hypoglycemic agents that enhance glucose uptake may lead to hypoglycemia. Therefore, plasma glucose levels should be monitored regularly in these patients to allow timely adjustment of hypoglycemic therapy (see section "Special Warnings and Precautions for Use").

Children

There are no data available on the use of this medicinal product in children.

Overdose

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

Side effects

The side effects (based on clinical trial data, literature, and post-marketing experience) are listed by organ system classes according to the Medical Dictionary for Regulatory Activities (MedDRA). Adverse reactions within each organ system class are categorized by frequency. Within each frequency group, adverse reactions are listed in order of decreasing severity.

The following adverse reactions are classified as follows: 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 (frequency cannot be estimated from available data).

Nervous system disorders: 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: frequency not known – pruritus, rash.

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 international normalized ratio (INR)³.

1 Convulsions have been reported in patients with or without a history of seizure activity who received oral or intravenous levocarnitine. Levocarnitine administration may increase the frequency and/or severity of seizures. In patients with predisposing factors, levocarnitine use 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 levocarnitine and coumarin derivatives (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicine is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via 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

5 ampoules in a blister pack; 1 or 2 blister packs in a cardboard box.

Incompatibilities

Incompatibility of levocarnitine with other medicinal products is not known.

Prescription status. Prescription only.

Manufacturer

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

Manufacturer's address

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.

Marketing Authorization Holder

SPERCO INTERNATIONAL LIMITED, Cyprus.

Address of the Marketing Authorization Holder

Spyrou Kyprianou, 57 BYBLOSERVE BUSINESS CENTER, 2nd Floor, 6051, Larnaca, Cyprus.