Ripronate

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

Composition:

Active substance: meldonium;

1 ml of solution contains 100 mg of meldonium dihydrate;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

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.

Effect on Carnitine Biosynthesis

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing the biosynthesis of carnitine. As a result, it prevents the transport of long-chain fatty acids across cell membranes, counteracting the accumulation of strong detergents — activated forms of non-oxidized fatty acids — within cells. Thus, meldonium prevents 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 [adenosine triphosphate] 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.

In turn, when biosynthesis of the carnitine precursor — GBB [gamma-butyrobetaine] — increases, NO-synthase is activated, resulting in improved blood rheological properties and reduced 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 basis of meldonium's efficacy lies in increased tolerance to cellular 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 — 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. As a result of GBB-esterase activity, 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 transformed 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 function of a "mediator." In contrast, 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 triggers a 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 (particularly 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 course treatment with meldonium in patients with stable angina pectoris shows that it reduces the frequency and intensity of angina attacks and decreases the need for glyceryl trinitrate. Meldonium exerts pronounced antiarrhythmic effects 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

In numerous clinical studies, the role of meldonium in treating chronic heart failure due to IHD has been evaluated, demonstrating its ability to increase exercise tolerance and the amount of work performed by patients.

A separate study conducted at cardiology institutes in Latvia and the Russian Federation assessed the efficacy of meldonium in patients with NYHA [New York Heart Association] functional class I–III heart failure of moderate severity. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified into NYHA class I. It has been established that meldonium improves myocardial inotropic function, increases exercise tolerance, enhances quality of life, and does not cause severe adverse effects.

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 stimulatory effects 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 circulatory 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.

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 eliminates psychological disturbances.

Meldonium positively affects 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

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. 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 animal 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 elimination half-life of meldonium ranges from 5.56 to 6.55 hours, and the terminal elimination period is 15.34 hours.

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 dysfunction, where bioavailability is 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, 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, the dose of meldonium should be reduced. Toxicity studies in rats using doses exceeding 100 mg/kg showed 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) revealed lipid accumulation in liver cells. Changes in liver function parameters were not 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, use of the drug in this patient group is contraindicated.

Clinical Characteristics

Indications. Use in complex therapy for the following diseases and conditions:

• Diseases of the heart and vascular system: stable exertional angina, chronic heart failure (NYHA functional classes 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;
• Recovery period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications

• Hypersensitivity to meldonium or to any of the excipients.
• Increased intracranial pressure (due to impaired venous outflow, intracranial tumors).
• Severe hepatic and/or renal insufficiency (insufficient safety data available).
• Pregnancy and/or breastfeeding.
• Pediatric age (lack of safety data).

Interaction with other medicinal products and other forms of interactions

Meldonium may be used concomitantly with long-acting nitrates and other antianginal agents for the treatment of stable exertional angina, as well as 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.

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

In patients with iron-deficiency anemia, combined use of iron preparations and meldonium improved the fatty acid composition in erythrocytes.

When meldonium is administered in combination with orotic acid to counteract ischemia/reperfusion-induced damage, an additional pharmacological effect is observed.

Meldonium helps eliminate pathological changes in the heart caused by azidothymidine (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 pentylentetrazole-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 cyclophosphamide-induced cardiotoxicity.

Carnitine deficiency induced by meldonium may enhance ifosfamide-induced cardiotoxicity.

Meldonium exerts protective effects against cardiotoxicity induced by indinavir and neurotoxicity induced by efavirenz.

The medicinal product should not be used concomitantly with other preparations 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. During treatment, liver and/or kidney function should be monitored in such patients.

Use during pregnancy or breastfeeding

Pregnancy. There is insufficient animal data available 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 females. It is unknown whether meldonium passes into human breast milk. Risk to newborns/infants cannot be excluded; therefore, the medicinal product is contraindicated for women during breastfeeding.

Ability to affect reaction rate when driving or operating machinery

Studies assessing the effect on the ability to drive 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 prior to administration is required.

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

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

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

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 population.

Overdose

Symptoms. Cases of overdose have not been reported. Meldonium has 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 cases of severe overdose, liver and kidney function should be monitored. Hemodialysis is not significantly effective in meldonium overdose due to its pronounced binding to blood proteins.

Adverse Reactions

Adverse effects are classified by organ systems and frequency of occurrence according to MedDRA [Medical Dictionary for Regulatory Activities]: 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, hypesthesia, tinnitus, vertigo, dizziness, gait disturbance, presyncope, 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:

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, injection site reactions, including pain at injection site.

Investigations:

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is highly important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, are encouraged to 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, and 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 category. Prescription only.

Manufacturer.

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

Manufacturer's address and location of business activity.

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey /
COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.