Ripronat

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RYPRONAT (RIPRONAT)

Composition:

Active substance: meldonium;

1 ml of solution contains meldonium dihydrate 100 mg;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Basic physico-chemical properties: clear, colorless solution.

Pharmacotherapeutic group

Other cardiac preparations. ATC code C01EB22.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Meldonium is a carnitine precursor and a structural analogue of gamma-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom.

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 cellular membranes, thus preventing the accumulation of strong detergents—activated forms of non-oxidized fatty acids—within cells. This action helps prevent cellular membrane damage.

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 biosynthesis sites (mitochondria) to its utilization sites (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, 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 concentration of fatty acids.

It is believed that the primary basis of meldonium's efficacy lies in enhancing cellular tolerance to metabolic stress (due to changes in fatty acid levels).

Mediator Function in the Hypothetical GBB-ergic System

It has been hypothesized 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 immediate 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, leading to increased GBB-ether concentration.

As previously noted, meldonium is a structural analogue of GBB and can perform mediator functions. However, 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 induces a 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 and exhibits myocardial protective effects (including against catecholamines and alcohol). It can prevent cardiac arrhythmias and reduce the size of myocardial infarction.

Ischemic Heart Disease (Stable Angina Pectoris)

Analysis of clinical data on the course treatment of stable exertional angina with meldonium has shown that it reduces the frequency and intensity of angina attacks and decreases the need for glyceryl trinitrate. Meldonium demonstrates pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while its effect is less pronounced in patients with supraventricular extrasystoles.

Of particular importance 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 treating chronic heart failure due to IHD, highlighting its ability to increase tolerance to physical exertion and enhance 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 evaluated in patients with NYHA functional class I–III moderate-severity heart failure. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified to 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.

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 CNS-stimulating properties—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 as part of combined therapy for acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory insufficiency). It normalizes the tone and resistance of cerebral capillaries and arterioles and restores their reactivity.

The impact 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 therapeutic activity assessments indicate dose-dependent positive effects of meldonium 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 of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (primarily by restoring physical function) and alleviates psychological disturbances.

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

Patients' overall neurological status improves (reduced brain nerve damage and reflex pathology, regression of paresis, improved motor coordination and autonomic functions).

Pharmacokinetics

The pharmacokinetics of meldonium were studied in healthy volunteers following intravenous and oral administration.

Absorption

After intravenous administration, meldonium's bioavailability is 100%. Maximum plasma concentration (Cmax) is achieved immediately after administration. Following multiple intravenous doses, Cmax reaches 25.5±3.63 µg/mL.

After intravenous administration, the area under the concentration-time curve (AUC) differs between 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. Animal studies have shown that meldonium penetrates into lactating animals' milk. It is unknown whether meldonium passes into human breast milk.

Biotransformation

Metabolism studies in experimental animals have shown that meldonium is primarily metabolized in the liver.

Excretion

Renal excretion plays a significant role in eliminating meldonium and its metabolites. After single intravenous doses of 250 mg, 500 mg, and 1000 mg, the early elimination half-life of meldonium ranges from 5.56 to 6.55 hours, while 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 may be increased, meldonium dosage should be reduced.

Renal Impairment

In patients with impaired renal function, where bioavailability may be increased, meldonium dosage 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, meldonium dosage 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. No changes in liver function parameters were observed in humans after 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 in children under 18 years of age; therefore, its use in this patient group is contraindicated.

Clinical Characteristics

Indications

In complex therapy for the following conditions:

• Cardiovascular diseases: 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 or to any other components of the medicinal product;
• Increased intracranial pressure (due to impaired venous outflow, intracranial tumors);
• Severe hepatic and/or renal insufficiency (insufficient safety data available);
• Pregnancy and/or lactation;
• Pediatric age (safety data not available).

Interaction with other medicinal products and other forms of interaction

Meldonium can be used in combination with long-acting nitrates and other antianginal agents for the treatment of stable exertional angina, and with cardiac glycosides and diuretics for the treatment of heart failure.

Meldonium can 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.

A positive effect of combined therapy with meldonium and lisinopril has been observed (vasodilation of major arteries, improved peripheral circulation and quality of life, reduction of mental and physical stress).

When iron preparations and meldonium were used concomitantly in patients with iron-deficiency anemia, improvement in fatty acid composition of erythrocytes was 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 pathologies 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 AZT or other drugs for AIDS treatment 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. A pronounced anticonvulsant effect of meldonium was demonstrated in pentetrazole-induced seizures. 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 caused by indinavir and neurotoxicity caused by efavirenz.

The medicinal product should not be used in combination with other products containing meldonium, as this may increase the risk of adverse reactions.

Special precautions for use

Many years of experience in the treatment of acute myocardial infarction and unstable angina in cardiology departments shows that meldonium is not a first-line drug in acute coronary syndrome.

The medicinal product should be used with caution in patients with a history of mild to moderate hepatic and/or renal impairment. During treatment, liver and/or kidney function should be monitored in such patients.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies are insufficient to assess the effects of meldonium on pregnancy, embryo/fetal development, delivery, and postnatal development. The potential risk to humans is unknown. The medicinal product is contraindicated during pregnancy.

Breastfeeding period

Available animal data indicate that meldonium passes into the milk of nursing animals. It is unknown whether meldonium is excreted in human breast milk. Risk to newborns/infants cannot be ruled out; therefore, the medicinal product is contraindicated during breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery

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

Method of Administration and Dosage

The medicinal product is intended for intravenous use. No special preparation of the solution is required prior to administration.

Due to the possible stimulatory effect, the medicinal product is recommended to be administered in the first half of the day.

Adults

The medicinal product should be administered at a dose of 500–1000 mg (5–10 mL) intravenously in 1 or 2 doses.

The duration of treatment is usually 10–14 days, after which treatment should be continued with an oral dosage form.

The total course of treatment lasts 4–6 weeks. The course of treatment 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 the medicinal product.

Patients with Renal Impairment

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

Patients with Hepatic Impairment

Patients with mild to moderate hepatic impairment should receive a reduced dose of the medicinal product.

Children

There is a lack of data on the safety and efficacy of meldonium in children under 18 years of age; therefore, the medicinal product is contraindicated in this patient group.

Overdose

Symptoms

Cases of overdose have not been reported. Meldonium is low-toxicity and does not cause life-threatening adverse reactions. In cases of reduced arterial pressure, symptoms such as headache, dizziness, tachycardia, and general weakness may occur.

Treatment

Symptomatic therapy. In cases of severe overdose, liver and kidney functions should be monitored. Hemodialysis is not significantly effective in meldonium overdose due to extensive protein binding in the blood.

Adverse Reactions

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

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, hypesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.

Cardiac disorders:

Rare – heart rhythm changes, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest 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, vomiting urge, 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 (ECG) abnormalities, tachycardia, eosinophilia*.

* Adverse effects observed in previously conducted uncontrolled clinical trials.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or 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

Store at temperatures not exceeding 25 °C in the original packaging, in a place inaccessible to children. Do not freeze.

Packaging

5 ml in an ampoule, 5 ampoules in a blister pack, 2 blister packs together with the instructions for medical use in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Mefar Ilac San. A.S. /
Mefar Ilac San. A.S.

Manufacturer's address and location of business activity

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey /
Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorization Holder

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.