Ripronat

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

Composition:

Active substance: meldonium;

1 hard capsule contains meldonium dihydrate 500 mg;

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

Capsule shell: titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules, size № 0, cap of matt red-brown color, body of matt yellow color, containing powder from white to almost white.

Pharmacotherapeutic group.

Agents acting on the cardiovascular system. 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 action on the body can be explained in two ways.

Effect on Carnitine Biosynthesis

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and consequently preventing the transport of long-chain fatty acids across cell membranes. Thus, it prevents the accumulation of strong detergents—activated forms of non-oxidized fatty acids—within cells, 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 sites of its biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and the utilization of these substances is optimized.

Conversely, 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 resumes and fatty acid levels gradually increase in cells.

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

Mediator Function in the Hypothetical GBB-ergic System

A hypothesis has been proposed that a neuronal signaling system—the GBB-ergic system—exists in the body, responsible for transmitting nerve impulses between cells. The mediator of this system is the final carnitine precursor—GBB-ether. As a result of GBB-esterase action, the mediator donates an electron to the cell, thereby transferring the electrical impulse and transforming 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 mentioned, meldonium is a structural analogue of GBB and can perform the functions of a "mediator." In contrast, GBB-hydroxylase does not recognize meldonium, so carnitine concentration does not increase but 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).

Effect on the Cardiovascular System

Animal studies have demonstrated that meldonium positively affects myocardial contractility, exhibits cardioprotective properties (including against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the size of myocardial infarction.

Ischemic Heart Disease (Stable Angina Pectoris)

Analysis of clinical data on the course treatment of stable angina pectoris with meldonium showed that it reduces the frequency and intensity of angina attacks and decreases the need for glyceryl trinitrate. It exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while the 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 affects atherosclerotic processes in coronary and peripheral vessels by reducing total plasma 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 analyzed, 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 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 NYHA class I. It has been established that meldonium improves myocardial inotropic function, increases exercise tolerance, and enhances quality of life without causing severe adverse effects. However, it should be noted that meldonium may cause mild hypotension. Other possible adverse effects include skin allergic reactions, headache, 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 meldonium's anti-hypoxic 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 effects—increased motor activity and physical endurance, stimulation of behavioral responses, and anti-stress effects—via 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). It 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, or tick-borne encephalitis) has been studied.

Results of therapeutic activity assessments indicate dose-dependent positive effects of meldonium on physical endurance and recovery of functional independence during convalescence.

Analysis of changes in individual and overall intellectual functions after meldonium administration revealed its positive impact on the recovery process of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (primarily through restoration of 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

Absorption

After single oral administration of meldonium, maximum plasma concentration (Cmax) ranges from 2.23 to 2.43 µg/mL, and after repeated dosing, it reaches 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. 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 single oral dose administration, the elimination half-life (t1/2) is approximately 3.5–4 hours. With repeated dosing, t1/2 differs, suggesting possible accumulation of meldonium in plasma.

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 and increased bioavailability, meldonium dosage should be reduced. There is an interaction between renal reabsorption of meldonium or its metabolites (e.g., 3-hydroxymeldonium) and carnitine, leading to 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 hepatic impairment and increased bioavailability, 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 hepatocytes. No changes in liver function parameters were observed in humans after administration of high doses (400–800 mg). However, possible fat infiltration into liver cells cannot be excluded.

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 in the following cases:

• 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 psycho-emotional overstrain;
• During convalescence after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications

• Hypersensitivity to meldonium or to any of the excipients of the medicinal product;
• 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 types of interactions

Meldonium may be used concomitantly with prolonged-action nitrates and other antianginal agents for the treatment of stable exertional angina, cardiac glycosides and diuretics for the treatment of heart failure.

Meldonium may be combined with anticoagulants, antiplatelet agents, antiarrhythmics, 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.

When meldonium is used concomitantly with lisinopril, a positive effect of combined therapy has been observed (vasodilation of major arteries, improvement of peripheral circulation and quality of life, reduction of mental and physical stress).

In patients with iron-deficiency anemia, concomitant use 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 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 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 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 inhibitor (NOS) 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 in cases of cardiotoxicity caused by indinavir and neurotoxicity caused by efavirenz.

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

Special precautions for use

Many years of experience in treating 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 mild to moderate hepatic and/or renal dysfunction in their medical history. During treatment, liver and/or kidney function should be monitored in such patients.

Due to the possible development of stimulating effects, the medicinal product is recommended to be administered in the first half of the day.

Use during pregnancy or breastfeeding

Pregnancy

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

Breastfeeding period

Available animal data indicate that meldonium passes into breast milk. It is unknown whether meldonium passes into human breast milk. A risk to newborns/infants cannot be excluded; therefore, the medicinal product is contraindicated during breastfeeding.

Ability to affect reaction rate when driving or operating machinery

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

Method of Administration and Dosage

Take orally, before or after meals. Swallow the capsules with water.

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

Adults

Cardiovascular diseases, cerebrovascular disorders

The medicinal product should be administered at a dose of 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, overstrain, and recovery period

The medicinal product should be administered at a dose of 500 mg per day. The maximum daily dose is 500 mg.

The duration of treatment course 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 dose reduction may be necessary.

Patients with renal impairment

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

Patients with hepatic impairment

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

Children

There are no 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

There are no reported cases of overdose. Meldonium is low-toxic and does not cause life-threatening adverse reactions. In cases of reduced arterial pressure, 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 its pronounced 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).

Immune system disorders:

Common – allergic reactions*; rare – hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions.

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 – changes in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain.

Vascular disorders:

Rare – increased/decreased blood pressure, hypertensive crisis, hyperemia, pallor of the skin.

Respiratory, thoracic and mediastinal disorders:

Rare – pharyngitis, cough, dyspnea, apnea.

Gastrointestinal disorders:

Common – dyspepsia*; rare – dysgeusia (metallic taste in mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain.

Skin and subcutaneous tissue disorders:

Rare – rash, generalized/maculopapular/papular 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.

Investigations:

Rare – electrocardiogram (ECG) abnormalities, increased heart rate, eosinophilia*.

During meldonium use, upper abdominal pain and migraine have been reported.

* 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 continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C, in the original packaging, and in a place inaccessible to children.

Packaging

15 capsules in a blister, 4 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

UORLД MEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of business activity

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar / Istanbul, Turkey.