Vasopro®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASOPRO® (VASOPRO®)

Composition:

Active substance: mildronate;

1 capsule contains mildronate (meldonium) equivalent to 100% substance 250 mg or 500 mg;

Excipients: potato starch, colloidal anhydrous silicon dioxide, calcium stearate;

Capsule shell composition: gelatin, titanium dioxide (E 171), azorubine, carmoisine (E 122).

Pharmaceutical form. Capsules.

Main physicochemical properties:
250 mg capsules – hard gelatin capsules № 1, body white, cap pink. Contents of capsules – crystalline powder of white or almost white color with a slight odor. The powder is hygroscopic;

500 mg capsules – hard gelatin capsules № 00, body white, cap pink. Contents of capsules – crystalline powder of white or almost white color with a slight odor. The powder is hygroscopic.

Pharmacotherapeutic group.
Other cardiac preparations. ATC code C01EB.

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 the biosynthesis of carnitine. 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, damage to cellular membranes is prevented.

Under ischemic conditions, reduced carnitine concentration delays beta-oxidation of fatty acids and optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores ATP transport from sites of its biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are provided with nutrients and oxygen, while utilization of these substances is optimized.

In turn, increased biosynthesis of the carnitine precursor—i.e., GBB—activates NO-synthase, improving blood rheological properties and reducing 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 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 signal transmission system—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 ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring the electrical impulse, and is converted into GBB. The hydrolyzed form of GBB is then actively transported to the liver, kidneys, and ovaries, where it is transformed 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.

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; therefore, carnitine concentration does not increase but decreases. Thus, by replacing the "mediator" and promoting increased GBB concentration, meldonium induces a 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.

Animal studies have demonstrated that meldonium positively influences myocardial contractile activity and exhibits myocardial protective effects (including 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 course treatment with meldonium in patients with stable exertional angina showed that the drug reduces the frequency and intensity of angina attacks, as well as the amount of nitroglycerin used. 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.

Of particular importance is the drug’s ability to reduce oxygen consumption at rest, 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.

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

In a separate study conducted at cardiology institutes in Latvia and Tomsk, the efficacy of meldonium was tested in patients with NYHA functional class I–III heart failure of moderate severity. 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 tolerance to physical exertion, and enhances patients’ quality of life, without causing severe adverse effects. However, mild hypotension may occur with meldonium use. Other possible adverse effects of meldonium include skin allergic reactions, headaches, 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.

Animal experiments have demonstrated the anti-hypoxic effect of meldonium and its ability to improve 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—activation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, and protection of internal organs against stress-induced changes.

Efficacy in neurological disorders.

It has been demonstrated that meldonium is 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 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 drug administration revealed a positive effect on the recovery process of intellectual functions during convalescence.

It has been established that meldonium improves convalescence-related quality of life (mainly due to restoration of physical function), and also alleviates psychological disturbances.

Meldonium exerts a positive influence on nervous system function—reducing neurological deficits during recovery.

Overall neurological status improves in patients (reduction in nerve and brain damage, reflex pathology, regression of paresis, improved motor coordination, and autonomic functions).

Pharmacokinetics.

Absorption.

After a single oral dose, maximum plasma concentration (Cmax) is 2.23–2.43 µg/mL, and after repeated dosing, 2.77 µg/mL. Time to reach maximum plasma concentration (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.

Metabolism studies in experimental animals 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 a single oral dose, the early elimination half-life (t1/2) of meldonium is approximately 3.5–4 hours. With repeated dosing, the elimination half-life differs. These results suggest possible accumulation of meldonium in 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, 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. Toxicity studies in rats administered meldonium at doses exceeding 100 mg/kg revealed 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) showed lipid accumulation in liver cells. However, no changes in liver function parameters were 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 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 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 psychoemotional overstrain;
• During convalescence after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium and/or to any excipient 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 can be used concomitantly with prolonged-action nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides, and diuretics (in heart failure). It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmic drugs, and other agents improving microcirculation.

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

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

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

Meldonium helps eliminate pathological changes in the heart 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 acquired immunodeficiency syndrome (AIDS).
In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazole, meldonium demonstrated pronounced anticonvulsant activity. In turn, pretreatment with 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 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 a protective effect against cardiotoxicity induced by indinavir and neurotoxicity induced by efavirenz.

Do not use meldonium capsules together with other medicinal 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 in medical history (liver and/or kidney function should be monitored).

Long-term 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 possible development of an excitatory effect, 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, parturition, and postnatal development. The potential risk in humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding. Available animal data 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 influence reaction speed when 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 use. 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.

Reduced work capacity, overexertion, and recovery period.

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

In elderly patients with impaired liver and/or kidney function, a reduction in meldonium dosage may be required.

Patients with impaired renal function.

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

Patients with impaired hepatic function.

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

Children.

There are 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 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 the drug's pronounced protein binding.

Side effects.

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

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

* Adverse effects observed in previously conducted uncontrolled clinical trials.

Shelf life.

2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in a dry place at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

250 mg capsules: 10 capsules per blister. 4 blisters per pack.

500 mg capsules: 10 capsules per blister. 6 blisters per pack.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.