Mildronate®

INSTRUCTIONS for medical use of the medicinal product MILDROnate® (MILDRONATE®)

Composition:

active substance: meldonium;

5 ml solution (1 ampoule) contains meldonium dihydrate 500 mg;

10 ml solution (1 ampoule) contains meldonium dihydrate 1000 mg;

excipients: water for injections.

Pharmaceutical form. Solution for injection.

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 prevents the transport of long-chain fatty acids across cell membranes, thus inhibiting the accumulation of strong detergents—activated forms of non-oxidized fatty acids—within cells. Consequently, damage to cellular membranes is prevented.

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

In turn, 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 enhanced tolerance to cellular 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 signaling 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 carnitine precursor—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, new GBB molecules are synthesized in response to stimulation, ensuring signal propagation.

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

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; therefore, carnitine concentration does not increase but decreases. Thus, meldonium, by replacing the "mediator" and promoting increased GBB concentration, triggers the corresponding physiological response. As a result, overall metabolic activity increases in other systems as well, for example, in the central nervous system (CNS).

Effect on the cardiovascular system.

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

Ischemic heart disease (stable exertional angina).

Analysis of clinical data on the course treatment of stable exertional angina with meldonium has shown that the drug reduces the frequency and intensity of angina attacks, as well as the amount of glyceryl trinitrate used. The drug demonstrates pronounced antiarrhythmic effects 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 levels and the atherogenic index.

Chronic heart failure.

In a relatively large number of clinical studies, the role of meldonium in the treatment of 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 patients with NYHA (New York Heart Association) functional class I–III heart failure of moderate severity. 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, increases tolerance to physical exertion, 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.

Effect on the CNS.

Animal experiments have demonstrated the anti-hypoxic effect of meldonium 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—increasing motor activity and physical endurance, stimulating behavioral responses, and exerting anti-stress effects—by stimulating the sympathoadrenal system, increasing catecholamine accumulation in the brain and adrenal glands, and protecting internal organs from stress-induced changes.

Efficacy in neurological disorders.

It has been demonstrated 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 evaluating the therapeutic activity of meldonium 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 drug 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 (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.

Following intravenous administration, the area under the concentration-time curve (AUC) differs after single and repeated doses of meldonium, 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 maternal 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 at 250 mg, 500 mg, and 1000 mg, the initial elimination half-life of meldonium is 5.56–6.55 hours, and the terminal 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, 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.

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 showed yellow discoloration of the liver and fat denaturation. Histopathological studies in animals after administration of high meldonium doses (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. No changes in liver function parameters were observed in humans after administration of high doses (400–800 mg). However, fat infiltration into liver cells cannot be ruled out.

Children

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

Clinical characteristics.

Indications.

As part of combination therapy for 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 heart and vascular system activity;
• 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 of the medicinal product;
• 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 may be used concomitantly with long-acting nitrates and other antianginal agents (in stable exertional angina), cardiac glycosides, and diuretics (in heart failure).

It may also be combined with anticoagulants, antiplatelet agents, antiarrhythmic drugs, and other agents improving microcirculation.

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

When iron-containing preparations and meldonium are used concomitantly in patients with iron-deficiency anemia, improvement in 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 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 zidovudine or other drugs for AIDS treatment has a beneficial effect in the treatment of acquired immunodeficiency syndrome (AIDS).

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazole, a pronounced anticonvulsant effect of meldonium was observed. In turn, when alpha2-adrenoblocker yohimbine at a dose of 2 mg/kg and a 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 for use.

Caution should be exercised when administering the drug to patients with mild or moderate hepatic and/or renal impairment (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 drug for acute coronary syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

There is insufficient animal data available to assess the effects of meldonium on pregnancy, embryonic/fetal development, delivery, and postnatal development. The potential risk to humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding.

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

Ability to influence reaction speed when driving or operating machinery.

Studies evaluating the effect of meldonium on the ability to drive or operate machinery have not been conducted.

Method of administration and dosage.

Intravenous use. The preparation of the drug prior to administration is not required.

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 either as a single dose or divided into two doses. The treatment duration usually lasts 10–14 days, after which therapy should be continued with the oral dosage form.

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

Elderly patients

Elderly patients with impaired liver and/or kidney function may require a reduced dose of meldonium.

Patients with renal impairment

Since the drug is eliminated from the body 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 lower dose of meldonium.

Children

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

Overdose.

Cases of meldonium overdose have not been reported. The drug is low-toxic 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 pronounced protein binding of the drug.

Adverse reactions.

Adverse effects are classified by organ systems and frequency of occurrence according to MedDRA: common (≥ 1/100 to < 1/10), rare (≥ 1/10000 to < 1/1000).

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

* Adverse reactions observed in previously conducted non-controlled clinical trials.

Shelf life.

5 years.

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

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach and sight of children.

Packaging.

5 ml or 10 ml in a colourless glass ampoule, hydrolytic class I, with a break line or dot.

5 ampoules in a blister pack (cavity) made of polyvinyl chloride film.

5 ml ampoules – 2 or 4 blister packs (cavities) are placed in a cardboard carton.

10 ml ampoules – 1 or 2 blister packs (cavities) are placed in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

Manufacturer responsible for batch release, including batch control/testing.

JSC "Grindex".

Manufacturer's name and address of manufacturing site.

53 Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorisation Holder.

JSC "Grindex".

Address of the Marketing Authorisation Holder.

53 Krustpils Street, Riga, LV-1057, Latvia.