Mildronate®

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

Composition:

Active substance: meldonium;

1 hard capsule contains 250 mg of meldonium dihydrate;

Excipients: potato starch, silicon dioxide, calcium stearate;

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

Dosage form. Hard capsules.

Main physico-chemical properties: white hard gelatin capsules. The contents of the capsules are a white crystalline powder with a slight odor. The powder is hygroscopic.

Pharmacotherapeutic group.

Other cardiac preparations. ATC code C01EB22.

Pharmacological properties.

Pharmacodynamics.

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. Influence on carnitine biosynthesis.

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

Under ischemic conditions, reduced carnitine concentration delays beta-oxidation of fatty acids, optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores adenosine triphosphate (ATP) transport from its site of biosynthesis (mitochondria) to its site of utilization (cytosol). Essentially, cells are better supplied with nutrients and oxygen, and 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 resumes and the amount of fatty acids gradually increases within cells.

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

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

A hypothesis has been proposed that a neuronal signal transmission system—termed 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 transmitting an electrical impulse, and itself is converted 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 GBB-ether concentration.

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 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).

Effects on the CNS.

In animal experiments, meldonium has demonstrated anti-hypoxic effects and improved cerebral circulation. Meldonium optimizes redistribution of cerebral blood flow in favor of ischemic areas and enhances neuronal resistance under hypoxic conditions.

Meldonium exerts a stimulatory effect on the CNS—increasing motor activity and physical endurance, stimulating behavioral responses, and demonstrating 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.

Rehabilitation processes have been studied in patients with neurological impairments (following cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis).

Therapeutic activity studies of meldonium indicate its 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 effect on the recovery process of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (primarily through restoration of physical function) and contributes to the alleviation of psychological disorders.

Meldonium has a positive impact 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.

Absorption

After single oral administration of meldonium at doses of 25, 50, 100, 200, 400, 800, or 150 mg, maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) increase proportionally to the administered dose. Time to reach maximum plasma concentration (tmax) is 1–2 hours. At repeated dosing, steady-state plasma concentration is achieved within 72–96 hours after the first dose. Accumulation of meldonium in plasma is possible. Food slightly delays absorption but does not alter Cmax and AUC values.

Distribution

Meldonium rapidly distributes from the bloodstream into tissues. Plasma protein binding increases over time after dose administration. Meldonium and its metabolites partially cross the placental barrier. Animal studies have demonstrated excretion of meldonium 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. The elimination half-life (t1/2) of meldonium is approximately 4 hours. With repeated dosing, the elimination half-life may differ.

Special patient groups

Elderly patients

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

Impaired renal function

In patients with impaired renal function and increased bioavailability, meldonium dosage should be reduced. Non-clinical studies have shown that oral administration of meldonium to animals at doses of 20, 100, and 500 mg/kg is low-toxic and does not affect kidney function. 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.

Impaired hepatic function

In patients with impaired liver function and increased bioavailability, meldonium dosage should be reduced. Toxicity studies in animals showed yellow discoloration of the liver and fat denaturation after administration of meldonium at doses exceeding 100 mg/kg. Histopathological studies in animals after high-dose meldonium administration (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. No changes in liver function parameters have been 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 use in children (under 18 years of age); therefore, its use in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy in the following cases:

• reduced work capacity, physical and psycho-emotional 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 (due to impaired venous outflow, intracranial tumors);
• severe hepatic and/or renal insufficiency (insufficient safety data available);
• children under 18 years of age;
• pregnancy;
• breastfeeding.

Interaction with other medicinal products and other types of interactions.

Meldonium can be used in combination with prolonged-action nitrates and other antianginal agents, cardiac glycosides, and diuretics. 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-adrenergic blockers, other antihypertensive agents, and peripheral vasodilators.

When meldonium is used concomitantly with lisinopril, a positive effect of combined therapy has been observed (vasodilation of major arteries, improved peripheral circulation and quality of life, reduction of mental and physical stress).

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

In patients with iron-deficiency anemia, co-administration of iron-containing drugs and meldonium improved the fatty acid composition in erythrocytes.

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. During seizures induced by pentetrazol, pronounced anticonvulsant action of meldonium was observed. In turn, when the alpha2-adrenergic blocker 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 a protective effect against cardiotoxicity caused by indinavir and neurotoxicity caused by efavirenz.

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

Special precautions for use.

Caution should be exercised when administering the medicinal product to patients with mild to moderate hepatic and/or renal impairment in their medical history (monitoring of liver and/or kidney function is recommended).

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient animal studies to evaluate the effect 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 study 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 influence reaction rate while driving or operating machinery.

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

Method of Administration and Dosage

For oral use. Swallow the capsules with water. The medicinal product can be taken orally either before or after a meal. Due to the possible stimulating effect, it is recommended to take the drug in the first half of the day.

Adults

The dose is 500 mg per day (2 capsules of 250 mg). The daily dose may be taken all at once or divided into two single doses. The maximum daily dose is 500 mg.

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

Elderly Patients

For elderly patients with impaired liver and/or kidney function, a reduced dose of meldonium may be required.

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 is no data on the safety and efficacy of meldonium in children (under 18 years of age). Therefore, 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 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 binding of the drug to blood proteins.

Adverse reactions.

Meldonium is generally well tolerated.

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 trials and during the post-marketing period:

* Adverse effects observed in previously conducted uncontrolled clinical trials.

Shelf life. 4 years.

Do not use after the expiry date.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Store in the original packaging to protect from moisture.

Keep out of reach of children.

Packaging.

10 capsules in a blister; 2, 4 or 6 blisters in a cardboard box.

Category of release.

Over-the-counter.

Manufacturer.

JSC "Grindeks", Latvia.

Manufacturer's address.

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

Marketing Authorisation Holder.

JSC "Grindeks".

Address of the Marketing Authorisation Holder.

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

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

Email: [email protected]