Cartan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARTAN (CARTAN)

Composition:

Active substance: levocarnitine;

1 ml of solution contains levocarnitine 200 mg;

Excipients: diluted hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: transparent solution, colorless to light yellow.

Pharmacotherapeutic group. Amino acids and their derivatives. Levocarnitine.

ATC code A16AA01.

Pharmacological Properties.

Pharmacodynamics.

Levocarnitine is a naturally occurring component in animal tissues, microorganisms, and plants. In humans, physiological requirements for carnitine are met through dietary intake of carnitine-containing foods (primarily meat products) and by endogenous synthesis in the liver from trimethyllysine. Only the L-isomer is biologically active. Levocarnitine plays an essential role in lipid metabolism as well as in the metabolism of ketone bodies. 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 also enhances carbohydrate oxidation in the Krebs tricarboxylic acid cycle, stimulates the activity of the key glycolysis enzyme pyruvate dehydrogenase, and promotes oxidation of branched-chain amino acids in skeletal muscles. Thus, levocarnitine directly or indirectly participates in most energy-producing processes, and its presence is essential for the oxidation of fatty acids, amino acids, carbohydrates, and ketone bodies.

Pharmacokinetics.

Absorption

Levocarnitine is absorbed by the epithelial cells 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 rate of excretion is directly proportional to the concentration of carnitine in the blood.

Metabolism

Levocarnitine is practically 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 deficiency leading to significant negative impact on quality of life;
• muscle weakness and/or myopathy;
• cardiomyopathy;
• uremic anemia unresponsive to erythropoietin treatment or requiring high doses of erythropoietin;
• loss of muscle mass due to malnutrition.

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.

Concomitant use of glucocorticoids leads to accumulation of levocarnitine in body tissues (except the liver). Other anabolic agents enhance the effect of the drug. There have been very rare reports of increased international normalized ratio (INR) in patients who concurrently received levocarnitine and coumarin derivatives (see sections "Special precautions" and "Adverse reactions"). INR or another appropriate coagulation test should be monitored weekly until stabilized, and thereafter monthly in patients taking such anticoagulants together with levocarnitine.

Special precautions for use.

Levocarnitine improves glucose uptake; therefore, administration of the medicinal product Cartan to patients with diabetes mellitus who are receiving antidiabetic medications 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 levocarnitine have not been evaluated in patients with renal insufficiency. Administration of high oral doses of levocarnitine to patients with severely impaired renal function or to patients with end-stage renal disease may lead to accumulation of potentially toxic metabolites, trimethylamine and trimethylamine-N-oxide, since these metabolites are normally excreted in urine. This situation has not been observed following intravenous administration of levocarnitine.

There are very rare reports of increased INR in patients who received levocarnitine concomitantly with coumarin derivatives (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Use during pregnancy or breastfeeding.

No teratogenic effects were observed during preclinical studies of the drug. When the highest tested dose of 600 mg/kg body weight was administered to 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. There is no experience with the use of the medicinal product in pregnant patients with primary systemic carnitine deficiency.

Considering the serious consequences of carnitine deficiency in a pregnant woman, the risk of discontinuing Cartan treatment for the mother is considered greater than the theoretical risk to the fetus if treatment is continued.

Levocarnitine is a normal component of human breast milk. The use of levocarnitine supplements in breastfeeding mothers has not been studied.

Ability to affect the speed of reactions while driving or operating machinery.

Unknown.

Administration and Dosage

The drug is administered intravenously slowly over 2–3 minutes.

Adults, Children, Infants, and Newborns

Therapy should preferably be monitored by measuring free and acylcarnitine levels both in blood plasma and urine.

Use in Congenital Metabolic Disorders

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

In 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 treatment with Cartan, plasma carnitine levels must be monitored.

Secondary carnitine deficiency is diagnosed when the ratio of acylcarnitine to free carnitine in blood 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 by evaluating the patient's clinical condition. Normalization of carnitine content in muscle tissue and cardiomyocytes typically occurs approximately 3 months after achieving normal plasma carnitine concentrations. If carnitine administration is discontinued, its levels will inevitably begin to decrease again. The need for a subsequent repletion course should be determined by periodic quantitative assessment of plasma carnitine levels and clinical monitoring of the patient.

Hemodialysis – Maintenance Therapy

After the intravenous loading dose of levocarnitine, maintenance therapy consists of 1 g of the drug per day administered orally. On dialysis days, Cartan should be administered intravenously at a dose of 1 g immediately after completion of the dialysis session.

Children

The drug is used in children (see section "Administration and Dosage").

Overdose

There have been no reports of levocarnitine toxicity in cases of overdose. 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; administer symptomatic and supportive therapy. No life-threatening cases of overdose have been reported.

Adverse reactions.

Adverse reactions from any source are listed in the table below classified by organ class according to the MedRA system. Adverse reactions within each organ class are categorized by frequency. Within each frequency group, adverse reactions are listed in order of decreasing severity. In addition, the corresponding frequency category for each adverse drug reaction is based on the following conventions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000).

* There have been very rare reports of increased INR in patients concurrently receiving levocarnitine and coumarin derivatives (acenocoumarol and warfarin) – see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction".

Shelf life. 3 years.

Storage conditions.

Store in a place protected from light and inaccessible to children, at a temperature not exceeding 25 °C, in the original packaging.

Packaging.

5 ml in an ampoule. 5 ampoules in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. DEMO SA Pharmaceutical Industry.

Manufacturer's address and place of business.

21st km National Road Athens – Lamia, Krioneri Attiki, 145 68, Greece /
21st km National Road Athens - Lamia, Krioneri Attiki, 14568, Greece.