Actovegin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AКTOVEGIN (ACTOVEGIN®)

Composition:

Active substance: 1 ml of the preparation contains: deproteinized hemoderivative from calf blood in the form of Actovegin concentrate, 40 mg of dry weight;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: yellowish-colored solution.

Pharmacotherapeutic group. Agents affecting the blood and hematopoietic system. Other hematological agents. ATC code B06A B.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action. Actovegin exhibits three main groups of effects: metabolic, neuroprotective, and microcirculatory. The inositol phosphate-oligosaccharides (IPOS) contained in Actovegin are responsible for improved oxygen utilization and uptake, enhanced energy metabolism, and increased glucose uptake. This action may be beneficial following tissue or organ injury, particularly in the brain, and may reduce lactate formation.

Several pathways have been identified through which the neuroprotective mechanism of Actovegin is mediated. Actovegin reduces apoptosis induced by beta-amyloid peptides (Aβ25–35). Beta-amyloid peptides act as triggers in a number of molecular and cellular processes, including oxidative stress and inflammation, ultimately leading to neuronal cell death, which in turn results in memory and cognitive impairment.

Nuclear factor kappa B (NF-κB) plays numerous roles in both the central and peripheral nervous systems. It regulates inflammatory processes that exacerbate the course of degenerative and vascular diseases and is involved in pain syndrome development, as well as in learning, memory, and neuroprotection.

Actovegin dose-dependently activates NF-κB reporter gene expression. This transient activation may at least partially explain the neuroprotective properties of Actovegin.

Another important mechanism of Actovegin involves the nuclear enzyme poly (ADP-ribose) polymerase (PARP). PARP plays a key role in detecting single-strand DNA breaks and in their repair. However, excessive activation of this enzyme may trigger processes within the cell that lead to the termination of oxidative metabolism. These processes may ultimately result in cell death due to depletion of energy reserves. It has been shown that Actovegin reduces PARP activity, thereby improving function and optimizing the morphological structure of both the central and peripheral nervous systems.

The positive effect of Actovegin on microcirculation is attributed to several effects: increased capillary blood flow velocity, reduced pericapillary zone, decreased tone of smooth muscles in precapillary arterioles and capillary sphincters, reduced arteriole-venular shunting of blood, increased capillary blood flow, and enhanced endothelial nitric oxide synthase function in the microcirculatory bed.

Various parameters in animal studies and clinical trials have shown that the effect occurs no later than 30 minutes after administration. Maximum effect is achieved within 3 hours after parenteral or oral administration (2–6 hours).

Clinical Efficacy and Safety

Cerebral Circulation Disorders, including Post-Stroke Cognitive Impairment and Dementia. Actovegin has demonstrated a positive effect in the symptomatic treatment of dementia and dementia-related conditions in over 450 patients across several small randomized clinical trials. Efficacy compared to placebo was demonstrated for endpoints related to cognitive function, daily activities, and overall clinical response, although no statistically significant improvement in speed of cognitive processes was observed.

In a 12-month randomized, double-blind, placebo-controlled study assessing safety and efficacy, the effect of Actovegin in patients with post-stroke cognitive impairment was compared to placebo. A total of 503 patients (250 receiving Actovegin) were randomized between the 5th and 7th day after ischemic stroke onset. The 6-month treatment period included up to 20 infusions (2000 mg daily), followed by oral administration of tablets (2 tablets of 200 mg three times daily). This was followed by a 6-month observation period during which patients were managed according to standard clinical practice. At 6 and 12 months, patients receiving Actovegin showed statistically significant improvements in scores on the extended cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog+) and the Montreal Cognitive Assessment (MoCA) compared to placebo-treated patients. At 3, 6, and 12 months, a greater proportion of patients in the Actovegin group met the responder criteria based on ADAS-cog+. The frequency of serious adverse events and mortality was similar in both treatment groups. The overall incidence of recurrent ischemic stroke during the study was within expected ranges for this patient population, although a slightly higher frequency was observed in the Actovegin group compared to placebo.

Peripheral Circulation Disorders and Their Consequences. Approximately 190 patients with peripheral arterial disease received Actovegin treatment for 10 to 42 days in several small comparative randomized trials, which demonstrated short-term superiority of Actovegin infusions over placebo. A 35–42% improvement in walking distance was observed in the Actovegin group compared to placebo.

In a 6-month randomized, double-blind, placebo-controlled study, the efficacy and safety of Actovegin in patients with Fontaine stage IIb peripheral arterial circulation disorders (claudication at distances < 200 m) were compared to placebo. A total of 366 subjects received intravenous infusions of Actovegin (1200 mg/day) (n = 184) or placebo (n = 182) daily for 2 weeks, followed by 2 Actovegin tablets (1200 mg/day) or placebo three times daily for the next 10 weeks. A 12-week observation period without study medication followed the treatment course to assess sustained efficacy and safety. The therapeutic effect of Actovegin was superior to placebo in increasing both initial claudication distance and absolute claudication distance at weeks 2 and 12, with benefits maintained for an additional 12 weeks after treatment completion. Results of this study indicate that Actovegin (12-week treatment), initially administered intravenously (2 weeks at 1200 mg/day) followed by oral administration (10 weeks at 1200 mg/day), has an acceptable safety and tolerability profile in patients with peripheral arterial circulation disorders (Fontaine stage IIb).

In an open-label randomized study, 60 patients with large trophic leg ulcers due to venous insufficiency received standard therapy with or without Actovegin. Actovegin was administered as daily intravenous infusions of 250 ml of 10% solution over 4 weeks. Mean ulcer healing time was 31 days in the Actovegin group and 42 days in the control group. Improvement in pain score from baseline was observed in both groups; specifically, in the Actovegin group, pain scores decreased from 4.47 to 1.77, while in the control group, they decreased from 4.13 to 2.07.

Diabetic Polyneuropathy (DPN). In a study involving 70 patients with diabetic polyneuropathy, statistically significant improvements in walking distance, nerve conduction velocity, and pain sensitivity were observed in patients treated with Actovegin compared to placebo. The difference in therapeutic effect versus placebo was approximately 6.5 m in walking distance, 0.9 m/s in nerve conduction velocity, and 6.8 points on the pain sensitivity scale (on a 100-point scale).

In a 6-month, double-blind, randomized, placebo-controlled study assessing safety and efficacy, 567 patients with type 2 diabetes and symptomatic diabetic distal polyneuropathy received 20 intravenous infusions of Actovegin (2000 mg/day) (n = 281) or placebo (n = 286) once daily for up to 36 days, followed by 3 Actovegin tablets (1800 mg/day) or placebo three times daily for 140 days. Treatment with Actovegin resulted in a significantly better outcome compared to placebo in the primary endpoint assessed by the Total Symptom Score (TSS), including positive neuropathic pain symptoms such as burning, paresthesia, and numbness of feet or legs. No significant differences in adverse event incidence were observed between the treatment and control groups.

Pharmacokinetics

Pharmacokinetic methods cannot be used to study the pharmacokinetic characteristics of Actovegin (absorption, distribution, and elimination of active ingredients) because the drug consists solely of physiological components normally present in the body.

Clinical characteristics.

Indications.

• Treatment of cerebrovascular disorders, including post-stroke cognitive impairments and dementia.
• Treatment of disorders of peripheral (arterial, venous) circulation and their complications (arterial angiopathy, venous trophic ulcer).
• Treatment of diabetic polyneuropathy (DPN).

Contraindications.

Hypersensitivity to the active substance, any component of the medicinal product, or to drugs of similar composition. Decompensated heart failure, pulmonary edema, oliguria, and anuria are general contraindications for infusion therapy; therefore, administration of the drug by infusion is contraindicated in these conditions due to the risk of potential hyperhydration.

Interaction with other medicinal products and other types of interactions.

There are no data regarding interactions between Actovegin and other drugs.

Special precautions for use

In a study involving patients with post-stroke cognitive impairment, a higher incidence of recurrent ischemic stroke was observed in the group treated with the drug Actovegin. The overall incidence of recurrent ischemic stroke during the study was within the expected range for this patient population; however, a slightly higher incidence was observed in the Actovegin group compared to the placebo group (see section "Pharmacodynamics"). The benefit-risk ratio should be carefully considered when continuing Actovegin treatment in patients who have recently experienced a stroke.

Intramuscular administration should not exceed 5 mL per day, as the solution is hypertonic.

The injection solution is compatible with 0.9% sodium chloride solution and 5% glucose solution.

Actovegin injection solution must be used under sterile conditions. Since the product does not contain preservatives, the ampoule contents are intended for single use only. Opened ampoules and prepared solutions should be used immediately. Unused medication and waste must be disposed of in accordance with local requirements.

Due to the potential risk of anaphylactic reactions, a test (hypersensitivity) injection is recommended. After administration of the test dose of Actovegin injection solution, patients should be monitored for signs and symptoms of hypersensitivity. Patients must remain under medical supervision for at least 30 minutes after drug administration, with full availability of medications and equipment necessary for emergency shock treatment, if required.

In case of fluid and electrolyte imbalances (e.g., hyperchloremia, hypernatremia), appropriate corrective measures should be taken.

The injection solution has a slightly yellowish tint. The intensity of coloration may vary between different batches of the product depending on the characteristics of the raw materials used; however, this does not negatively affect the drug's activity or clinical response.

Do not use cloudy solutions or solutions containing visible particles.

The active substance in Actovegin contains phenylalanine, which may be harmful to patients with phenylketonuria.

Actovegin contains up to 13.7 mg of sodium per 1 mL of product, which should be taken into account for patients on a low-salt (low-sodium) diet.

The active substance in Actovegin contains potassium. Each 1 mL of Actovegin injection solution contains up to 2.5 mg of potassium, which should be considered for patients with impaired renal function and for patients on a potassium-controlled diet.

Use during pregnancy or breastfeeding

The drug may be used during pregnancy or breastfeeding only if the therapeutic benefit to the mother clearly outweighs the potential risk to the fetus or infant. When Actovegin was used in cases of placental insufficiency, rare fatal outcomes were observed, which could have been consequences of the underlying disease. The use of Actovegin in placental insufficiency is not recommended. Use of Actovegin during breastfeeding has not been associated with any adverse effects in either the mother or the infant.

Effect on the ability to drive or operate machinery

Actovegin has no or negligible effect on the ability to drive or operate machinery. However, possible adverse effects on the nervous system should be taken into account (see section "Adverse reactions").

Method of administration and dosage.

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

How to open ampoules with a break point:

Actovegin, injection solution, is administered intravenously, intraarterially, or intramuscularly and may be added to infusion solutions.

For infusion use, 10–50 mL of Actovegin injection solution should be added to 200–300 mL of a base solution (isotonic saline or 5% glucose solution).

When administering Actovegin as an infusion, infusion systems equipped with 15 µm filters should be used. The recommended infusion rate is approximately 2 mL/min.

Intramuscular administration should be performed slowly, with no more than 5 mL per day, as the solution is hypertonic.

Specific dosage regimens are based on clinical trial data. General dosage recommendations are also provided.

Treatment of cerebrovascular disorders.

General dosing regimen:

Initially, 10 mL (400 mg) intravenously daily for 2 weeks, followed by 5–10 mL (200–400 mg) intravenously several times per week for at least 4 weeks.

Dosing for post-stroke cognitive disorders and dementia:

Initially, 50 mL (2000 mg) daily as an intravenous infusion for up to 20 infusions, followed by transition to oral tablet form of Actovegin.

Treatment of peripheral (arterial, venous) circulation disorders and their complications (arterial angiopathy, venous trophic ulcer).

General dosing regimen:

Depending on the severity of the patient's condition and clinical presentation, initially administer 10–20 mL (400–800 mg) intravenously or intraarterially daily; for subsequent treatment, administer 5 mL (200 mg) intravenously or slowly intramuscularly daily or several times per week.

Dosing regimen for peripheral arterial circulation disorders, Fontaine stage IIb:

Initially, 30 mL (1200 mg) daily as an intravenous infusion for 2 weeks, followed by transition to oral tablet form of Actovegin.

Dosing regimen for arterial angiopathy:

Initially, 20–50 mL (800–2000 mg) intravenously or intraarterially daily or several times per week; total duration up to 4 weeks.

Dosing regimen for venous trophic ulcer:

Initially, 10 mL (400 mg) intravenously or 5 mL (200 mg) intramuscularly daily or several times per week, depending on the healing process. In cases of large ulcers, 25 mL (1000 mg) as an intravenous infusion daily for 4 weeks.

Treatment of diabetic polyneuropathy (DPN).

General dosing regimen:

Depending on the severity of clinical symptoms, initially 10–20 mL (400–800 mg) intravenously or intraarterially daily; for subsequent treatment, 5 mL (200 mg) intravenously or slowly intramuscularly daily or several times per week.

Dosing for symptomatic diabetic distal polyneuropathy in patients with type 2 diabetes mellitus:

Initially, 50 mL (2000 mg) daily as an intravenous infusion for up to 20 infusions over a maximum of 36 days, followed by transition to oral tablet form of Actovegin.

Children. Currently, there are no data on the use of Actovegin in children; therefore, the drug is not recommended for this patient group.

Overdose. Cases of Actovegin overdose are unknown. Given the pharmacological properties of the medicinal product, no additional adverse effects are expected.

Side effects.

The following criteria are used to classify the frequency of adverse reactions based on the recommendations of the Council for International Organizations of Medical Sciences (CIOMS): very common (≥ 1/10); common (≥ 1/100 but < 1/10); uncommon (≥ 1/1,000 but < 1/100); rare (≥ 1/10,000 but < 1/1,000); very rare (< 1/10,000).

Immune system:

Rare: hypersensitivity reactions, including allergic reactions. Anaphylactoid (allergic) reactions may occur, which can manifest as:

Immune system and skin – possible hypersensitivity reactions, including allergic reactions, anaphylactic and anaphylactoid reactions up to anaphylactic shock, increased body temperature, chills, angioneurotic edema.

Rare: skin hyperemia, skin rashes, pruritus, urticaria, increased sweating, swelling of the skin and/or mucous membranes, hot flushes, changes at the injection site;

Gastrointestinal tract – dyspeptic symptoms, including epigastric pain, nausea, vomiting, diarrhea;

Cardiovascular system – chest pain, increased heart rate (tachycardia), dyspnea, acrocyanosis, pallor, arterial hypotension or hypertension;

Respiratory system – increased respiratory rate, chest tightness, difficulty swallowing and/or breathing, throat pain, suffocation attack;

Nervous system – headache, general weakness, dizziness, loss of consciousness, excitement, tremor, paresthesia;

Musculoskeletal system – muscle and/or joint pain, back pain.

In such cases, treatment with Actovegin, injection solution, must be discontinued and symptomatic therapy should be initiated.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging. Keep out of reach of children!

Incompatibility. The medication should not be mixed in the same container with other solutions, except as specified in the section "Instructions for use and dosage."

Packaging. 2 ml in an ampoule; 25 ampoules per cardboard box.

5 ml in an ampoule; 5 ampoules per cardboard box.

10 ml in an ampoule; 5 ampoules per cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "Kusum Pharm", Ukraine / LLC «Kusum Pharm», Ukraine.

(packaging of in-bulk manufacturer Takeda Austria GmbH, Austria).

Manufacturer's name and address.

54, Skryabina str., Sumy, Sumy region, 40020, Ukraine.