Altum

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALТUM (ALTUM)

Composition:

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

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

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: 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 gamma-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom. Its action on the body can be explained in two ways.

1. Effect on carnitine biosynthesis

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing the biosynthesis of carnitine. As a result, it interferes with the transport of long-chain fatty acids across cell membranes, thus preventing the accumulation of a strong detergent—activated forms of non-oxidized fatty acids—within cells. This prevents damage to cellular membranes.

Under ischemic conditions, reduced carnitine concentration delays beta-oxidation of fatty acids and optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores adenosine triphosphate (ATP) transport from sites of its biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and the utilization of these substances is optimized.

On the other hand, increased biosynthesis of the carnitine precursor, i.e., GBB, activates NO-synthase, resulting in improved blood rheological properties and reduced peripheral vascular resistance.

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

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

1. Mediator function in the hypothetical GBB-ergic system

A hypothesis has been proposed that a neuronal signal transmission 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-ether. 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, in response to stimulation, new GBB molecules are synthesized, ensuring signal propagation.

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

As previously noted, meldonium is a structural analogue of GBB and can perform the function of a "mediator." In contrast, GBB-hydroxylase does not recognize meldonium, so carnitine concentration does not increase but decreases. Thus, by replacing the "mediator" and promoting increased GBB concentration, meldonium triggers the corresponding physiological response. As a result, overall metabolic activity increases, including in other systems such as the central nervous system (CNS).

Effect on the cardiovascular system

Animal studies have shown that meldonium positively affects myocardial contractile activity. It exhibits cardioprotective properties (including protection against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the area of myocardial infarction.

Ischemic heart disease (stable exertional angina)

Analysis of clinical data on course treatment with meldonium in patients with stable exertional angina demonstrated that the drug reduces the frequency and intensity of angina attacks, as well as the amount of nitroglycerin used. The drug exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, although the effect is less pronounced 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 levels and the atherogenic index.

Chronic heart failure

In a relatively large number of clinical studies, the role of meldonium in treating chronic heart failure due to IHD has been analyzed, and its ability to increase tolerance to physical exertion and the amount of work performed by patients with heart failure has been noted.

In a separate study conducted at cardiology institutes in Latvia and Tomsk, the efficacy of meldonium was evaluated in cases of mild-to-moderate chronic heart failure classified as functional class I–III according to the New York Heart Association (NYHA) classification. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified to NYHA class I. It has been established that meldonium improves myocardial inotropic function and increases tolerance to physical exertion, thereby improving 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.

Effect on the CNS

Animal experiments have demonstrated meldonium's anti-hypoxic effects and its influence on cerebral circulation. The drug optimizes redistribution of cerebral blood flow in favor of ischemic areas and increases neuronal resistance under hypoxic conditions.

The drug has a stimulating effect on the CNS—increased motor activity and physical endurance, stimulation of behavioral responses, and anti-stress action—activation 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

It has been proven that meldonium is an effective agent in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory 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 impairments (after cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis) has been studied.

Results of evaluating meldonium's therapeutic activity indicate its dose-dependent positive effect 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 effect 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 has a positive effect on nervous system function, reducing neurological deficits during recovery.

Overall neurological status improves in patients (reduced 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.

After intravenous administration, the area under the concentration-time curve (AUC) differs after single and repeated doses, indicating possible 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 single intravenous doses of meldonium (250 mg, 500 mg, and 1000 mg), the initial elimination half-life ranges from 5.56 to 6.55 hours, while the terminal elimination half-life is 15.34 hours.

Special patient groups

Elderly patients

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

Renal impairment

In patients with impaired renal function, where bioavailability is increased, 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, leading to increased renal clearance of carnitine. Meldonium, GBB, and the combination of meldonium/GBB have no direct effect on the renin-angiotensin-aldosterone system (RAAS).

Hepatic impairment

In patients with impaired liver function, where bioavailability is increased, the dose of meldonium should be reduced. Toxicity studies in rats administered meldonium at doses exceeding 100 mg/kg revealed yellow discoloration of the liver and fat denaturation. Histopathological studies in animals after administration of high doses of meldonium (400 mg/kg and 1600 mg/kg) showed lipid accumulation in liver cells. However, changes in liver function parameters were not observed in humans after administration of high doses (400–800 mg). Nevertheless, possible fat infiltration of liver cells cannot be excluded.

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:

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

Contraindications.

• Hypersensitivity to meldonium and/or to any of the excipients;
• increased intracranial pressure (due to impaired venous outflow, intracranial tumors);
• severe hepatic and/or renal insufficiency (insufficient safety data available);
• pregnancy or breastfeeding;
• pediatric age (under 18 years).

Interaction with other medicinal products and other forms 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 may also be combined with anticoagulants, antiplatelet agents, antiarrhythmics, and other drugs improving microcirculation.

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

In patients with iron-deficiency anemia, concomitant administration of iron preparations and meldonium improved fatty acid composition in erythrocytes.

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

Meldonium helps eliminate cardiac alterations 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 beneficial effect in the treatment of AIDS.

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentylentetrazole, a pronounced anticonvulsant effect of meldonium was observed. However, when the alpha2-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 induced by indinavir and neurotoxic effects induced by efavirenz.

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

Special precautions for use.

Caution should be exercised when administering the drug to patients with mild or moderate hepatic and/or renal impairment in their medical history (monitoring of liver and/or kidney function is recommended). Long-term experience in treating acute myocardial infarction and unstable angina in cardiology departments shows that meldonium is not a first-line agent in acute coronary syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies are insufficient to evaluate the effects of meldonium on pregnancy, embryonic/fetal development, parturition, and postnatal development. The potential risk to humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding period

Available animal data indicate that meldonium passes into maternal milk. It is unknown whether meldonium passes into human breast milk. Risk to newborns/infants cannot be ruled out; therefore, meldonium is contraindicated during breastfeeding.

Ability to affect reaction rate when driving or operating machinery.

Studies evaluating the effect of meldonium 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 stimulating 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 duration of treatment is usually 10–14 days, after which treatment 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 Renal Impairment

Since the drug is eliminated via the kidneys, patients with mild to moderate renal impairment should receive a lower dose of meldonium.

Patients with Hepatic Impairment

Patients with mild to moderate hepatic impairment should receive a reduced dose of meldonium.

Children

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

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 hypotension, headache, dizziness, tachycardia, and general weakness may occur. Treatment is symptomatic.

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

Hemodialysis is not significantly effective in meldonium overdose due to its pronounced protein binding.

Adverse reactions.

Adverse reactions are classified according to organ systems and frequency of occurrence according to MedDRA: frequently, rarely.

Adverse reactions observed in clinical studies and in the post-marketing period:

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

5 ml in an ampoule, 5 ampoules in a blister pack, 2 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhym-Kharkiv".

Manufacturer's address and place of business.

36 Severina Pototskoho Street, Kharkiv, Kharkiv region, 61115, Ukraine.