Carnelius

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARNE LIUS (CARNELIUS)

Composition:

Active substance: levocarnitine;

1 ml of solution contains levocarnitine 200 mg;

Excipients: hydrochloric acid 10%, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear colorless or slightly yellowish solution, practically free from particles.

Pharmacotherapeutic group. Amino acids and their derivatives. Levocarnitine.

ATC code A16AA01.

Pharmacological Properties

Pharmacodynamics

Levocarnitine is a naturally occurring substance essential for energy metabolism in mammals. It has been demonstrated that this substance facilitates the transport of long-chain fatty acids into cellular mitochondria, thereby providing substrate for oxidation and subsequent energy production. Fatty acids are used as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the primary substrate for energy production. Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in blood plasma, erythrocytes, and/or tissues. It has not been possible to determine which symptoms are related to carnitine deficiency and which are due to the underlying organic acidemia, since levocarnitine administration may exacerbate symptoms of both conditions. According to published data, carnitine is capable of promoting the elimination of excess organic or fatty acids in patients with fatty acid metabolism disorders and/or specific organic acidopathies that lead to the biocumulation of acyl-CoA esters. Secondary carnitine deficiency may result from inborn errors of metabolism or iatrogenic factors such as hemodialysis. Levocarnitine may alleviate metabolic disturbances in patients with congenital defects leading to the accumulation of toxic organic acids. This effect has been demonstrated in conditions such as glutaric aciduria type II, methylmalonic aciduria, propionic acidemia, and medium-chain acyl-CoA dehydrogenase deficiency. In such patients, auto-intoxication occurs due to the accumulation of acyl-CoA compounds, which disrupt intermediary metabolism. Subsequent hydrolysis of acyl-CoA to its free acid leads to acidosis, which may be life-threatening. Levocarnitine eliminates acyl-CoA by forming acylcarnitine, which is rapidly excreted from the body. Carnitine deficiency is biochemically defined as abnormally low levels of free carnitine in plasma (<20 μmol/L one week after birth) and may be associated with low tissue and/or urinary concentrations. Additionally, this condition may be associated with an increased plasma acylcarnitine/levocarnitine ratio (>0.4) or abnormally elevated urinary acylcarnitine levels. In preterm infants and newborns, secondary deficiency is defined by plasma levocarnitine concentrations below age-specific normal values. In patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis, low plasma carnitine concentrations and elevated acylcarnitine/carnitine ratios may occur. This may be due to reduced intake of meat and dairy products, impaired synthesis in the kidneys, and losses via dialysate. Some clinical symptoms commonly observed in hemodialysis patients—such as malaise, muscle weakness, cardiomyopathy, and cardiac arrhythmias—may be associated with impaired carnitine metabolism. Studies using levocarnitine have demonstrated that its administration to ESRD patients on hemodialysis leads to increased plasma levocarnitine concentrations.

Pharmacokinetics

Plasma concentration profiles of levocarnitine following a slow 3-minute intravenous bolus injection of a 20 mg/kg dose are described by a two-compartment model. After a single intravenous dose, approximately 76% of the administered levocarnitine dose was excreted in urine within the first 24 hours. Based on plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half-life was 0.585 hours, and the mean apparent terminal elimination half-life was 17.4 hours. Total clearance of levocarnitine (dose / area under the plasma concentration-time curve (AUC), adjusted for endogenous background concentrations) averaged 4 L/h. Levocarnitine did not bind to plasma proteins or albumin in studies, regardless of concentration or species, including humans. Although the efficacy of the drug in increasing carnitine concentrations in dialysis patients with ESRD has been established, the impact of additional carnitine supplementation on signs and symptoms of carnitine deficiency and on clinical outcomes in this population remains uncertain.

Clinical characteristics

Indications

For emergency and long-term treatment of patients with an inborn metabolic disorder leading to secondary carnitine deficiency.

For prevention and treatment of carnitine deficiency in patients with end-stage renal disease undergoing dialysis.

Contraindications. Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interactions

Concomitant use of glucocorticoids leads to accumulation of levocarnitine in body tissues (except liver). Other anabolic agents enhance the effect of the medicinal product. In patients who received levocarnitine concomitantly with coumarin-derived anticoagulants (see sections "Special precautions for use" and "Side effects"), very rare cases of increased international normalized ratio (INR) have been observed. When levocarnitine is used concomitantly with such anticoagulants, INR or another appropriate coagulation test should be monitored weekly until values become stable, and monthly thereafter.

Special precautions for use

Hypersensitivity reactions. Serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm, have been reported following administration of the drug, predominantly in patients with end-stage renal disease on dialysis. Some reactions occurred within minutes after intravenous administration of the drug. If a serious hypersensitivity reaction occurs, administration of the drug must be discontinued immediately and appropriate treatment initiated. When considering re-administration of the drug, the risks and benefits should be carefully evaluated for each individual patient who previously experienced a severe hypersensitivity reaction. If the decision is made to re-administer the drug, patients should be closely monitored for recurrence of signs and symptoms of severe hypersensitivity reactions.

The safety and efficacy of oral levocarnitine have been evaluated in patients with renal insufficiency. Long-term administration of high oral doses of levocarnitine to patients with severe renal impairment or to patients with end-stage renal disease on dialysis may lead to accumulation of potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), as these metabolites are normally excreted in urine.

Levocarnitine enhances glucose uptake, and therefore administration of the drug to patients with diabetes mellitus receiving antidiabetic medications may result in hypoglycemia. Plasma glucose levels should be monitored regularly in such patients to allow timely adjustment of therapy.

Very rare cases of increased INR have been observed in patients who were concurrently taking levocarnitine and coumarin-derived anticoagulants (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Use during pregnancy or breastfeeding

Pregnancy. Reproductive studies in rats and rabbits administered levocarnitine at doses 3.8 times the human dose on a body surface area basis revealed no evidence of impaired fertility or embryotoxic effects. Since animal reproductive studies do not always predict effects in humans, the drug should be used during pregnancy only if clearly needed. However, adequate and well-controlled studies in pregnant women have not been conducted.
Lactation. Specific studies on the use of levocarnitine in women during breastfeeding have not been conducted. Levocarnitine is a normal component of human breast milk. Considering the serious consequences of carnitine deficiency for the pregnant woman, the risk of discontinuing levocarnitine therapy for the mother is considered greater than the theoretical risk to the fetus with continued treatment.

Ability to affect reaction rate when driving or operating machinery.

It is unknown whether the medicinal product affects the ability to drive or operate machinery.

Administration and Dosage

The medicinal product should be administered intravenously slowly over 2–3 minutes.

Parenteral preparations should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. Metabolic Disorders

The recommended dose is 50 mg/kg administered as a slow bolus injection over 2–3 minutes or by infusion. Patients with severe metabolic crisis usually require a loading dose followed by an equivalent total dose administered over the subsequent 24 hours. The medicinal product should be administered by infusion or intravenous injection every 3 or 4 hours, and in no case should the interval exceed 6 hours. It is recommended that all subsequent daily doses remain at 50 mg/kg or adjusted according to therapeutic requirements. The maximum recommended dose is 300 mg/kg.

It is advisable to determine plasma carnitine concentration prior to initiating this parenteral therapy. Weekly and monthly monitoring is also recommended. This monitoring should include biochemical blood analysis, vital signs, plasma carnitine concentrations (free carnitine plasma levels should range between 35 and 60 µmol/L), and overall clinical status. Dosing should be individualized based on the specific inherited metabolic disorder and severity of symptoms during treatment. In cases of acute decompensation, recommended doses may be increased up to 100 mg/kg/day, divided into 3–4 doses. Higher doses have been used, although an increased risk of adverse reactions, particularly diarrhea, may occur.

Patients with ESRD on Hemodialysis

The recommended initial dose is 10–20 mg/kg body weight administered as a slow 2–3 minute bolus injection into the venous blood circuit after each dialysis session. Therapy may be initiated if minimum plasma levocarnitine concentrations (pre-dialysis) are below normal (40–50 µmol/L). Dose adjustments should be based on pre-dialysis levocarnitine plasma levels. Dose reduction (e.g., to 5 mg/kg post-dialysis) may be considered starting at the third or fourth week of therapy.

Compatibility and Stability. Levocarnitine is compatible and stable when mixed with parenteral solutions such as 0.9% sodium chloride solution or Ringer's lactate solution, at concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500 mL (8 mg/mL).

Children. The medicinal product can be used in children from the first day of life.

Overdose

Symptoms.

There are no confirmed reports of levocarnitine toxicity in overdose. High doses of levocarnitine may cause diarrhea.

Treatment.

If administered orally, measures should be taken to remove the drug from the gastrointestinal tract. Provide symptomatic and supportive treatment. Levocarnitine is readily removed from plasma by dialysis. To date, no life-threatening cases of overdose have been reported.

Adverse Reactions

The adverse reactions are listed by organ systems.

All the adverse reactions listed below occur very rarely (< 1/10000).

Gastrointestinal disorders: Various mild gastrointestinal disturbances have been observed during prolonged oral administration of levocarnitine, including transient nausea and vomiting, abdominal pain, and diarrhea. A specific body odor has also been reported in patients. Reducing the dose often reduces or eliminates gastrointestinal symptoms and the specific body odor.

Blood and lymphatic system disorders: In very rare cases, an increase in INR (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use") has been observed in patients.

Nervous system disorders: Seizures have occurred in patients both with and without a history of seizure activity following administration of levocarnitine, either orally or intravenously. In patients with a history of seizure activity, an increase in frequency and/or severity of seizures has been reported.

Immune system disorders: Serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm, have been reported following administration of levocarnitine, primarily in patients with end-stage renal disease on dialysis. Some reactions occurred within minutes after intravenous administration of levocarnitine. If a severe hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate medical treatment initiated. For patients who have experienced a severe hypersensitivity reaction to levocarnitine, the risks and benefits of re-administration should be individually assessed. If re-administration is considered, patients should be monitored closely for signs and symptoms of hypersensitivity. Tolerance should be carefully monitored during the first week of treatment and after any dose increase. Intravenous administration of levocarnitine is generally well tolerated.

General disorders and administration site conditions: Specific body odor.

Laboratory findings: Increased international normalized ratio (INR). Mild myasthenia has been reported in patients with uremia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Incompatibilities. The medicinal product should only be mixed with solutions specified in the section "Method of administration and dosage".

Packaging. 5 ml in a vial, 5 vials in a blister pack in a carton.

Prescription category. Prescription only.

Manufacturer. HELP S.A.

Manufacturer's address and place of business. Pefkini Ioanninon, Ioannina, 45500, Greece