Cardonat l-carnitine

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

Composition:

Active substance: levocarnitine;

1 ml of solution contains levocarnitine 200 mg;

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

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear liquid with a characteristic odor.

Pharmacotherapeutic group.

Amino acids and their derivatives. 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. Although the myocardium has the ability to use various substrates for energy production, it typically utilizes fatty acids. Therefore, carnitine plays an important role in cardiac metabolism, since fatty acid oxidation is strictly dependent on the availability of sufficient amounts of the substance. Experimental studies have shown that reduced levels of carnitine in myocardial tissue 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 functional impairments: acute and chronic ischemia, heart failure, heart failure associated with diphtheritic myocarditis, and drug-induced cardiotoxicity (propranolol, adriamycin).

Levocarnitine has demonstrated therapeutic efficacy in the following pathologies:

• Primary carnitine deficiency, characterized by phenotypes such as lipid storage myopathy, hepatic encephalopathy of Reye syndrome type, and/or progressive dilated cardiomyopathy.
• Secondary carnitine deficiency in patients with organic acidurias of genetic origin (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. In fact, endogenous levocarnitine 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 muscles positively correlates with its loss into dialysate fluid.

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

Pharmacokinetics

Following oral administration, levocarnitine undergoes degradation by intestinal bacteria, resulting in the formation of trimethylamine (TMA) and γ-butyrobetaine. Since the amount of levocarnitine entering systemic circulation in unchanged form is approximately 10–20%, it is considered that intestinal metabolism is responsible for the elimination of about 80–90% of the oral dose.

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

Prolonged 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 (congenital) carnitine deficiency.

Secondary carnitine deficiency.

Contraindications.

Hypersensitivity to the components of the drug.

Interaction with other medicinal products and other forms of interactions.

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", "Adverse reactions"). When these agents are used concomitantly, monitoring of INR or other coagulation tests should be performed weekly until stabilization, and monthly thereafter (see section "Special precautions").

Concomitant use of levocarnitine with agents that induce hypocarnitinemia by enhancing renal excretion of carnitine (e.g., valproic acid, pivonate-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 lead to hypoglycemia. In such patients, plasma glucose levels should be monitored regularly to allow timely adjustment of the hypoglycemic therapy regimen.

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 in patients with severe renal insufficiency or end-stage renal disease on hemodialysis may result in the accumulation 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 following intravenous administration of levocarnitine.

Levocarnitine is a physiological substance; therefore, the risk of dependence or addiction is absent.

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

This medicinal product contains 39.23 mmol (or 0.8984 mg)/ml of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

No teratogenic effects of levocarnitine were observed 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 clinical relevance of these findings to humans is unknown.

Adequate clinical studies in pregnant women have not been conducted. During pregnancy, this 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 benefit to the mother outweighs the potential risk to the infant due to excessive carnitine exposure.

Fertility

No negative effects on fertility were observed in clinical studies.

Ability to affect reaction speed when driving or operating machinery.

No effect.

Administration and Dosage

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. A dosing syringe or measuring cup should be used for accurate dosing.

During treatment with this medicinal product, it is advisable to monitor free carnitine and acylcarnitine 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 congenital metabolic disorder and the severity of the patient's condition during treatment.

Generally, the recommended oral dose ranges from 100 to 200 mg/kg per day, administered in 2–4 divided doses. In milder cases, a lower dose (50–100 mg/kg per day) may be sufficient.

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

Higher doses (up to 400 mg/kg/day) or intravenous administration of levocarnitine at a daily dose of 100 mg/kg may be required during acute metabolic disturbances.

Secondary Carnitine Deficiency in Patients Undergoing Hemodialysis

If significant clinical improvement has been achieved after the initial course of intravenous administration, maintenance therapy may be continued orally at a dose of 1 g per day. On dialysis days, the medicinal product should be taken orally after the dialysis procedure.

The maximum daily dose for adults is 6 g (30 mL).

Children

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

Table

The maximum daily dose for children is 3 g (15 ml).

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

Special patient categories

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 the accumulation of potentially toxic metabolites TMA and TMAO (see section "Special instructions").

Elderly patients

There is no need for dosage adjustment or additional precautions in these 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 lead to hypoglycemia. In such patients, plasma glucose levels should be monitored continuously to allow timely adjustment of hypoglycemic therapy (see section "Special instructions").

Children

CARDONAT L-CARNITINE can be administered to children (full-term and preterm newborns) from the first day of life.

Overdose

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

Adverse reactions.

Adverse reactions (based on clinical trial data, literature, and post-marketing experience) are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA) and are classified by the following frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <100), rare (≥1/10,000, <1,000), very rare (<1/10,000), frequency not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing severity.

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

2 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 air, and sweat (see section "Pharmacological properties. Pharmacokinetics").

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 precautions for use").

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions following drug registration is extremely 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. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

60 mL or 100 mL in a polyethylene terephthalate container or 100 mL in a glass container, closed with a tamper-evident cap.

60 mL container with dosing syringe or 100 mL container with dosing spoon and dosing syringe, packed in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

Ukrainian-Spanish joint venture "Sperco Ukraine".

Manufacturer's address and location of business activity.

21027, Ukraine, Vinnytsia, 600-Richchia St., 25.

Tel.: + 38(0432)52-30-36. E-mail: [email protected]

www.sperco.ua