Ripronat

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

Composition:

Active substance: meldonium;

1 hard capsule contains 250 mg or 500 mg of meldonium;

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

250 mg capsule (body and cap): titanium dioxide (E 171), iron oxide yellow (E 172), gelatin;

500 mg capsule (body and cap): titanium dioxide (E 171), iron oxide yellow (E 172), quinoline yellow (E 104), azorubine (E 122), Ponceau 4R (E 124), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

250 mg capsules: hard, glossy beige-colored capsules containing a homogeneous powder of white or almost white color;

500 mg capsules: hard, glossy capsules with a red cap and a beige body, containing a homogeneous powder of white or almost white color.

Pharmacotherapeutic group.

Other cardiac preparations. ATC code C01EB22.

Pharmacological Properties.

Pharmacodynamics.

Meldonium is a carnitine precursor 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.

Effect on carnitine biosynthesis.

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis. As a result, it hinders 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, cellular membrane damage is prevented.

Under ischemic conditions, reduced carnitine concentration delays fatty acid beta-oxidation, 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 the utilization of these substances is optimized.

Conversely, when biosynthesis of the carnitine precursor—GBB—increases, nitric oxide synthase (NO synthase) is activated, leading to 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 primary basis of meldonium’s efficacy lies in increasing cellular tolerance to metabolic stress (through modulation of 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 precursor of carnitine—GBB ether. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring an 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, 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 "mediator" functions. However, unlike GBB, gamma-butyrobetaine hydroxylase does not recognize meldonium, so carnitine concentration does not increase but decreases. Thus, meldonium, by replacing the "mediator" and promoting increased GBB concentration, triggers the corresponding physiological response. As a result, overall metabolic activity increases in other systems as well, such as the central nervous system (CNS).

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 enhances neuronal resistance under hypoxic conditions.

Meldonium exerts 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.

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 shows a positive effect on the recovery of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (primarily due to restoration of physical function) and eliminates psychological disturbances.

Meldonium has 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).

Effect on the cardiovascular system.

Animal studies have shown that meldonium positively influences myocardial contractile activity and exhibits cardioprotective effects (including protection against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces myocardial infarct size.

Ischemic heart disease (stable exertional angina).

Analysis of clinical data on course administration of meldonium in the treatment of stable exertional angina shows that it reduces the frequency and intensity of angina attacks and decreases the need for glyceryl trinitrate. It exerts pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, with less pronounced effects 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 enhance work capacity in heart failure patients.

In a separate study conducted at cardiology institutes in Latvia and Tomsk, the efficacy of meldonium in heart failure of NYHA (New York Heart Association) functional classes I–III of moderate severity was evaluated. 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 tolerance to physical exertion, and enhances patients’ quality of life, without causing severe adverse effects. However, 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.

Pharmacokinetics.

Absorption.

After single oral administration, the maximum plasma concentration (Cmax) of meldonium is 2.23–2.43 µg/mL, and after repeated dosing, it reaches 2.77 µg/mL. The 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 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 impaired renal function and increased bioavailability, meldonium dosage should be reduced. Non-clinical studies have shown that oral administration of meldonium to animals at doses of 20, 100, and 500 mg/kg is low in toxicity and does not affect kidney function. 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. There is no direct effect of meldonium, GBB, or the meldonium/GBB combination on the renin-angiotensin-aldosterone system.

Hepatic impairment.

In patients with impaired liver function and increased bioavailability, meldonium dosage should be reduced. Toxicity studies in rats showed that doses exceeding 100 mg/kg caused 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 high-dose administration (400–800 mg). However, hepatic fat infiltration 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 in the following cases:

• diseases of the heart and vascular system: stable exertional angina, chronic heart failure (I–III NYHA functional class), 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 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 (there are insufficient data on safety of use);
• pregnancy and breastfeeding period;
• pediatric age (there are no data on safety of use).

Interaction with other medicinal products and other forms of interaction.

Meldonium may be used in combination 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, antiarrhythmic agents, 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.

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, simultaneous use of iron preparations and meldonium improved the fatty acid composition in erythrocytes.

When meldonium is used in combination with orotic acid to eliminate ischemia/reperfusion-induced injuries, 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 the treatment of AIDS has a positive effect in the treatment of acquired immunodeficiency syndrome (AIDS).

In the test of loss of righting reflex induced by ethanol, meldonium reduced the duration of sleep. In seizures induced by pentetrazole, a pronounced anticonvulsant effect of meldonium was observed. In turn, when alpha2-adrenoblocker yohimbine at a dose of 2 mg/kg and nitric oxide synthase (NOS) inhibitor N-(G)-nitro-L-arginine at a dose of 10 mg/kg were administered prior to meldonium therapy, the anticonvulsant effect of meldonium was completely blocked.

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 in combination with other drugs containing meldonium, as this increases 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 a history of mild to moderate hepatic and/or renal function impairment. Liver and/or kidney function should be monitored during treatment in such patients.

Due to the possible development of a stimulating effect, the medicinal product 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. 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. The risk to newborns/infants cannot be excluded; therefore, the medicinal product is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration.

The medicinal product is intended for oral administration. Capsules should be swallowed with water, regardless of food intake.

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, overexertion, and recovery period.

The medicinal product should be administered at a dose of 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 course is 4–6 weeks. The course of treatment may be repeated 2–3 times per year.

Elderly patients.

For elderly patients with impaired liver and/or kidney function, a dose reduction of the medicinal product may be necessary.

Patients with impaired kidney function.

Since meldonium is eliminated from the body via the kidneys, patients with mild to moderate kidney impairment should receive a reduced dose of the medicinal product.

Patients with impaired liver function.

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

Children.

There is a lack of data on the safety and efficacy of meldonium use 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, headache, dizziness, tachycardia, and general weakness may occur.

Treatment.

Symptomatic therapy. In case 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 according to MedDRA (Medical Dictionary for Regulatory Activities) by system organ class and frequency of occurrence: 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 up to shock.

Psychiatric disorders:

Rare — excitement, fear, obsessive thoughts, sleep disturbances.

Nervous system disorders:

Common — headache*; rare — paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbances, pre-syncope, syncope.

Cardiac disorders:

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

Vascular disorders:

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

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 reflex, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation.

Skin and subcutaneous tissue disorders:

Rare — rash, generalized/maculopapular/papular eruptions, 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, swelling, facial edema, leg edema, feeling of warmth, feeling of cold, cold sweat.

Investigations:

Common — dyslipidemia, increased C-reactive protein levels; rare — electrocardiogram (ECG) abnormalities, tachycardia, eosinophilia*.

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

Upper abdominal pain and migraine have been reported with the use of meldonium.

Suspected adverse reactions reporting.

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

250 mg capsules: 10 capsules per blister; 4 or 6 blisters per cardboard box.

500 mg capsules: 15 capsules per blister; 4 blisters per cardboard box.

Prescription category.

By prescription only.

Manufacturer.

K.O. Rompharm Company S.R.L. /
S.C. Rompharm Company S.R.L.

Manufacturer's address and location of business operations.

1A Eroilor Street, Otopeni, 075100, Ilfov County, Romania /
Romania, Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov.

Marketing Authorization Holder.

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