Ripronat

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

Composition:

Active substance: mildronate;

1 hard capsule contains mildronate dihydrate 250 mg;

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

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

Pharmaceutical form. Hard capsules.

Main physico-chemical properties: hard gelatin capsules, size № 1, cap and body of matting yellow color, containing powder from white to almost white.

Pharmacotherapeutic group.

Agents acting on the cardiovascular system. Other cardiac drugs. Mildronate. 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. 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 impedes 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 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 ATP transport from its biosynthesis sites (mitochondria) to sites of utilization (cytosol). Essentially, cells are better supplied with nutrients and oxygen, and utilization of these substances is optimized.

Conversely, when biosynthesis of the carnitine precursor—gamma-butyrobetaine (GBB)—increases, nitric oxide (NO) synthase is activated, 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 primary basis for meldonium’s efficacy lies in enhancing cellular tolerance to metabolic stress (associated with changes in fatty acid levels).

Mediator Function in the Hypothetical GBB-ergic System

A hypothesis has been proposed that the body contains a neuronal signaling system—the GBB-ergic system—responsible for transmitting nerve impulses between cells. The mediator of this system is the final carnitine precursor—GBB ester. 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, 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 noted, meldonium is a structural analogue of GBB and can perform mediator-like functions. However, GBB hydroxylase does not recognize meldonium, so carnitine concentration does not increase but rather decreases. Thus, by replacing the natural mediator and promoting increased GBB concentration, meldonium triggers 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 cardioprotective properties (including protection 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 angina pectoris with meldonium has shown that it reduces the frequency and intensity of angina attacks and decreases the need for glyceryl trinitrate. Meldonium exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, although 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 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 evaluated the role of meldonium in treating chronic heart failure due to IHD. It has been shown to increase exercise tolerance and the amount of work performed by patients with heart failure.

A separate study conducted at cardiology institutes in Latvia and Tomsk assessed the efficacy of meldonium 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. Meldonium has been shown to improve myocardial inotropic function, increase exercise tolerance, and enhance quality of life without causing severe adverse effects. However, mild hypotension may occur. Other possible adverse effects of meldonium 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.

Effects 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 properties—increasing motor activity and physical endurance, stimulating behavioral responses—and anti-stress effects—activating 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 treatment of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral 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 (following cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis) has been studied.

Results of therapeutic activity assessments indicate a dose-dependent positive effect of meldonium 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 impact on the recovery of intellectual functions during convalescence.

Meldonium improves convalescent quality of life (primarily through restoration of physical function) and alleviates psychological disturbances.

Meldonium exerts a beneficial effect on nervous system function, reducing neurological deficits during recovery.

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

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 is 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 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 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 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 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 in children under 18 years of age; therefore, the use of this medicinal product 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 heart and vascular system activity;
• 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 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 data on safety of use).

Interaction with other medicinal products and other forms of interactions.

Meldonium can 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 can 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, concomitant administration of iron preparations and meldonium improved 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 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 pentetrazol, a pronounced anticonvulsant effect of meldonium was established. 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 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 the risk of adverse reactions may increase.

Special precautions for use.

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 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 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 are insufficient to assess the effects of meldonium on pregnancy, embryonic/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 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 influence reaction rate when driving or operating machinery

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

Method of Administration and Dosage

Administer orally, during 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 once or divided into two doses. The maximum daily dose is 1000 mg.

Reduced work capacity, fatigue, 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 is 4–6 weeks. The treatment course may be repeated 2–3 times per year.

Elderly patients

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

Patients with impaired kidney function

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 impaired liver function

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

Children

There is no safety and efficacy data on the use 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, 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 its pronounced protein binding.

Adverse Reactions

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

Immune system disorders:

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

Psychiatric disorders:

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

Nervous system disorders:

Common – headache*; rare – paraesthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.

Cardiac disorders:

Rare – change 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 – throat inflammation, 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 – polyuria.

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*.

Abdominal pain in the upper part of the abdomen and migraine have been reported with the use of mildronate.

*Adverse effects observed in previously conducted uncontrolled clinical trials.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all cases of 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 and in a place inaccessible to children.

Packaging:

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

Prescription status:

Prescription only.

Manufacturer:

UORLД MEDICINE ILAC SAN. VE TIDJ. A.S.
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of its business operations:

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