INSTRUCTION FOR MEDICAL USE

ELARI

TRADE NAME

Elari

 INTERNATIONAL NONPROPRIETARY NAME

Levocarnitine

 PHARMACEUTICAL FORM

Oral solution.

Description: clear colourless or light-yellow solution.

 COMPOSITION

Vial of the drug contains

Active ingredient: levocarnitine 1.0 g.

Excipients: malic acid, sodium benzoate, saccharine sodium, orange flavour, purified water.

 ATC CODE                А16АА01

 PHARMACOTHERAPEUTIC GROUP

Other alimentary tract and metabolism products. Amino acids and derivatives.

 PHARMACOLOGICAL PROPERTIES             PHARMACODYNAMICS

Carnitine is a naturally occurring component of cells in which it plays an essential part in energy production and transport. Carnitine is practically the only essential factor for penetration of long- chain fatty acids to mitochondria and for participation of these in β-oxidation; moreover, carnitine controls the transport of mitochondria-produced energy to the cytoplasm by way of adenine-nucleotide-translocase enzyme modulation.

The highest concentrations of carnitine are observed in skeletal muscles and in myocardium. Myocardium, in spite of the ability to use various substrates to obtain energy, usually uses fatty acids. Therefore carnitine plays an important part in the cardiac metabolism, since fatty acid oxidation is strictly dependent on the availability of the sufficient amount of the substance. Experimental studies demonstrated that in different conditions of stress, acute ischaemia, diphtheritic myocarditis, the carnitine level in myocardial tissues may reduce. Studies in various animal models confirmed the beneficial effect of carnitine in different artificially induced alterations of the heart function: acute and chronic ischaemia, heart failure conditions, heart failure associated with diphtheritic myocarditis, drug-induced cardiotoxicity (propranolol, adriamycin).

Levocarnitine has demonstrated therapeutic activity in the following pathologies:

-     primary carnitine deficiency, characterized by such phenotypes as myopathy with lipid accumulation, hepatic encephalopathy of the Reye’s syndrome type and/or progressive dilated cardiomyopathy.

-   secondary carnitine deficiency in patients with organic acidurias of genetic origin (propionic acidemia, methylmalonic aciduria, isovalerianic acidemia) and in patients with genetic defects of β-oxidation. In such situations the secondary deficiency is manifested in the accumulation of fatty acid esters. In effect, endogenous levocarnitine acts as a buffer for various fatty acids which cannot be metabolized.

-     secondary carnitine deficiency in patients undergoing intermittent hemodialysis. Muscle levocarnitine depletion is directly related to its loss from the dialysis fluid.

Typical muscle symptoms in such patients after a hemodialysis session are improved in levocarnitine therapy.

PHARMACOKINETICS

Orally administered levocarnitine is decomposed by intestinal bacteria, which results in formation of trimethylamine (ТМА) and γ-butyrobetaine. Since the amount of the drug which penetrates unchanged into the systemic circulation is about 10-20%, it is considered that intestinal metabolism accounts for excretion of approximately 80-90% of the oral dose of levocarnitine.

The intestinal metabolism products – γ-butyrobetaine and TMA – are absorbed, and γ- butyrobetaine is excreted unchanged in urine, while TMA, during hepatic metabolism, is converted into trimethylamine-N-oxide (TMAO) which is recovered in urine together with a small amount of TMA in the unchanged form.

Long-term oral administration of levocarnitine in patients with severe renal failure or in patients undergoing dialysis may result in accumulation of TMA and TMAO in blood, and, consequently, lead to trimethylaminuria, a pathologic condition characterized with a strong fish-like odour of urine, exhaled air and sweat of the patients.

 THERAPEUTIC INDICATIONS

Primary and secondary carnitine deficiency.

 POSOLOGY AND METHOD OF ADMINISTRATION

Primary and secondary carnitine deficiency associated with genetic diseases

The daily oral dose depends on age and body weight: from birth to 2 years – 150 mg/kg of body weight; age 2 to 6 years – 100 mg/kg of body weight; age 6 to 12 years – 75 mg/kg of body weight; age over 12 years and adults – 2-4 g depending on the severity of the disease and considering the doctor’s opinion.

Secondary carnitine deficiency associated with hemodialysis

The daily oral dose is 2-4 g.

Elari oral solution is administered only after dilution. The amount of solution for a single dose should be diluted in a glass of water.

Special populations

Patients with renal failure

Patients with severe renal dysfunction should not receive long-term oral treatment with high doses of levocarnitine due to the risk of accumulation of potentially dangerous metabolites TMA and TMAO.

Elderly patients

No special precautions and dose alteration of Elari are required for elderly patients. The safety profile observed in clinical studies is comparable in the elderly and in young patients.

Diabetic patients

Administration of levocarnitine in diabetic patients who receive insulin or oral hypoglycemic agents improving glucose utilization may result in hypoglycemia, therefore the glycemic level should be regularly monitored in such patients in order to timely adjust the hypoglycemic therapy.

 CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients of the drug.

 ADVERSE REACTIONS

Adverse reaction, the information about which is received from various sources (clinical studies, literature and postmarketing experience), are listed below according to the MedDRA organ and

organ system classification. Adverse reactions are classified by frequency within each class. Within each category, adverse reactions are presented in the order of decreasing their seriousness.

The following adverse reactions are classified according to the following convention: very common (≥ 1/10); common (≥ 1/100, but < 1/10); uncommon (≥ 1/1000, but < 1/100); rare (≥ 1/10000, but < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).

Nervous system disorders: uncommon – headache; not known – convulsions¹, dizziness.

Cardiac disorders: not known – palpitation.

Vascular disorders: uncommon – hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: not known – dyspnea.

Gastrointestinal disorders: common – vomiting, nausea, diarrhea, abdominal pain; uncommon – dysgeusia, dyspepsia, dry mouth.

Skin and subcutaneous tissue disorders: uncommon – abnormal skin odour²; not known – pruritus, rash.

Musculo-skeletal and connective tissue disorders: uncommon – muscle cramps; not known – myasthenia³, muscle strain.

General disorders and administration site conditions: uncommon – chest pain, abnormal feelings, pyrexia.

Investigations: uncommon – increased arterial pressure; very rare – increased International normalized ratio (INR)⁴.

¹ Cases of convulsions were reported in patients with or without convulsive activity, who received oral or intravenous levocarnitine. Administration of levocarnitine may increase the frequency and/or severity of the convulsive attack. Levocarnitine treatment may induce convulsions in patients with pre-disposing risk factors.

² Long-term oral administration of levocarnitine in patients with severe renal failure or in patients undergoing dialysis may result in accumulation of TMA and TMAO in blood and consequently lead to trimethylaminuria, a pathologic condition characterized with a strong fish- like odour of urine, exhaled air and sweat of the patients.

³ Mild myasthenia symptoms were described in patients with uremia.

⁴ Very rare cases of increased INR were registered in patients receiving concomitant therapy with coumarin agents.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicinal product is important. Healthcare professionals are asked to report any serious adverse reactions or novel adverse reactions which are not described in this section, according to the National pharmacovigilance system.

SPECIAL WARNINGS

Administration of levocarnitine in diabetic patients receiving insulin or oral hypoglycemic agents which improve glucose utilization may result in hypoglycemia, therefore the glycemic level should be regularly monitored in such patients in order to timely adjust the hypoglycemic therapy.

Administration of levocarnitine in patients with a history of convulsive activity may increase the frequency and/or severity of the convulsive attack. Levocarnitine treatment may induce convulsions in patients with pre-disposing risk factors.

Safety and efficiency of oral levocarnitine have not been demonstrated in patients with renal failure. Long-term oral use of high doses of levocarnitine in patients with severe renal failure or with the terminal stage of renal failure, who are undergoing dialysis, may result in accumulation of potentially toxic metabolites ТМА and ТМАО, since these metabolites are usually excreted in urine. This is not observed in intravenous administration of levocarnitine.

Levocarnitine is a physiological substance and does not impose a risk of addiction or dependence.

Very rare cases of increased INR were registered in patients receiving concomitant therapy with coumarin agents. Patients undergoing concomitant therapy with anticoagulants and Elari should have the INR or other respective coagulation parameters monitored weekly until stabilization of the values and monthly thereafter.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

The drug has no effect on the ability to drive and use machines.

 ADMINISTRATION DURING PREGNANCY AND LACTATION

Fertility

Beneficial effects were observed, and no safety concerns were revealed in clinical fertility studies.

Pregnancy

Reproductive studies were performed in rats and rabbits. No evidence of the teratogenic effect were observed in either species. In rabbits, in contrast to rats, a statistically insignificant increase in post-implantation losses was observed at the maximum studied dose (600 mg/kg daily), as compared to the control group. Relevance of these findings to humans is unknown. No respective clinical studies have been performed in pregnant women.

Elari may be used during pregnancy only when the expected benefit of the therapy for the mother outweighs the potential risk for the foetus.

Lactation

Levocarnitine is a natural component of breast milk. Administration of levocarnitine in breast- feeding women has not been studied.

Elari may be used during lactation only when the expected benefit of the therapy for the mother outweighs the potential risk for the child due to the excessive carnitine exposure.

 DRUG INTERACTIONS

Interaction of levocarnitine and coumarin agents cannot be ruled out. Very rare cases of increased INR were registered in patients receiving concomitant therapy with coumarin drugs. Patients undergoing concomitant therapy with anticoagulants and Elari should have the INR or other respective coagulation parameters monitored weekly until stabilization of the values and monthly thereafter.

Simultaneous administration of levocarnitine with drugs inducing hypocarnitinemia due to increased renal excretion of carnitine (valproic acid, pivalic acid-containing prodrugs, cephalosporins, cisplatin, carboplatin and ifosfamide) may reduce availability of levocarnitine.

 OVERDOSE

Overdose and long-term administration of levocarnitine were associated with diarrhea. Levocarnitine is easily eliminated from blood by way of dialysis.

 PACKAGING

Oral solution in amber glass vial of 10 ml closed with white plastic cap. 10 vials together with an instruction for medical use in a carton box.

 STORAGE CONDITIONS

Store in a dark place at a temperature not exceeding 25°С.

Keep out of reach of children!

SHELF LIFE

4 years from the date of manufacture.