Meldonium nextpharm

INSTRUCTIONS for medical use of the medicinal product Meldonium Nextpharm (MeldoniumNextpharm)

Composition:

Active substance: meldonium dihydrate;

1 ml of solution contains 100 mg of meldonium dihydrate;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear, colorless solution.

Pharmacotherapeutic group

Cardiovascular drugs. Other cardiac preparations. Meldonium. ATC code C01EB22.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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 interferes with the transport of long-chain fatty acids across cell membranes, thus preventing the accumulation of strong detergents—activated forms of non-oxidized fatty acids—within cells. This mechanism helps prevent damage to cellular membranes.

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 supplied with nutrients and oxygen, and utilization of these substances is optimized.

Conversely, increased biosynthesis of the carnitine precursor—gamma-butyrobetaine (GBB)—activates NO synthase, leading to improved blood rheological properties and reduced peripheral vascular resistance.

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

It is believed that the primary basis for meldonium’s efficacy is increased cellular tolerance to metabolic stress (due to changes in 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 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, leading to increased GBB ester concentration.

As previously mentioned, meldonium is a structural analogue of GBB and can perform the function of a "mediator." However, GBB hydroxylase does not recognize meldonium, so carnitine concentration does not increase but rather decreases. Thus, meldonium, by replacing the "mediator" and 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).

Effects on the cardiovascular system

Animal studies have demonstrated that meldonium positively affects myocardial contractility, possesses 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-based use of meldonium in the treatment of stable exertional angina shows that it reduces the frequency and intensity of angina attacks and decreases the required dosage of glyceryl trinitrate. Meldonium exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while its effect is less pronounced in patients with supraventricular extrasystoles.

Particularly important is meldonium’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 plasma cholesterol levels and the atherogenic index.

Chronic heart failure

Numerous clinical studies have analyzed the role of meldonium in the treatment of chronic heart failure due to IHD. It has been shown to increase exercise tolerance and the amount of physical work performed by patients with heart failure.

A separate study conducted at cardiology institutes in Latvia and Tomsk evaluated the efficacy of meldonium in heart failure of functional classes I–III according to the New York Heart Association (NYHA) classification, with moderate severity. Under 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 exercise tolerance, enhances patients’ quality of life, and does not cause 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

Animal experiments have demonstrated meldonium’s antihypoxic effects and its influence on cerebral circulation. It optimizes redistribution of cerebral blood flow in favor of ischemic areas and increases neuronal resistance under hypoxic conditions.

Meldonium has a stimulatory 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

Meldonium has been proven effective in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral insufficiency). It 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 impairments (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 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 by restoring physical function) and eliminates psychological disturbances.

Meldonium exerts 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

Meldonium pharmacokinetics have been studied in healthy volunteers after intravenous and oral administration.

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 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 milk in lactating females.

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. After single intravenous doses of 250 mg, 500 mg, and 1000 mg, the initial elimination half-life of meldonium ranges from 5.56 to 6.55 hours, while the terminal half-life is 15.34 hours.

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 (see section "Administration and dosage").

Renal impairment

In patients with impaired renal function, where bioavailability may be increased, the dose of meldonium should be reduced (see section "Administration and dosage"). 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 (see section "Administration and dosage"). 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 doses of meldonium (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. No changes in liver function parameters were 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, the use of this 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 the heart and vascular system;
• acute and chronic ischemic disorders of cerebral circulation;
• reduced work capacity, physical and psycho-emotional overstrain;
• during the recovery period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications

• Hypersensitivity to meldonium and/or to any of the excipients of the medicinal product;
• increased intracranial pressure (in case of 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 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 iron-deficiency anemia, co-administration of iron preparations and meldonium improved fatty acid composition in erythrocytes.

When meldonium was used in combination with orotic acid to counteract ischemia/reperfusion-induced injuries, an additional pharmacological effect was 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 AIDS treatment has a positive effect in the treatment of AIDS.

In the test of ethanol-induced loss of righting reflex, meldonium reduced the duration of sleep. In seizures induced by pentetrazole, 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 blocked 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 induced by indinavir and neurotoxicity induced by efavirenz.

Do not use in combination 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 a history of mild to 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 are insufficient animal studies to assess the effects of meldonium on pregnancy, embryonic/fetal development, labor, 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. The risk to newborns/infants cannot be excluded; therefore, meldonium is contraindicated during breastfeeding.

Ability to influence reaction rate when 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 intravenous use.

The medicinal product does not require special preparation 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

The dose is 500–1000 mg (5–10 mL) administered intravenously either as a single dose or divided into two doses. The duration of treatment is usually 10–14 days, after which therapy should be continued with an oral dosage form.

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

Elderly Patients

Elderly patients with impaired liver and/or kidney function may require a reduced dose of meldonium (see section "Pharmacokinetics").

Patients with Renal Impairment

Since meldonium is eliminated via the kidneys, patients with mild to moderate renal impairment should receive a reduced dose of the medicinal product (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Patients with Hepatic Impairment

Patients with mild to moderate hepatic impairment should receive a reduced dose of meldonium (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Children

There are no data on the safety and efficacy of meldonium in children (under 18 years of age); therefore, the use of meldonium in this patient population is contraindicated.

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 hypotension, 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 its pronounced protein binding.

Adverse Reactions

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

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

*Adverse reactions observed in previously conducted non-controlled clinical trials.

Reports have also been received regarding the occurrence of upper abdominal pain and migraine associated with the use of mildronate.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Keep out of reach and sight of children. Store at a temperature not exceeding 25 ºC.

Do not freeze.

Packaging

5 ml in a vial, 5 vials in a blister pack; 2 blister packs in a cardboard box.

Prescription status

Prescription only.

Manufacturer

UORLID MEDITSIN ILAT SAN. VE TIDJ. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of business activity

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey /
COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.