Actovegin

Pharmacological properties

Actovegin is a deproteinized hemoderivative from calf blood containing only physiological substances with a molecular weight of 5000 da.

Actovegin is characterized by three main effects: metabolic, neuroprotective and microcirculatory. Inositol phosphate oligosaccharides (IFOs), which are part of the Actovegin preparation, are responsible for improving utilization and absorption of oxygen, as well as for improving energy metabolism and glucose uptake. Such an action can potentially be beneficial after lesions or damage to tissues and organs, in particular the brain, and reduce the formation of lactate.

Several ways have been identified along which the neuroprotective mechanism of action of the drug Actovegin is realized, due to the effect on the structure of beta-amyloid peptides (Aβ25–35) that induce apoptosis. Amyloid beta peptides act as triggers in a number of molecular and cellular processes, including oxidative stress and inflammation, which as a result leads to the death of a neuron, and this, in turn, leads to impaired memory and cognitive functions.

Nuclear factor kappa B (NF-kB) performs numerous functions in the processes of both the central and peripheral nervous systems. It regulates the process of inflammation, worsening the course of degenerative and vascular disorders, and is a factor that is involved in the formation of pain, learning, memory and neuroprotection.

Actovegin activates the NF-kB expression reporter gene in a dose-dependent manner, and this transient activation may at least partially explain the neuroprotective properties of Actovegin.

Another important mechanism of action of Actovegin is associated with the nuclear enzyme poly (ADP-ribose) -polymerase (PARP). PARP plays an important role in the detection of single-stranded DNA breaks and in the repair process, however, excessive activation of this enzyme can cause processes in the cell that lead to the completion of oxidative metabolism. These processes can ultimately lead to cell death due to the exhaustion of energy reserves. It was revealed that Actovegin reduces the activity of PARP, which improves functioning and optimizes the morphological structure of the central and peripheral nervous system.

The positive effect of Actovegin on microcirculation is due to its effects such as an increase in the speed of blood flow in the capillaries, a decrease in the pericapillary zone and a decrease in the smooth muscle tone of precapillary arterioles and capillary sphincters, a decrease in arteriovenous venous shunting of blood with an increase in blood flow in the capillary bed and an increase in the function of the endothelial oxide riverbed.

Clinical Efficiency and Safety

Cerebral circulatory disorders, including post-stroke cognitive impairment and dementia. Actovegin has shown beneficial effects in the symptomatic treatment of dementia and dementia-related conditions in more than 450 patients through several small randomized clinical trials. Efficacy compared with placebo at endpoints regarding cognitive function, daily activity, and overall clinical response was demonstrated, while no statistically significant improvement in the speed of cognitive processes was found.

In a 12-month, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy, the effect of Actovegin in patients with post-stroke cognitive impairment was compared with placebo. 503 patients were randomized (250 patients received Actovegin) from the 5th to the 7th day after the onset of ischemic stroke.The 6-month treatment period included ≤20 infusions (2000 mg daily) followed by the administration of the drug in the form of tablets (2 tablets of 200 mg 3 times a day), after which a 6-month follow-up treatment was carried out, during which the patients were administered with standard clinical practice. At the 6th and 12th month, patients receiving Actovegin showed statistically significant changes in the number of points on the extended cognitive subscale of the Alzheimers disease rating scale (ADAS-cog +) and the Montreal cognitive function rating scale (MoCA) compared with patients who received a placebo. On the 3rd, 6th and 12th month, the majority of patients in the group receiving the Actovegin preparation showed a response to treatment according to the ADAS-cog + scale. The incidence of serious adverse events and deaths was similar in both treatment groups. The overall frequency of repeated ischemic stroke during the study was within the range expected for this patient population, however, a slightly higher frequency was observed in the Actovegin group compared with the placebo group.

Peripheral blood flow disorders and their consequences. About 190 patients with peripheral arterial disease received Actovegin treatment for a period of 10 to 42 days as part of several small comparative randomized trials that showed the short-term benefit of Actovegin infusions over placebo. An improvement in the form of an increase in walking distance by 35–42% was demonstrated in the group receiving the drug Actovegin, compared with the placebo group.

In an open, randomized study, 60 patients with large trophic ulcers of the lower extremities against venous insufficiency received a standard treatment regimen with or without Actovegin. The drug Actovegin was administered in the form of daily iv infusions of 250 ml of 10% solution for 4 weeks. The average healing time for ulcers was 31 days (in the group receiving the drug Actovegin) and 42 days (in the group not receiving the drug Actovegin). An improvement in the number of points on the pain intensity scale compared with the initial level was observed in both groups, in particular in the group receiving the drug Actovegin, there was a decrease in the number of points from 4.47 to 1.77, and in the other study group from 4.13 up to 2.07.

Diabetic polyneuropathy. The study, which involved 70 patients with diabetic polyneuropathy, showed statistically significant changes in walking distance, speed of nerve impulse and pain sensitivity in patients treated with Actovegin compared with the placebo group. The difference in the therapeutic effect of the placebo was about 6.5 m at walking distance, 0.9 m / s in the speed of the nerve impulse and 6.8 points on the pain sensitivity scale (100-point scale).

In a 6-month, double-blind, randomized, placebo-controlled study evaluating the safety and efficacy of 567 patients with type II diabetes mellitus and symptomatic diabetic distal polyneuropathy, they received 20 iv infusions of Actovegin (2000 mg / day) (n = 281) or placebo (n = 286) once a day for 20–36 days, after which 3 tablets of Actovegin (1800 mg / day) or placebo 3 times a day for 140 days were received. When using Actovegin, a better effect was observed compared with placebo according to the assessment of the endpoint on the General Symptom Score (TSS) scale, including positive neuropathic pain symptoms, burning, paresthesia and numbness of the feet or legs, impaired vibration sensitivity and improved quality of life for patients. There were no significant differences in the distribution of adverse events between the treatment group and the control group.

PharmacokineticsUsing pharmacokinetic methods, it is impossible to study the pharmacokinetic characteristics of Actovegin (absorption, distribution and elimination of active ingredients), since it consists only of physiological components that are usually found in the body.

The results obtained in animal studies and in clinical trials have shown that the effect of the drug begins no later than 30 minutes after its administration. The maximum effect is achieved 3 hours after parenteral administration or oral administration of the drug (2-6 hours).

Indications

Treatment of cerebrovascular diseases of vascular origin, including post-stroke cognitive impairment and dementia. treatment of disorders of peripheral (arterial, venous) blood circulation and their complications (arterial angiopathy, venous trophic ulcer). treatment of diabetic polyneuropathy.

Application

Actovegin, injection solution, is in ampoules with a break point.

How to open ampoules with a break point. Point the top of the ampoule with the color dot up. Let the solution drain down from the top of the ampoule, gently tapping and shaking the ampoule. Break off the top of the ampoule.

a) General recommendations. Actovegin, solution for injection, used in / in, / a or / m; It can also be added to infusion solutions.

Depending on the severity of the patient’s condition and the clinical picture, 10-20 ml of Actovegin, r-ra for injection, iv or iv daily are first administered; for further treatment, 5 ml iv are injected slowly or IM daily or several times a week.

For use in the form of infusions, it is necessary to add 10-50 ml of the drug Actovegin, solution for injection, to 200-300 ml of the main solution (isotonic physiological solution or 5% glucose solution). Depending on the severity of the patient’s condition and the clinical picture, 1-2 infusions of iv or iv are carried out daily or several times a week, the total dose is 10–20 infusions. When using the drug in the form of infusions, infusion systems with 15 microns filters should be used. The recommended infusion rate is about 2 ml / min.

V / m solution is administered slowly, not more than 5 ml / day, because it is hypertonic.

b) Dosing depending on the indications for use

For diseases of the brain of vascular origin: first 10 ml iv daily for 2 weeks, then 5-10 ml iv several times a week for at least 4 weeks.

In arterial angiopathy: add 20-50 ml of the drug to the main solution, apply iv or iv daily or several times a week; the duration of treatment is about 4 weeks.

With venous trophic ulcer: 10 ml iv or 5 ml iv daily or several times a week, depending on the healing process.

In diabetic polyneuropathy: the initial dose is 50 ml (2000 mg) per day in the form of iv infusion for 3 weeks, followed by switching to tablets - 2-3 tablets 3 times a day (up to 1800 mg) for at least 4– 5 months

Contraindications

Hypersensitivity to any components of the drug or medicines with a similar composition. decompensated heart failure, pulmonary edema, oliguria, anuria are common contraindications to infusion therapy, therefore, the introduction of the drug in the form of infusions in these conditions is contraindicated in view of possible overhydration.

Side effects

The following are the adverse reactions that may occur in patients as a result of the use of Actovegin. anaphylactoid (allergic) reactions may occur, which may occur:

from the immune system and skin: hypersensitivity reactions are possible, including allergic reactions, anaphylactic and anaphylactoid reactions up to the development of anaphylactic shock, fever, chills, angioedema, skin hyperemia, skin rashes, itching, urticaria, sweating, skin swelling and / or mucous membranes, hot flashes, changes in the injection site;

from the digestive tract: dyspeptic symptoms, including pain in the epigastric region, nausea, vomiting, diarrhea;

from the cardiovascular system: pain in the heart, increased heart rate (tachycardia), shortness of breath, acrocyanosis, pallor of the skin, arterial hypotension or hypertension;

on the part of the respiratory system: rapid breathing, feeling of constriction in the chest, difficulty swallowing and / or breathing, sore throat, asthma attack;

from the nervous system: headache, general weakness, dizziness, loss of consciousness, agitation, trembling (tremor), paresthesia;

from the musculoskeletal system: pain in the muscles and / or joints, lower back pain.

In such cases, treatment with Actovegin should be discontinued and symptomatic therapy should be used.

special instructions

It is advisable to administer no more than 5 ml of solution in oil, since it is hypertonic.

The injection solution is compatible with 0.9% sodium chloride solution and 5% glucose solution. The drug Actovegin, solution for injection, should be used under sterile conditions. Since the preparation does not contain preservatives, the contents of the ampoule are intended for single use. Open ampoules and ready-made solution should be used immediately. Unused product and waste should be disposed of in accordance with local regulations.

In connection with the possibility of anaphylactic reactions, it is recommended to conduct a test injection (hypersensitivity test). In case of development of water-electrolyte metabolic disorders (for example, hyperchloremia, hypernatremia), it is necessary to carry out an appropriate correction. The injection solution has a slightly yellowish tint. The color intensity can vary from one batch to another depending on the characteristics of the raw materials used, however this does not adversely affect the activity of the drug or its sensitivity.

You can use only a transparent solution without visible particles.

The solution contains sodium. This should be considered for patients who are on a controlled sodium diet.

Use during pregnancy and lactation. The drug should be used during pregnancy and lactation only when the expected benefit to the mother outweighs the possible risk to the fetus or child. During the use of the drug Actovegin with placental insufficiency, although rare, fatal cases were observed, which could be a consequence of the underlying disease. The use of the drug Actovegin during breastfeeding was not accompanied by negative effects for either the mother or the baby.

Children. Data on the use of the drug in children are not available, therefore, the drug is not recommended for use in this category of patients.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Actovegin does not have or has very little effect on the ability to drive vehicles or other mechanisms. However, possible manifestations of side effects from the nervous system should be considered (see ADVERSE EFFECTS).

Interactions

There is no data on the interaction of actovegin with other drugs.

Incompatibility. The drug should not be mixed in one container with other solutions, with the exception of those indicated in the APPLICATION section.

Overdose

Cases of overdose of Actovegin are unknown.

Storage conditions

At a temperature not exceeding 25 ° c in the original packaging.

UA / CVM / 1018/0009