Levocarnitine

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

Composition:

Active substance: levocarnitine;

1 ampoule (5 ml) of solution contains levocarnitine, calculated as the anhydrous substance — 1000 mg;

Excipients: water for injections, concentrated hydrochloric acid.

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 A16A A01.

Pharmacological Properties

Pharmacodynamics

Levocarnitine is a naturally occurring substance essential for energy metabolism in mammals. It has been demonstrated that this substance facilitates the entry of long-chain fatty acids into cellular mitochondria, thereby delivering 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 specifically to carnitine deficiency and which are due to the underlying organic acidemia, since administration of levocarnitine may exacerbate symptoms of both conditions. According to literature data, carnitine is capable of promoting the elimination of excess organic or fatty acids in patients with disorders of fatty acid metabolism and/or specific organic acidopathies that bioaccumulate 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 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 these patients, auto-intoxication occurs due to accumulation of acyl-CoA compounds, which disrupt intermediary metabolism. Subsequent hydrolysis of acyl-CoA to its free acid leads to acidosis, which can be life-threatening. Levocarnitine promotes the elimination of acyl-CoA by forming acylcarnitine, which is rapidly excreted from the body. Carnitine deficiency is defined biochemically as abnormally low levels of free carnitine in plasma—less than 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 (greater than 0.4) or abnormally elevated urinary acylcarnitine concentration. In preterm infants and newborns, secondary deficiency is defined by plasma levocarnitine concentrations below age-specific normal reference ranges.

In patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis, low plasma carnitine concentrations and elevated acylcarnitine/carnitine ratios may occur due to reduced intake of meat and dairy products, impaired synthesis in the kidneys, and loss into dialysate fluid. Some clinical symptoms commonly observed in hemodialysis patients—such as malaise, muscle weakness, cardiomyopathy, and cardiac arrhythmias—may be related to impaired carnitine metabolism.

Studies using levocarnitine have shown 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 administration of a 20 mg/kg dose of levocarnitine are described by a two-compartment model. After a single intravenous dose, approximately 76% of the administered dose was excreted in urine within 0–24 hours. Using 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), including endogenous background concentrations) averaged 4.00 L/hour.

Levocarnitine was not bound to plasma proteins or albumin in studies conducted at any concentrations or in any species, including humans.

Although the efficacy of the medicinal product in increasing carnitine concentrations in dialysis patients with ESRD has been demonstrated, the effect of supplemental carnitine administration on the signs and symptoms of carnitine deficiency and on clinical outcomes in this population has not been established.

Clinical characteristics.

Indications.

For emergency and long-term treatment of patients with congenital metabolic disorders 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 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.

In patients who received levocarnitine concomitantly with coumarin-derived anticoagulants (see sections "Special precautions" and "Adverse reactions"), very rare cases of increased international normalized ratio (INR) have been observed. INR or another appropriate coagulation test should be performed weekly until values stabilize, and monthly thereafter in patients taking such anticoagulants together with levocarnitine.

Special precautions for use

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 function impairment or to patients on dialysis may lead to accumulation of potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in urine.

Levocarnitine improves glucose utilization; therefore, administration of the drug to patients with diabetes mellitus who are receiving antidiabetic therapy may result in hypoglycemia. Plasma glucose levels should therefore be monitored regularly in such patients to allow timely adjustment of therapy.

Very rare cases of increased INR have been observed in patients who concurrently received levocarnitine and coumarin-derived anticoagulants (see sections "Interaction with other medicinal products and other types of interactions" and "Undesirable effects").

Use during pregnancy or breastfeeding

Pregnancy

Reproductive studies conducted in rats and rabbits administered doses 3.8 times higher than the human dose based on body surface area showed no evidence of impaired fertility or fetal harm due to levocarnitine.

Since animal reproductive studies do not always predict human response, levocarnitine should be used during pregnancy only if clearly needed. However, adequate and well-controlled studies in pregnant women are lacking.

Breastfeeding period

The use of levocarnitine during breastfeeding has not been specifically studied. Levocarnitine is a normal component of human breast milk.

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

Ability to affect reaction speed when driving or operating machinery. Unknown.

Administration and Dosage

Levocarnitine is administered by slow intravenous injection over 2–3 minutes.

Metabolic Disorders

The recommended dose is 50 mg/kg as a slow bolus injection over 2–3 minutes or by infusion. Patients with severe metabolic crisis often receive a loading dose, followed by an equivalent dose over the next 24 hours. The drug should be administered by infusion or intravenous injection every 3 or 4 hours, and in no case less frequently than every 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 recommended that plasma carnitine concentration be measured prior to initiating this parenteral therapy. Weekly and monthly monitoring is also recommended. This monitoring should include biochemical blood tests, vital signs,

measurements of plasma carnitine concentration (plasma free carnitine concentration should be maintained between 35 and 60 μmol/L), and overall clinical status.

Hemodialysis Patients with Carnitine Deficiency

The recommended initial dose is 10–20 mg/kg body weight as a slow 2–3-minute bolus injection into the venous blood circuit following each dialysis session. Initiation of therapy may be indicated when pre-dialysis plasma levocarnitine concentrations 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 by the third or fourth week of therapy.

Hemodialysis Maintenance Therapy

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

Levocarnitine is compatible and stable when mixed with parenteral solutions of 0.9% sodium chloride or Ringer's lactate at concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500 mL (8.0 mg/mL).

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

Overdose

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

Treatment. Measures should be taken to remove the drug from the gastrointestinal tract in cases of oral ingestion. Symptomatic and supportive therapy should be administered. Levocarnitine is readily removed from plasma by dialysis. No life-threatening overdose cases have been reported.

Adverse Reactions

All of the adverse reactions listed below occur very rarely.

Gastrointestinal system 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 some patients. Reducing the dose often diminishes or eliminates gastrointestinal symptoms and the occurrence of specific body odor.

Blood and lymphatic system disorders

In very rare cases, increased INR has been observed in patients (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Nervous system reactions

Seizures have been reported in patients with or without prior seizure activity following both oral and intravenous administration of levocarnitine. In patients with pre-existing seizure disorders, an increase in seizure frequency and/or severity has been observed.

Hypersensitivity reactions

There have been official reports of serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm, following administration of levocarnitine, primarily in patients with end-stage renal disease undergoing dialysis. Some reactions occurred within minutes after intravenous administration of levocarnitine.

If a severe hypersensitivity reaction occurs, levocarnitine therapy should be discontinued immediately and appropriate medical treatment initiated. The risks and benefits of re-administering levocarnitine should be carefully considered in individual patients following a severe reaction. If a decision is made to re-administer the drug, patients must be closely monitored for signs and symptoms of hypersensitivity reactions.

Tolerance should be carefully monitored during the first week of treatment and after any dose increase. Intravenous administration of levocarnitine is generally well tolerated.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows ongoing 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. 2 years.

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

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 5 mL in a brown glass ampoule; 5 ampoules per blister pack made of film; 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Lubnipharm".

Manufacturer's address and place of business. 16, Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.