Accordin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AКCORDIN (ACCORDIN)

Composition:

Active substance: 3-(2,2,2-trimethylhydrazinium) propionate dihydrate (meldonium);

1 ml of solution contains 3-(2,2,2-trimethylhydrazinium) propionate dihydrate (meldonium) 100 mg;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical characteristics: clear colorless liquid.

Pharmacotherapeutic group. Other cardiac preparations. ATC code C01EB22.

Pharmacological Properties

Pharmacodynamics

Meldonium is a precursor of carnitine and a structural analogue of γ-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom. Its effects on the body can be explained in two ways.

1. Effect on carnitine biosynthesis.

Meldonium reversibly inhibits γ-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis. As a result, it prevents the transport of long-chain fatty acids across cell membranes, thus avoiding the accumulation of strong detergents—activated forms of non-oxidized fatty acids—within cells. This mechanism helps prevent damage to cellular membranes.

Under ischemic conditions, reduced carnitine concentration leads to inhibition of fatty acid β-oxidation, which optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores ATP transport from its biosynthesis sites (mitochondria) to sites of utilization (cytosol). Essentially, cells are better supplied with nutrients and oxygen, and the utilization of these substances is optimized.

An increase in the biosynthesis of carnitine's precursor—i.e., GBB—activates nitric oxide (NO) synthase, thereby improving blood rheological properties and reducing peripheral vascular resistance.

When meldonium concentration decreases, carnitine biosynthesis resumes and the amount of fatty acids gradually increases within cells.

It is believed that the primary basis for meldonium’s efficacy lies in increasing cellular tolerance to metabolic stress (due to changes in fatty acid levels).

2. Mediator function in the hypothetical GBB-ergic system.

A hypothesis has been proposed that a neuronal signaling system—the GBB-ergic system—exists in the body, responsible for transmitting nerve impulses between cells. The mediator of this system is the final precursor of carnitine—GBB ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring the electrical impulse and converting into GBB. The hydrolyzed form of GBB is then actively transported to the liver, kidneys, and ovaries, where it is converted into carnitine. In somatic cells, new GBB molecules are synthesized in response to stimulation, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, leading to increased concentration of GBB ester.

As previously mentioned, meldonium is a structural analogue of GBB and can act as a mediator. However, GBB hydroxylase does not recognize meldonium, so carnitine concentration does not increase but rather decreases. Thus, by replacing the natural mediator and promoting increased GBB concentration, meldonium triggers a corresponding physiological response. This leads to increased overall metabolic activity in various systems, including the central nervous system (CNS).

Effects on the cardiovascular system. Animal studies have demonstrated that meldonium positively influences myocardial contractility. It exhibits cardioprotective properties (including protection against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the size of myocardial infarction.

Ischemic heart disease (stable angina pectoris). Clinical data analysis of meldonium treatment in patients with stable exertional angina shows that the drug reduces the frequency and intensity of angina attacks and decreases the need for glyceryl trinitrate. Meldonium exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while a weaker effect is observed in patients with supraventricular extrasystoles. Particularly important is the drug’s ability to reduce oxygen consumption at rest, which is considered an effective criterion for antianginal therapy in IHD. Meldonium favorably affects atherosclerotic processes in coronary and peripheral vessels by reducing total serum cholesterol and the atherogenic index.

Chronic heart failure. It has been established that meldonium improves myocardial inotropic function, increases exercise tolerance, and enhances patients’ quality of life without causing severe adverse effects.

In cases of severe heart failure, meldonium should be used in combination with other conventional heart failure therapies.

Effects on the CNS. Meldonium has demonstrated anti-hypoxic effects and beneficial effects on cerebral circulation. The drug optimizes redistribution of cerebral blood flow in favor of ischemic areas and increases neuronal resistance under hypoxic conditions. Meldonium has stimulatory effects on the CNS, including increased motor activity and physical endurance, stimulation of behavioral responses, and anti-stress activity—via stimulation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, and protection of internal organs from stress-induced changes.

Efficacy in neurological disorders. Meldonium has been proven effective as part of combined therapy for acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral insufficiency). Meldonium normalizes the tone and resistance of cerebral capillaries and arterioles and restores their reactivity.

The effect of meldonium on the rehabilitation process in patients with neurological deficits (after cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis) has been studied. Therapeutic efficacy data indicate dose-dependent positive effects on physical endurance and restoration of functional independence during recovery.

Analysis of changes in individual and overall intellectual functions after meldonium administration revealed a positive impact on the recovery process of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (primarily due to restoration of physical function) and eliminates psychological disturbances.

Meldonium exerts positive effects on nervous system function by reducing neurological deficits during recovery.

Overall neurological status improves (reduction in brain nerve damage and reflex pathology, regression of paresis, improved motor coordination and autonomic functions).

Pharmacokinetics

Pharmacokinetics were studied in healthy volunteers after intravenous and oral administration of meldonium.

Absorption. Bioavailability is 100%. Maximum plasma concentration (Cmax) is achieved immediately after administration. After intravenous administration of multiple doses, Cmax reaches 25.5±3.63 µg/mL.

Following intravenous administration, the area under the concentration-time curve (AUC) differs after single and repeated doses, indicating potential accumulation of meldonium in plasma.

Distribution. Meldonium rapidly distributes from the bloodstream into tissues with high cardiac affinity. Meldonium and its metabolites partially cross the placental barrier. Animal studies have shown that meldonium penetrates into breast milk.

Biotransformation. Metabolism studies in experimental animals have shown that meldonium is primarily metabolized in the liver.

Elimination. Renal excretion plays a significant role in the elimination of meldonium and its metabolites. After a single intravenous dose of 250 mg, 500 mg, or 1000 mg, the early elimination half-life of meldonium ranges from 5.56 to 6.55 hours, and the terminal elimination half-life is 15.34 hours.

Special patient groups

Elderly patients. In elderly patients with impaired liver or kidney function, where bioavailability is increased, the dose of meldonium should be reduced.

Impaired renal function. In patients with impaired kidney function and increased bioavailability, the dose of meldonium should be reduced. There is an interaction between renal reabsorption of meldonium or its metabolites (e.g., 3-hydroxymeldonium) and carnitine, resulting in increased renal clearance of carnitine. Meldonium, GBB, and the combination of meldonium/GBB have no direct effect on the renin-angiotensin-aldosterone system (RAAS).

Impaired liver function. No changes in liver function parameters have been observed in humans after administration of high doses of the drug (400–800 mg). However, hepatic lipid infiltration cannot be ruled out.

Children. There are no data on the safety and efficacy of meldonium use in children under 18 years of age; therefore, its use in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy of the following conditions:

• cardiovascular diseases: stable exertional angina, chronic heart failure (NYHA functional class I-IIІ), cardiomyopathy, functional disorders of the heart and vascular system;
• acute and chronic ischemic disorders of cerebral circulation;
• reduced work capacity, physical and psycho-emotional overstrain;
• during convalescence period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium and/or to any of the excipients of the drug;
• increased intracranial pressure (due to impaired venous outflow, intracranial tumors);
• severe hepatic and/or renal insufficiency (insufficient safety data available).

Interaction with other medicinal products and other types of interactions.

Meldonium can be used concomitantly with prolonged-action nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides, and diuretics (for heart failure). It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmic drugs, and other agents improving microcirculation.

Meldonium may enhance the effects of drugs containing glyceryl trinitrate, nifedipine, β-adrenoblockers, and other antihypertensive agents and peripheral vasodilators.

When iron-containing drugs and meldonium are used simultaneously in patients with iron-deficiency anemia, improvement in the fatty acid composition of erythrocytes has been observed.

When meldonium is used in combination with orotic acid to counteract ischemia/reperfusion-induced damage, an additional pharmacological effect is observed.

Meldonium helps eliminate cardiac changes caused by zidovudine (AZT) and indirectly affects oxidative stress reactions induced by AZT, which lead to mitochondrial dysfunction. The use of meldonium in combination with AZT or other drugs for the treatment of acquired immunodeficiency syndrome (AIDS) has a positive effect in the treatment of AIDS.

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazol, a pronounced anticonvulsant effect of meldonium was established. When the α2-adrenoblocker yohimbine at a dose of 2 mg/kg and the nitric oxide synthase (NOS) inhibitor N-(G)-nitro-L-arginine at a dose of 10 mg/kg were administered prior to meldonium therapy, the anticonvulsant effect of meldonium was completely blocked.

Overdose of meldonium may enhance cardiotoxicity caused by cyclophosphamide.

Carnitine deficiency induced by meldonium may enhance cardiotoxicity caused by ifosfamide.

Meldonium exerts protective effects against cardiotoxicity caused by indinavir and neurotoxic effects caused by efavirenz.

Do not use together with other medicinal products containing meldonium, as this may increase the risk of adverse reactions.

Special precautions.

Caution should be exercised when administering the drug to patients with a history of mild to moderate hepatic and/or renal impairment (liver and/or kidney function should be monitored). Meldonium is not a first-line drug for acute coronary syndrome.

Use during pregnancy or breastfeeding.

Pregnancy. The potential risk to humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding period. Animal data indicate that meldonium passes into maternal milk. It is unknown whether meldonium passes into human breast milk. A risk to newborns/infants cannot be ruled out; therefore, meldonium is contraindicated during breastfeeding.

Ability to influence reaction rate while driving or operating machinery.

Studies assessing the effect on the ability to drive or operate machinery have not been conducted.

Administration and Dosage.

Intravenous use. The drug does not require special preparation prior to administration.

Due to the possible stimulatory effect, the drug is recommended to be administered in the first half of the day.

Adults. The dose is 500–1000 mg (5–10 mL) administered intravenously as a single dose or divided into two doses. The treatment duration usually lasts 10–14 days, after which therapy should be continued with an oral dosage form.

The total treatment course lasts 4–6 weeks. The course may be repeated 2–3 times per year.

Elderly patients. In elderly patients with impaired liver and/or kidney function, a reduced dose of meldonium may be considered.

Patients with impaired kidney function. Since the drug is excreted by the kidneys, patients with mild to moderate kidney impairment should receive a lower dose of meldonium.

Patients with impaired liver function. Patients with mild to moderate liver impairment should receive a lower dose of meldonium.

Children.

There is no data on the safety and efficacy of meldonium in children under 18 years of age; therefore, meldonium is contraindicated in this patient population.

Overdose.

Cases of meldonium overdose have not been reported. The drug is low in toxicity and does not cause life-threatening adverse effects.

In cases of low blood pressure, headache, dizziness, tachycardia, and general weakness may occur. Treatment is symptomatic.

In case of severe overdose, liver and kidney functions should be monitored.

Hemodialysis is not significantly effective in meldonium overdose due to the drug's pronounced protein binding.

Adverse reactions.

Adverse effects are classified according to organ systems and MedDRA frequency terms: common, rare.

Reporting of suspected adverse reactions

Reporting adverse reactions following the registration of a medicinal product is of great importance. It allows monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

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 an ampoule, 5 ampoules in a blister, 1 or 2 blisters per carton, or 100 ampoules per carton.

Prescription status.

Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and location of its operations.

36 Severina Pototskogo Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.