Mildralax-zdorovya

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MILDRALEX-ZDOROVYE (MILDRALEX-ZDOROVYE)

Composition:

Active substance: meldonium;

1 capsule contains meldonium dihydrate 250 mg or 500 mg;

Excipients: potato starch, calcium stearate, colloidal anhydrous silicon dioxide; the capsule shell contains titanium dioxide (E 171), gelatin.

Pharmaceutical form: Hard capsules.

Main physicochemical properties: white-colored hard gelatin capsules.

The capsule contents consist of a mixture containing white granules and powder with a slight odor. The presence of agglomerates is acceptable. The manufacturer's trademark – ZT – may be printed on the capsule.

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.

Effect 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—activated forms of non-oxidized fatty acids. Consequently, cellular membrane damage is prevented.

Under ischemic conditions, reduced carnitine concentration leads to delayed beta-oxidation of fatty acids, optimizing cellular oxygen consumption, stimulating glucose oxidation, and restoring ATP transport from its biosynthesis sites (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and the utilization of these substances is optimized.

Conversely, when biosynthesis of the carnitine precursor—i.e., GBB—increases, nitric oxide synthase (NO-synthase) is activated, resulting in improved blood rheological properties and reduced peripheral vascular resistance.

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

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

Mediator Function 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 transferring 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, new GBB molecules are synthesized in response to stimulation, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, increasing the 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, meldonium—both by replacing the "mediator" and by promoting increased GBB concentration—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. It has been established that meldonium exerts a positive effect on myocardial contractile activity. It possesses myocardial protective properties (including protection 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 angina pectoris with meldonium shows that the drug reduces the frequency and intensity of angina attacks and decreases the required amount of glyceryl trinitrate. 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 and the atherogenic index.

Chronic Heart Failure. Meldonium has been shown to increase tolerance to physical exertion and the volume of work performed by patients with heart failure.

The efficacy of meldonium has been studied in patients with NYHA functional class I–III moderate-severity heart failure. Under meldonium therapy, 59–78% of patients initially diagnosed with functional class II heart failure were reclassified to functional class I. It has been established that meldonium improves myocardial inotropic function and increases exercise tolerance, enhances quality of life, and does not cause severe adverse effects. However, meldonium may cause mild hypotension. Other possible adverse effects include skin allergic reactions, headache, 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. Meldonium has demonstrated anti-hypoxic effects and improves 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, accumulating catecholamines in the brain and adrenal glands, and protecting internal organs from stress-induced changes.

Efficacy in Neurological Disorders. Meldonium has been proven effective as part of combination therapy for 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 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 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 a positive influence 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 a single oral dose, Cmax is 2.23–2.43 μg/mL, and after repeated dosing, it is 2.77 μg/mL. 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, and plasma protein binding is 78%. Meldonium and its metabolites partially cross the placental barrier.

Biotransformation. 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 of meldonium is approximately 3.5–4 hours. With repeated dosing, the elimination half-life differs, suggesting possible accumulation of meldonium in blood 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, 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.

Hepatic Impairment. In patients with impaired liver function, where bioavailability may be increased, the dose of meldonium should be reduced. Administration of meldonium at doses exceeding 100 mg/kg has been associated with yellow discoloration of the liver and fat denaturation. After high doses of meldonium (400 mg/kg and 1600 mg/kg), lipid accumulation in liver cells has been observed. However, no changes in liver function parameters have been observed in humans after administration of high doses (400–800 mg). Fat infiltration of 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, 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 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).

Interaction with other medicinal products and other forms of interaction.

Meldonium may be used concomitantly with prolonged-action 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, antiarrhythmics, and other drugs improving microcirculation.
Meldonium may enhance the effects of medicinal products containing glyceryl trinitrate, nifedipine, beta-adrenoblockers, and other antihypertensive agents and peripheral vasodilators.

In patients with chronic heart failure receiving meldonium and lisinopril to reduce symptom manifestations, a positive effect of combined therapy has been 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, co-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 zidovudine or other drugs for the treatment of acquired immunodeficiency syndrome (AIDS) has a beneficial effect in AIDS therapy.
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 demonstrated. 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 neurotoxicity induced by efavirenz.

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

Special precautions for use

Patients with mild to moderate hepatic and/or renal impairment should use the drug with caution (liver and/or kidney function should be monitored).

Long-term clinical experience in the treatment of 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 potential for stimulating effects, 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 assess the effects of meldonium on pregnancy, embryonic/fetal development, delivery, and postnatal development. The potential risk in humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding

Available data from animal studies 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 speed while 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

For oral administration, taken during or after a meal. Swallow the capsule with water. Due to the possible stimulating effect, the drug is recommended to be taken in the first half of the day.

Adults.

Cardiovascular diseases, cerebrovascular disorders.

The dose is 500–1000 mg per day. The daily dose may be taken all at once or divided into two doses. The maximum daily dose is 1000 mg.

For reduced work capacity, overexertion, and during convalescence.

The daily dose should not exceed 500 mg.

The 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 dose reduction of meldonium may be required.

Patients with renal impairment.

Since the drug is excreted by the kidneys, patients with mild to moderate renal impairment should receive a reduced 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, 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.

With reduced arterial 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 extensive plasma protein binding.

Adverse reactions.

Adverse reactions are classified by organ systems and MedDRA frequency: common (≥1/100, <1/10), rare (≥1/10,000, <1/100), very rare (<1/10,000).

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

* Adverse reactions observed in previously conducted uncontrolled clinical trials.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

Capsules 250 mg, 10×4 in blisters in a carton or 500 mg, 10×6 in blisters in a carton.

Prescription status. By prescription only.

Manufacturer. Limited liability company "Pharmaceutical Company "Zdorovye".

Manufacturer's address and location of business activity.

22, Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.