Mildracor-novopharm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MILDRAKOR-NOVOFARM

Composition:

Active substance: mildronate;

1 ml contains 100 mg of mildronate;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear colorless liquid.

Pharmacotherapeutic group. Agents affecting the cardiovascular system. 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 carnitine biosynthesis and consequently interfering with 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 — thereby protecting cellular membranes from damage.

Under ischemic conditions, reduced carnitine concentration delays beta-oxidation of fatty acids, optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores ATP transport from its site of biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, while the utilization of these substances is also 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 increasing cellular tolerance to metabolic stress (associated with changes in fatty acid levels).

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

A hypothesis has been proposed that a neuronal signal transmission system — the GBB-ergic system — exists in the body, responsible for transmitting nerve impulses between cells. The mediator of this system is the immediate precursor of carnitine — GBB ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thus 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, in response to stimulation, new GBB molecules are synthesized again, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, leading to increased concentration of GBB ester.

As previously mentioned, meldonium is a structural analogue of GBB and can act as a mediator. In contrast, GBB-hydroxylase does not recognize meldonium; therefore, carnitine concentration does not increase but decreases. Thus, by replacing the natural mediator and promoting increased GBB concentration, meldonium induces a 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 shown that meldonium positively affects myocardial contractility, 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 meldonium in patients with stable exertional angina shows that the drug reduces the frequency and intensity of angina attacks, as well as the amount of nitroglycerin required. The drug exerts pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while the effect is less pronounced 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.

In numerous clinical studies, the role of meldonium in treating chronic heart failure due to IHD has been evaluated, demonstrating its ability to increase tolerance to physical exertion and enhance the amount of work performed by patients with heart failure.

The efficacy of meldonium in treating NYHA functional class I–III moderate-severity heart failure has been confirmed. 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, increases exercise tolerance, 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 meldonium’s anti-hypoxic effects 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: increased motor activity and physical endurance, stimulation of behavioral responses, as well as anti-stress effects — stimulation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, and protection of internal organs from stress-induced changes.

Efficacy in neurological disorders.

Meldonium has been proven effective 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, 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 (mainly due to restoration of physical function) and eliminates psychological disturbances.

Meldonium exerts a positive influence on nervous system function, manifested by reduced 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.

The area under the concentration-time curve (AUC) after single and repeated intravenous doses of meldonium differs, 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 breast milk.

Biotransformation

Animal studies have shown that meldonium is primarily metabolized in the liver.

Excretion

Renal excretion plays a significant role in the elimination of meldonium and its metabolites. After single intravenous doses of meldonium (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 renal impairment, 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 high-dose meldonium administration (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. However, no changes in liver function parameters were observed in humans after administration of high doses (400–800 mg). Nevertheless, fat infiltration of 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, the use of the drug 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 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;
• increased intracranial pressure (due to impaired venous outflow, intracranial tumors);
• severe hepatic and/or renal insufficiency (insufficient data on safety of use).

Interaction with other medicinal products and other types of interactions.

Meldonium may be used in combination with long-acting nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides and diuretic medicinal products (for heart failure). It may also be combined with anticoagulants, antiplatelet agents, antiarrhythmic agents and other medicinal products improving microcirculation.

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

In patients with iron-deficiency anemia, concomitant use 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 injuries, an additional pharmacological effect is observed.

Meldonium helps eliminate cardiac changes 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 medicinal products for AIDS treatment has a positive impact 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 pentylentetrazole, a pronounced anticonvulsant effect of meldonium was demonstrated. In turn, pretreatment with the alpha2-adrenoblocker yohimbine at a dose of 2 mg/kg and with the nitric oxide synthase (NOS) inhibitor N-(G)-nitro-L-arginine at a dose of 10 mg/kg completely blocks the anticonvulsant effect of meldonium.

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 the risk of adverse reactions may increase.

Special precautions for use.

Caution should be exercised when administering the medicinal product to patients with a history of mild to moderate hepatic and/or renal function 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 medicinal agent in acute coronary syndrome.

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 breast milk. It is unknown whether meldonium is excreted in human breast milk. Risk to newborns/infants cannot be excluded; therefore, meldonium is contraindicated during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

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

Dosage and Administration

Administer intravenously. No special preparation of the medicinal product is required prior to administration. Due to the possible stimulating effect, the medicinal product is recommended to be administered in the first half of the day.

Adults

Cardiovascular diseases; cerebrovascular disorders

The dose is 500–1000 mg (5–10 mL) per day. The dose may be administered once daily or divided into two doses. Maximum daily dose − 1000 mg.

Reduced work capacity, physical and psycho-emotional overstrain, and recovery period after cerebrovascular disorders, head injuries, and encephalitis

The dose is 500 mg (5 mL) per day. Maximum daily dose − 500 mg.

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

Elderly patients

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

Patients with impaired kidney function

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

Patients with impaired liver function

Patients with mild to moderate hepatic impairment should receive a lower dose of meldonium.

Children

There is no safety and efficacy data available for the use 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 medicinal product 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 its pronounced binding to blood proteins.

Side effects.

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

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

Immune system disorders

Often: allergic reactions.

Rarely: hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions up to shock.

Psychiatric disorders

Rarely: excitement, fear, obsessive thoughts, sleep disturbances.

Nervous system disorders

Often: headaches.

Rarely: paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.

Cardiac disorders

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

Vascular disorders

Rarely: increased/decreased blood pressure, hypertensive crisis, hyperemia, pallor.

Respiratory, thoracic and mediastinal disorders

Often: respiratory tract infections.

Rarely: pharyngitis, cough, dyspnea, apnea.

Gastrointestinal disorders

Often: dyspepsia.

Rarely: dysgeusia (metallic taste in mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation.

Skin and subcutaneous tissue disorders

Rarely: rash, generalized/maculopapular/papular rash, pruritus.

Musculoskeletal and connective tissue disorders

Rarely: back pain, muscle weakness, muscle spasms.

Renal and urinary disorders

Rarely: pollakiuria.

General disorders and administration site conditions

Rarely: 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

Often: dyslipidemia, increased level of C-reactive protein.

Rarely: electrocardiogram (ECG) abnormalities, increased heart rate, eosinophilia.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 25 °C. Do not freeze.

Incompatibilities.

Not known. The medicinal product must not be mixed in the same syringe with other medicinal products.

Packaging.

5 ml in a vial; 5 vials in a blister pack; 1 or 2 blister packs in a cardboard carton.

Prescription category. Prescription only.

Manufacturer. Limited liability company "Novopharm-Biosyntez".

Manufacturer's address and location of business activity.

38 Zhutomyrska Street, city of Zvyahel, Zvyahelskyi district, Zhytomyr region, 11700, Ukraine.