Ripronat

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

Composition:

Active substance: mildronate;

1 ml of solution contains 100 mg of mildronate;

1 ampoule (5 ml) of solution contains 500 mg of mildronate;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Other cardiac preparations. 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.

Effect on carnitine biosynthesis.

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and consequently interfering with the transport of long-chain fatty acids across cell membranes. Thus, it prevents the accumulation within cells of a strong detergent—activated forms of non-oxidized fatty acids. As a result, cellular membrane damage is prevented.

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 sites of its biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and utilization of these substances is optimized.

Conversely, when biosynthesis of the carnitine precursor, i.e., GBB, increases, nitric oxide (NO) synthase is activated, resulting in improved blood rheological properties and reduced peripheral vascular resistance.

When meldonium concentration decreases, carnitine biosynthesis is again enhanced, and the amount of fatty acids gradually increases 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—termed 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 is converted 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 again, 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 function of a "mediator." In contrast, GBB-hydroxylase does not recognize meldonium, so carnitine concentration does not increase but rather decreases. Thus, meldonium, by replacing the "mediator" and promoting increased GBB concentration, triggers a corresponding physiological response. As a result, overall metabolic activity increases in other systems as well, for example, in the central nervous system (CNS).

Effects on the cardiovascular system.

Animal studies have demonstrated that meldonium positively affects myocardial contractility, exhibits cardioprotective properties (including protection 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 administration of meldonium in the treatment of stable exertional angina shows that it reduces the frequency and intensity of angina attacks and decreases the amount of nitroglycerin used. Meldonium exerts pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while a lesser effect is observed 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.

In a number of clinical studies, the role of meldonium in the treatment of chronic heart failure due to IHD has been analyzed, demonstrating its ability to increase exercise tolerance 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 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 and increases exercise tolerance, thereby improving 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 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 a stimulant 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.

It has been proven that meldonium is an effective agent 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 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 meldonium administration revealed a positive effect on the recovery process of intellectual functions during convalescence.

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

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

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

Pharmacokinetics.

Meldonium pharmacokinetics have been studied in healthy volunteers following intravenous and oral administration.

Absorption.

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

Following intravenous administration, the area under the concentration-time curve (AUC) differs after single and repeated doses, indicating possible meldonium accumulation 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 the milk of lactating females. 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.

Elimination.

Renal excretion plays a significant role in the elimination of meldonium and its metabolites. After single intravenous doses of meldonium (250 mg, 500 mg, and 1000 mg), the early elimination half-life ranges from 5.56 to 6.55 hours, and the terminal elimination half-life is 15.34 hours.

Special patient groups.

Elderly patients.

In elderly patients with impaired liver and kidney function, where bioavailability is increased, meldonium dosage should be reduced.

Renal impairment.

In patients with impaired renal function, where bioavailability is increased, 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 impaired liver function, where bioavailability is increased, meldonium dosage 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 meldonium doses (400 mg/kg and 1600 mg/kg) showed lipid accumulation in liver cells. Changes in liver function parameters in humans after administration of high doses (400–800 mg) were not observed. However, fat infiltration into 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 this medicinal product in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy of the following disorders:

• 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 period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium or to any other components of the medicinal product;
• Increased intracranial pressure (in case of impaired venous outflow, intracranial tumors);
• Severe hepatic and/or renal insufficiency (insufficient safety data available);
• Pregnancy and/or breastfeeding;
• Pediatric age (safety data not available).

Interaction with other medicinal products and other forms of interactions.

Meldonium can be used in combination with long-acting 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 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).

As a result of concomitant administration of iron preparations and meldonium in patients with iron-deficiency anemia, improvement of fatty acid composition in erythrocytes was observed.

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

Meldonium helps eliminate cardiac pathological changes 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 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, pronounced anticonvulsant action of meldonium was established. 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 has 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 preparations containing meldonium, as the risk of adverse reactions may increase.

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 for 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. During treatment, monitoring of liver and/or kidney function should be performed in such patients.

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies are insufficient to assess the effects of meldonium on pregnancy, embryonic/fetal development, labor, 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 females. It is unknown whether meldonium passes into human breast milk. A risk to newborns/infants cannot be ruled out; therefore, the medicinal product is contraindicated during breastfeeding.

Effects on ability to drive and use machines.

No studies have been conducted to assess the effects on the ability to drive or operate machinery.

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 stimulating 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 once or twice daily.

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

The total course of treatment lasts 4–6 weeks. The treatment course 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, a lower dose of the medicinal product should be used in patients with mild to moderate renal impairment.

Patients with Hepatic Impairment.

A lower dose of the medicinal product should be used in patients with mild to moderate hepatic impairment.

Children.

There is no safety and efficacy data available for the use 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 in 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 extensive protein binding in the blood.

Side effects

Adverse effects are classified by organ systems and MedDRA frequency terms: 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 – agitation, 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 – change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/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/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, edema, facial swelling, leg swelling, feeling of warmth, feeling of cold, cold sweat, reactions at the injection site, including pain at the injection site.

Investigations:

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

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical 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 a temperature not exceeding 25 °C, in a place inaccessible to children. Do not freeze.

Packaging.

5 ml in a glass ampoule; 5 ampoules in a blister pack; 2 blister packs in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

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

Marketing Authorization Holder.

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