Mildronate®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MILDRONAТ® (MILDRONAT®)

Composition:

Active substance: meldonium dihydrate;

1 hard capsule contains 500 mg of meldonium dihydrate;

Excipients: potato starch, silicon dioxide, calcium stearate;

Capsule (body and cap): titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: white hard gelatin capsules. The contents of the capsules – white crystalline powder with a slight odor. The powder is hygroscopic.

Pharmacotherapeutic group.

Other cardiac preparations. ATC code C01EB22.

Pharmacological properties.

Pharmacodynamics. Meldonium dihydrate (hereinafter referred to as meldonium) is a carnitine precursor and a structural analogue of gamma-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 gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and consequently preventing the transport of long-chain fatty acids across cell membranes. Thus, it prevents the accumulation within cells of a potent detergent — activated forms of non-oxidized fatty acids. As a result, damage to cellular membranes is prevented.

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.

Conversely, 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 increases again, and the amount of fatty acids gradually rises within cells.

It is believed that the efficacy of meldonium is based on increased cellular tolerance to metabolic stress (due to changes in fatty acid levels).

2. Function as a mediator in the hypothetical GBB-ergic system.

A hypothesis has been proposed suggesting the existence in the body of a neuronal signal transmission system — the GBB-ergic system — which mediates the transfer of nerve impulses between cells. The mediator of this system is the immediate carnitine precursor — GBB-ether. Under the action of GBB-esterase, the mediator donates an electron to the cell, thereby transferring the electrical impulse, and is converted into GBB. The hydrolyzed form of GBB is then actively transported to the liver, kidneys, and ovaries, where it is transformed 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 mentioned, 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 rather decreases. Thus, meldonium, both by replacing the "mediator" and by promoting increased GBB concentration, induces 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 against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the size of myocardial infarction.

Ischemic heart disease (stable angina pectoris).

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 nitroglycerin used. The drug demonstrates pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while a lesser 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 influences atherosclerotic processes in coronary and peripheral vessels by reducing total serum cholesterol levels and the atherogenic index.

Chronic heart failure.

In a 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 heart failure of functional classes I–III according to the New York Heart Association (NYHA) classification, of moderate severity. Under the influence of 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. However, it should be noted that meldonium may cause mild hypotension. Other possible adverse effects of meldonium include skin allergic reactions, headaches, and epigastric discomfort.

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 beneficial effect 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 — including stimulation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, and protection against stress-induced internal organ 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 rehabilitation process in patients with neurological impairments (after cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis) has been studied.

Results of 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 (mainly 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 of patients improves (reduced brain nerve damage and reflex pathology, regression of paresis, improved motor coordination and autonomic functions).

Pharmacokinetics.

Absorption

After a single oral dose, maximum plasma concentration (Cmax) ranges from 2.23 to 2.43 µg/mL, and after repeated dosing, it reaches 2.77 µg/mL. Time to reach maximum plasma concentration (tmax) is 1–3 hours. Oral bioavailability is 78%. Food slightly delays absorption.

Distribution

Meldonium rapidly distributes from the bloodstream into tissues. The volume of distribution is 88.07 ± 8.56 L. Plasma protein binding is 78%. Meldonium and its metabolites partially cross the placental barrier.

Biological transformation

Studies on metabolism 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 oral dose, the early elimination half-life (t1/2) of meldonium is approximately 3.5–4 hours. With repeated dosing, the elimination half-life differs. These results suggest possible accumulation of meldonium in plasma.

Special patient groups

Elderly patients

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

Renal impairment

In patients with impaired renal function, where bioavailability may be 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 may be 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. Changes in liver function parameters in humans after administration of high doses (400–800 mg) have not been observed. However, possible 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, the use of the drug in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy in the following cases:

• 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 after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium and/or to any excipient of the medicinal product;
• increased intracranial pressure (in case of impaired venous outflow, intracranial tumors);
• severe hepatic and/or renal insufficiency (there are insufficient data on safety of use);

Interaction with other medicinal products and other forms of interaction.

Meldonium can be used in combination 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, beta-adrenoblockers, and other antihypertensive agents and peripheral vasodilators.

In patients with chronic heart failure who received meldonium and lisinopril to reduce symptom severity, a positive effect of combined therapy was observed (vasodilation of major arteries, improvement of peripheral circulation and quality of life, reduction of mental and physical stress).

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 counteract ischemia/reperfusion-induced damage, an additional pharmacological effect is observed.

Meldonium helps eliminate pathological changes in the heart 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. During seizures induced by pentetrazol, pronounced anticonvulsant action of meldonium was established. In turn, when alpha2-adrenoblocker yohimbine at a dose of 2 mg/kg and 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 has protective effects against cardiotoxicity caused by indinavir and neurotoxicity 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 to moderate hepatic and/or renal impairment in their medical history (liver and/or kidney function should be monitored).

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.

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

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. 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 excluded; therefore, meldonium is contraindicated during breastfeeding.

Ability to affect reaction rate while driving or operating machinery

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

Method of Administration and Dosage

Administer orally, either before or after meals. Swallow the capsule with water. Due to the possible stimulating effect, the medication is recommended to be taken in the first half of the day.

Adults

Cardiovascular diseases, cerebrovascular disorders

The daily dose is 500–1000 mg. The total daily dose can be taken as a single dose or divided into two doses. The maximum daily dose is 1000 mg.

For reduced work capacity, overexertion, and during convalescence

The daily dose is 500 mg. The maximum daily dose is 500 mg.

The duration of treatment course is 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, dose reduction of meldonium may be required.

Patients with impaired kidney function

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

Patients with impaired liver function

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 is contraindicated in this patient group.

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 arterial pressure, symptoms such as 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 the pronounced binding of the drug to blood proteins.

Adverse reactions.

Adverse effects are classified by organ systems and frequency of occurrence according to MedDRA: common (≥ 1/100 to < 1/10), rare (≥ 1/10,000 to < 1/100).

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

* Adverse reactions observed in previously conducted uncontrolled clinical trials.

Reports have been received of abdominal pain in the upper abdomen and migraine associated with the use of mildronate.

Shelf life. 4 years.

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

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep in the original packaging to protect from moisture.

Keep out of reach and sight of children.

Packaging.

10 capsules in a blister; 2, 6 or 9 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Grindeks", Latvia.

Manufacturer's address and place of business.

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

Tel./Fax: +371 67083205 / +371 67083505

Email: [email protected]