Mildralax-zdorovya

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

Composition:

Active substance: meldonium (trimethylhydrazinium propionate);

1 ml of solution contains meldonium dihydrate 100 mg;

Excipient: 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 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. As a result, it impedes 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. This mechanism helps prevent damage to cellular membranes.

Under ischemic conditions, reduced carnitine concentration leads to inhibition of fatty acid beta-oxidation, optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores 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.

Conversely, when biosynthesis of carnitine’s precursor—i.e., GBB—is increased, nitric oxide (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 intracellular levels of fatty acids.

It is believed that the basis of meldonium’s efficacy lies in enhancing cellular tolerance to metabolic stress (via modulation of fatty acid levels).

1. Mediator function in the hypothetical GBB-ergic system.

A hypothesis has been proposed that a neuronal signaling 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 ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring an electrical impulse and converting into GBB. The hydrolyzed form of GBB is 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 ester.

Meldonium, being a structural analogue of GBB, 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, 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).

Effects on the cardiovascular system.
It has been established that meldonium exerts a positive effect on myocardial contractility and possesses myocardial protective properties (including protection against catecholamines and alcohol). It can prevent cardiac arrhythmias and reduce the size of myocardial infarction.

Ischemic heart disease (IHD, 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 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 influences atherosclerotic processes in coronary and peripheral vessels by reducing total serum cholesterol levels and the atherogenic index.

Chronic heart failure.
Meldonium has been shown to increase tolerance to physical exertion and the amount 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 into functional class I. It has been established that meldonium improves myocardial inotropic function and increases exercise tolerance, thereby enhancing 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.

Effects on the CNS.
Meldonium has demonstrated anti-hypoxic effects and beneficial effects 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 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 capillary and arteriolar tone and resistance in the brain and restores their reactivity.

The effect of meldonium on the rehabilitation process in patients with neurological deficits (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 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 by restoring 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 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, indicating potential 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. It has been established that meldonium penetrates into breast milk.

Biotransformation. 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 early elimination half-life ranges from 5.56 to 6.55 hours, and the terminal elimination half-life is 15.34 hours.

Special patient groups.

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

Renal impairment. In patients with impaired renal function and increased bioavailability, 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 and increased bioavailability, 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. Following 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 were observed in humans after administration of high doses (400–800 mg). 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.

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 of the drug;
• 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 interactions.

Meldonium may be used concomitantly with prolonged-action nitrates and other antianginal agents (stable exertional angina), cardiac glycosides, and diuretics (heart failure). It may also be combined with anticoagulants, antiplatelet agents, antiarrhythmic agents, and other drugs improving microcirculation.

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

When used concomitantly with iron preparations in patients with iron-deficiency anemia, improvement in the 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 damage 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 AIDS 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 pentetrazol, a pronounced anticonvulsant effect of meldonium was demonstrated. In turn, 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 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 (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.

Use during pregnancy or breastfeeding.

Pregnancy. There is insufficient animal data available to assess the effects of meldonium on pregnancy, embryonic/foetal 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. A risk to newborns/infants cannot be excluded; therefore, meldonium is contraindicated during breastfeeding.

Ability to affect reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

Administer intravenously. No special preparation of the drug prior to administration is 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) per day, administered either as a single dose or divided into two doses. The treatment duration usually lasts 10–14 days, after which therapy continues with the oral dosage form. The total course of treatment lasts 4–6 weeks. The treatment 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 excreted through 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.

Safety and efficacy of meldonium in children under 18 years of age have not been established; therefore, meldonium is contraindicated in this patient population.

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

Hemodialysis is not significantly effective in meldonium overdose due to extensive plasma protein binding.

Adverse Reactions

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

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

Immune system disorders:
Common: allergic reactions*;
Rare: hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions up to shock.

Psychiatric disorders:
Rare: excitement, fear, obsessive thoughts, sleep disturbances.

Nervous system disorders:
Common: headache*;
Rare: paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.

Cardiac disorders:
Rare: change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/pain.

Vascular disorders:
Rare: increased/decreased blood pressure, hypertensive crisis, hyperemia, pallor.

Respiratory, thoracic and mediastinal disorders:
Common: respiratory tract infections;
Rare: pharyngitis, cough, dyspnea, apnea.

Gastrointestinal disorders:
Common: dyspepsia*;
Rare: dysgeusia (metallic taste in mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation.

Skin and subcutaneous tissue disorders:
Rare: rash, generalized/maculopapular rash, pruritus.

Musculoskeletal and connective tissue disorders:
Rare: back pain, muscle weakness, muscle spasms.

Renal and urinary disorders:
Rare: pollakiuria.

General disorders and administration site conditions:
Rare: general weakness, chills, asthenia, edema, facial swelling, leg swelling, feeling of warmth, feeling of cold, cold sweat, injection site reactions, including pain at injection site.

Investigations:
Common: dyslipidemia, increased C-reactive protein level;
Rare: electrocardiogram abnormalities, increased heart rate, eosinophilia*.

* Adverse effects observed in previously conducted uncontrolled clinical trials.

Shelf life. 4 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 ampoules, 10 ampoules per box; 5x2 in blisters per box.

Prescription status. By prescription only.

Manufacturer.
Limited Liability Company "Pharmaceutical Company "Zdorov'ya".

Manufacturer's address and place of business.
22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.