Almiba

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

Composition:

Active substance: levocarnitine;

1 ampoule (5 ml) contains levocarnitine 1 g;

Excipients: hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Amino acids and their derivatives. Levocarnitine. ATC code A16A A01.

Pharmacological Properties.

Pharmacodynamics.

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

Pharmacokinetics.

Absorbed levocarnitine is transported via blood to various organs and tissues. The presence of membrane-bound proteins in certain tissues, including red blood cells, which bind carnitine, suggests that specific transport systems in blood and cellular uptake mechanisms are required for its active utilization in certain tissues.

The concentration of levocarnitine in blood serum and tissues depends on the activity of metabolic processes, the rate of levocarnitine biosynthesis, dietary characteristics, and the speed of carnitine transport into and out of tissues, as well as its metabolic rate and excretion. All these factors may influence tissue carnitine concentrations.

Absorption

Levocarnitine is absorbed by epithelial cells of the small intestine and enters the bloodstream relatively slowly; absorption is likely associated with an active trans-luminal mechanism. Oral absorption is limited (< 10%) and variable.

Distribution

Absorbed levocarnitine is transported to various organs via blood; erythrocyte transport systems are believed to be involved in this process.

Excretion

Levocarnitine is excreted predominantly in urine. The excretion rate is directly proportional to the concentration of carnitine in blood.

Metabolism

Levocarnitine is almost not metabolized in the body.

Clinical characteristics.

Indications.

Treatment of 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 deficit leading to significant negative impact on quality of life;
• muscle weakness and/or myopathy;
• cardiopathy;
• anemia unresponsive to erythropoietin treatment or requiring high doses of erythropoietin;
• loss of muscle mass.

Contraindications.

Hypersensitivity to the components of the drug.

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 Almibi.

In some cases, co-administration of levocarnitine with coumarin anticoagulants may increase the international normalized ratio (INR); therefore, concomitant use requires caution. INR or other coagulation tests should be monitored weekly until stabilized, and monthly thereafter in patients taking these anticoagulants together with levocarnitine.

Special precautions for use

Levocarnitine improves glucose utilization; therefore, its use in patients with diabetes mellitus who are receiving treatment with oral hypoglycemic agents may lead to hypoglycemia. In such cases, plasma glucose levels should be monitored regularly to allow timely adjustment of therapy.

Prolonged oral administration of high doses of levocarnitine is not recommended in patients with severe renal impairment or end-stage renal disease (ESRD), as it may lead to accumulation in blood of potentially toxic metabolites—trimethylamine (TMA) and trimethylamine-N-oxide (TMAO)—due to insufficient renal excretion. This accumulation results in increased TMA excretion in urine.

There have been reports of isolated cases of changes in international normalized ratio (INR) in patients receiving levocarnitine concomitantly with coumarin anticoagulants. Appropriate monitoring is required when levocarnitine is used together with coumarin anticoagulants.

Use during pregnancy or breastfeeding

Reproductive studies have been conducted in rats and rabbits. No teratogenic effects were observed in either species during preclinical investigations. When the highest studied dose of 600 mg/kg body weight was administered to rabbits, a statistically insignificant increase in post-implantation fetal loss during early pregnancy was noted. The clinical relevance of these findings to humans is unknown. There is no experience with the use of Almibi in pregnant patients with primary systemic carnitine deficiency.

Considering the serious consequences of carnitine deficiency in pregnant women, the risk of discontinuing treatment is considered to be greater than the theoretical risk to the fetus if treatment is continued.

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

Ability to influence reaction speed when driving or operating machinery

Unknown.

Administration and Dosage

Almibuu is administered intravenously slowly over 2–3 minutes.

Use in congenital metabolism disorders

During therapy, it is advisable to monitor levels of carnitine and acylcarnitine both in blood plasma and urine.

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

In cases of acute decompensation, the recommended dose may reach up to 100 mg/kg per day administered in 3–4 doses. Higher doses may be used if necessary, although this may intensify adverse effects, particularly diarrhea.

Secondary carnitine deficiency in patients undergoing hemodialysis

Prior to initiating Almibuu therapy, plasma carnitine levels should be monitored.

Secondary carnitine deficiency is diagnosed when the ratio of acylcarnitine to free carnitine in 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. The overall response should be assessed by monitoring plasma levels of acylcarnitine and free carnitine, as well as evaluating the patient's clinical condition. Normalization of carnitine content in muscle tissue and cardiomyocytes occurs approximately 3 months after achieving normal plasma carnitine concentrations. If carnitine administration is discontinued, levels will inevitably begin to decrease again. The need for repeat loading courses of treatment should be determined by periodic quantitative measurement of plasma carnitine levels and monitoring of the patient's condition.

Hemodialysis – maintenance therapy

After completing the intravenous loading phase of levocarnitine, maintenance therapy consists of 1 g of the drug daily administered orally. On dialysis days, the drug should be taken orally as a 1 g dose immediately after completion of the dialysis session.

Overdose

There have been no reports of levocarnitine toxicity in cases of overdose. Supportive therapy should be administered in case 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, and provide symptomatic and supportive therapy. There have been no reports of life-threatening overdose cases.

Adverse reactions.

Mild gastrointestinal disturbances were observed during prolonged oral administration of levocarnitine, including transient nausea and vomiting, abdominal pain, and diarrhea. Reducing the dose often diminishes or eliminates gastrointestinal symptoms. During prolonged oral administration of levocarnitine, a specific body odor should be monitored (reducing the dose alleviates or eliminates the drug-induced odor). When levocarnitine is administered with coumarin anticoagulants, an increased international normalized ratio (INR) is possible. Tolerability of Almibi should be carefully monitored during the first week of treatment and after any dose increase. Intravenous administration of levocarnitine is generally well tolerated.

Shelf life.

4 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging.

5 ml in an ampoule, 5 ampoules in a tray, 1 or 2 trays in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Mefar Ilac San. A.S. / Mefar Ilac San A.S.

Manufacturer's address and location of business operations.

Ramazanoglu Mah. Ensar Cad. No. 20, Kurtkoy, Pendik, Istanbul, 34906, Turkey.

Marketing authorization holder.

Grand Medical Group AG / Grand Medical Group AG.

Address of the marketing authorization holder.

Kornmarkt 10, CH-6004, Luzern, Switzerland.