Cavinton

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAVINTON (CAVINTON)

Composition:

Active substance: vinpocetine;

1 ml of concentrate for infusion solution contains 5 mg of vinpocetine;

Excipients: ascorbic acid, sodium metabisulfite (E 223), tartaric acid, benzyl alcohol, sorbitol (E 420), water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: colorless or slightly greenish, clear solution.

Pharmacotherapeutic group. Psychostimulants. Psychostimulants and nootropic agents. ATC code N06B X18.

Pharmacological Properties

Pharmacodynamics

Vinpocetine is a compound with a complex mechanism of action that exerts beneficial effects on brain metabolism and improves its blood supply, as well as enhances blood rheological properties.

Vinpocetine exhibits neuroprotective effects: the drug attenuates the harmful effects of cytotoxic reactions caused by excitatory amino acids. It inhibits potential-dependent Na⁺ and Ca²⁺ channels, as well as NMDA and AMPA receptors. Vinpectine enhances the neuroprotective effect of adenosine.

Vinpocetine stimulates cerebral metabolism: it increases the uptake and utilization of glucose and O₂ by brain tissue. The drug enhances brain resistance to hypoxia; increases transport of glucose—the primary energy source for the brain—across the blood-brain barrier; shifts glucose metabolism toward the more energetically favorable aerobic pathway; selectively inhibits Ca²⁺-calmodulin-dependent cyclic GMP phosphodiesterase (PDE); increases levels of cAMP and cGMP in the brain. Vinpocetine elevates ATP concentration and the ATP/AMP ratio; enhances reuptake of noradrenaline and serotonin in the brain; stimulates the ascending noradrenergic system; possesses antioxidant activity. As a result of all the aforementioned effects, vinpocetine exerts a cerebroprotective action.

Vinpocetine improves cerebral microcirculation: it inhibits platelet aggregation, reduces pathologically elevated blood viscosity, increases erythrocyte deformability, and inhibits adenosine uptake, thereby improving O₂ transport in tissues by reducing O₂ affinity to erythrocytes.

Vinpocetine selectively increases cerebral blood flow: it increases the cerebral fraction of cardiac output; reduces vascular resistance in the brain without affecting systemic circulation parameters (arterial pressure, cardiac output, pulse rate, total peripheral resistance); the drug does not induce a "steal effect." Moreover, under vinpocetine administration, blood supply improves in damaged (but not yet necrotized) ischemic areas with low perfusion ("reverse steal effect").

Pharmacokinetics

Distribution. In studies involving oral administration of the drug in rats, radiolabeled vinpocetine was found in the highest concentrations in the liver and gastrointestinal tract. Maximum tissue concentrations were observed 2–4 hours after drug administration. Radioactivity concentration in the brain did not exceed that in the blood.

In humans: plasma protein binding is 66%. Absolute oral bioavailability of vinpocetine is 7%. The volume of distribution is 246.7 ± 88.5 L, indicating extensive tissue binding. The clearance value of vinpocetine (66.7 L/h) exceeds hepatic plasma flow (50 L/h), suggesting extrahepatic metabolism of the compound.

Elimination. With repeated oral administration of the drug at doses of 5 mg and 10 mg, vinpocetine demonstrates linear kinetics; steady-state plasma concentrations are 1.2 ± 0.27 ng/mL and 2.1 ± 0.33 ng/mL, respectively. Elimination half-life in humans is 83 ± 1.29 hours. Studies using radiolabeled compound showed that the main elimination route is via urine and feces in a ratio of 60%:40%. A greater amount of radiolabel was found in bile in rats and dogs, but significant enterohepatic recirculation was not observed. Apovincaminic acid is excreted by the kidneys via simple glomerular filtration; the elimination half-life of this substance varies depending on the dose and route of vinpocetine administration.

Metabolism. The main metabolite of vinpocetine is apovincaminic acid (AVA), which is formed in humans at 25–30%. After oral administration, the area under the curve (AUC) of AVA is twice that after intravenous administration, indicating formation of AVA during presystemic metabolism of vinpocetine. Other identified metabolites include hydroxyvinpocetine, hydroxy-AVA, dihydroxy-AVA-glycinate, and their conjugates with glucuronides and/or sulfates. In each of the studied species, only a few percent of the administered dose of vinpocetine was excreted unchanged.

An important and significant property of vinpocetine is the lack of need for dose adjustment in patients with liver or kidney disease, due to the drug's metabolism and absence of accumulation.

Changes in pharmacokinetic properties under special conditions (e.g., age, presence of concomitant diseases). Since vinpocetine is primarily indicated for therapy in elderly patients, in whom changes in drug kinetics—such as reduced absorption, altered distribution and metabolism, and decreased elimination—are observed, studies evaluating the drug's kinetics specifically in this age group, especially with long-term use, were necessary. Results of such studies demonstrated that vinpocetine kinetics in elderly individuals do not significantly differ from those in younger individuals, and accumulation does not occur. Standard doses of the drug can be used in patients with impaired liver or kidney function, as vinpocetine does not accumulate in these patients, allowing prolonged administration.

Clinical characteristics.

Indications.

Neurology. For the treatment of various forms of cerebrovascular pathology: conditions following stroke, vertebrobasilar insufficiency, vascular dementia, cerebral atherosclerosis, post-traumatic and hypertensive encephalopathy. Helps reduce psychological and neurological symptoms in cerebrovascular pathology.

Ophthalmology. For the treatment of chronic vascular pathology of the choroid (vascular layer of the eye) and retina.

Otorhinolaryngology. For the treatment of presbycusis (age-related hearing loss) due to acute vascular pathology, toxic (drug-induced) damage, or damage of other nature (idiopathic, noise-induced), Meniere's disease, and tinnitus.

Contraindications.

Acute phase of hemorrhagic cerebral stroke, severe ischemic heart disease, severe forms of arrhythmia.

Pregnancy, breastfeeding period. Contraindicated in women of reproductive age who do not use a reliable method of contraception.

Hypersensitivity to the active substance or to any of the excipients.

Use in children is contraindicated (due to lack of data from adequate clinical studies).

Interaction with other medicinal products and other types of interactions.

During clinical studies, no interactions were observed when vinpocetine was administered concomitantly with beta-blockers such as clonolol and pindolol, or with clomethiazole, glybenclamide, digoxin, acenocoumarol, or hydrochlorothiazide. In isolated cases, an additional effect was observed when alpha-methyldopa was used concomitantly with vinpocetine; therefore, regular monitoring of blood pressure is necessary when this combination is used.

Although clinical data do not confirm interactions, caution is recommended when vinpocetine is used concomitantly with medicinal products affecting the central nervous system, as well as during concomitant antiarrhythmic and anticoagulant therapy.

Special precautions for use

In patients with increased intracranial pressure, arrhythmia or long QT syndrome, as well as those receiving antiarrhythmic drugs, therapy with this medicinal product should only be initiated after careful assessment of the benefits and risks associated with its use.

QT interval prolongation

ECG monitoring is recommended in patients with long QT syndrome or when concomitantly using medicinal products that may prolong the QT interval.

Excipients

The product contains a small amount of sorbitol (160 mg/2 ml); therefore, in patients with diabetes mellitus, blood glucose levels should be monitored periodically during treatment.

In patients with hereditary fructose intolerance or deficiency of the enzyme fructose-1,6-diphosphatase, use of this medicinal product should be avoided. A detailed family history regarding hereditary fructose intolerance symptoms should be obtained from each patient prior to administration.

Due to the presence of benzyl alcohol (20 mg in 2 ml), hypersensitivity reactions may occur. Large amounts of this excipient should be used with caution and only when necessary, particularly in patients with impaired liver or kidney function, due to the risk of accumulation and toxicity (metabolic acidosis).

Due to the presence of sodium metabisulfite (2 mg in 2 ml), the medicinal product may in rare cases cause severe allergic reactions and bronchospasm.

This medicinal product contains less than 1 mmol (23 mg) of sodium per ampoule, i.e. it is nearly sodium-free.

Mutagenicity. Vinpocetine has no mutagenic effect.

Carcinogenicity. Vinpocetine has no carcinogenic effect.

Use during pregnancy or breastfeeding.

Vinpocetine is contraindicated during pregnancy, breastfeeding, and in women of childbearing potential who are not using reliable contraception.

Reproductive studies. According to study results, vinpocetine did not affect fertility in male and female animals. Oral administration of vinpocetine to animals during pregnancy resulted in developmental toxicity, including teratogenic effects at clinically relevant exposures based on mg/m² body surface area. In addition, embryofetal mortality was observed in animals treated with high doses.

Pregnancy. Vinpocetine crosses the placenta, but concentrations in the placenta and fetal blood are lower than in maternal blood. Reproductive toxicity, including developmental malformations, has been observed in animal studies. In animal studies, administration of high doses of vinpocetine was associated in some cases with placental hemorrhage and abortion, primarily as a result of enhanced placental circulation.

Breastfeeding. Vinpocetine passes into breast milk. In studies using radiolabeled vinpocetine, radioactivity in breast milk was ten times higher than in maternal blood. The amount excreted in milk within 1 hour amounts to 0.25% of the administered dose. Since vinpocetine is excreted in breast milk and there is no data on its effects on newborns, the use of vinpocetine during breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

There are no data on the effects of vinpocetine on the ability to drive or operate machinery; however, the possibility of somnolence, dizziness, and vertigo occurring during treatment should be considered.

Method of Administration and Dosage

The drug must be administered only as a slow intravenous infusion! (The infusion rate must not exceed 80 drops per minute!)

The drug must not be administered intramuscularly, nor may it be administered intravenously without prior dilution!

The initial daily dose for adults is generally 20 mg in 500 ml of infusion solution. This dose may be increased up to 1 mg/kg body weight per day over 2–3 days, depending on the patient's tolerance of the drug.

The average duration of treatment is 10–14 days. The usual daily dose is 50 mg/day (50 mg in 500 ml of infusion solution), calculated for a body weight of 70 kg.

After completion of the infusion course, continuation of therapy with Kavinton tablets is recommended.

Kavinton, concentrate for infusion solution, may be diluted with any type of physiological solution or infusion solutions containing glucose (e.g., "Salsol", Ringer's solution, "Rindex", "Reomacrodex"). The infusion solution should be used within 3 hours after preparation. See also section "Incompatibility".

Renal and Hepatic Impairment

Dosage adjustment is not required in patients with kidney or liver disease.

Children

Use of the drug in children is contraindicated (due to lack of data from appropriate clinical studies).

Overdose

Based on literature data, administration of the drug at a dose of 1 mg/kg body weight may be considered safe. Since there are no data on administration of doses exceeding this amount, higher doses must not be used.

Adverse reactions.

Cavinton concentrate for infusion solution is a safe medication, as confirmed by safety studies that included data from tens of thousands of patients and demonstrated that even the most frequently occurring adverse effects did not fall into the "Common >1/100" category according to MedDRA definitions. That is, adverse effects with the highest probability of occurrence were recorded at a frequency of less than 1%. For this reason, the "Common" frequency category is absent in the table below.

Adverse reactions listed below are classified by system organ classes and specified according to frequency as per MedDRA terminology:

Table 1.

Shelf life. 5 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging to protect from light. Keep the medicine out of the reach of children.

Incompatibility.

The concentrate for solution for infusion is chemically incompatible with heparin; therefore, they must not be mixed in the same syringe. However, concomitant anticoagulant therapy may be administered.

The concentrate for solution for infusion is also incompatible with infusion solutions containing amino acids; therefore, during treatment, vinpocetine infusion must not be used simultaneously with infusion solutions containing amino acids.

Packaging.

2 ml in an ampoule; 5 ampoules in a plastic tray; 2 plastic trays in a cardboard pack.

Prescription category. Prescription only. For hospital use only.

Manufacturer.

JSC "Gedeon Richter".

Manufacturer's address.

19-21 Demre utca, Budapest, H-1103, Hungary