Gekoven

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GEKOVEN (GEKOVEN)

Composition:

Active substances: hydroxyethyl starch 130/0.4; sodium chloride;

100 ml of solution contain hydroxyethyl starch 130/0.4 (average molecular weight 130000, molar substitution degree 0.4), calculated as dry substance, 6.0 g; sodium chloride 0.9 g;

Excipient: water for injections.

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear, colorless or slightly yellowish liquid. Theoretical osmolarity — 308 mosmol/L, pH 3.8–6.5.

Pharmacotherapeutic group. Plasma substitutes and perfusion solutions. Hydroxyethylated starch preparations. ATC code B05A A07.

Pharmacological Properties

Pharmacodynamics. The medicinal product Hekoven is a colloid used for blood volume expansion. Its pharmacological properties, such as increasing intravascular volume and hemodilution, depend on the molar substitution of hydroxyethyl groups (0.4), average molecular weight (130,000 Da), concentration (6%), as well as dose and infusion rate. The hydroxyethyl starch (HES 130/0.4) contained in Hekoven is derived from waxy maize starch, with a degree of substitution (C2/C6 ratio) of approximately 8–12.

It is known that infusion of 500 mL HES 130/0.4 over 30 minutes in volunteers resulted in a plateau-like increase in volume of approximately 100% of the infused volume, which was maintained for about 4 to 6 hours.

The therapeutic effect of HES 130/0.4 in expanding circulating blood volume is 100% and persists for at least 6 hours.

Pharmacokinetics. The pharmacokinetics of hydroxyethyl starch are complex and depend on molecular weight, primarily on the degree of molar substitution and substitution pattern (C2/C6 ratio). After intravenous administration, molecules with a molecular weight below the renal threshold of elimination (60,000–70,000 Da) are excreted unchanged in urine, whereas larger molecules are cleaved by plasma α-amylase before the degradation products are also eliminated by the kidneys.

The average molecular weight of Hekoven in plasma in vivo during the first minutes after infusion is 70,000–80,000 Da and remains above the elimination threshold throughout the treatment period.

The volume of distribution is approximately 5.9 liters. Thirty minutes after the end of infusion, the plasma concentration of Hekoven is still 75% of the maximum concentration. After 6 hours, the plasma concentration decreases to 14% of the maximum concentration. After a single dose of 500 mL Hekoven, hydroxyethyl starch molecules are completely eliminated from the body within 24 hours.

Following administration of 500 mL, plasma clearance of the drug is 31.4 mL/min, with an AUC (area under the plasma concentration-time curve) of 14.3 mg/mL/h, indicating nonlinear pharmacokinetics. After a single 500 mL dose, the elimination half-life values from plasma are: t1/2 α = 1.4 hours, t1/2 β = 12.1 hours.

When equivalent doses (500 mL) were administered to volunteers with stable moderate to severe renal impairment, AUC values moderately increased by a factor of 1.7 (95% confidence interval: 1.44–2.07) in patients with creatinine clearance < 50 mL/min compared to those with creatinine clearance ≥ 50 mL/min. The degree of renal impairment did not affect the terminal elimination half-life or the maximum concentration of hydroxyethyl starch. With creatinine clearance ≥ 30 mL/min, 59% of the administered dose was recovered in urine, compared to 51% with creatinine clearance between 15 and < 30 mL/min.

Even after daily administration of 500 mL of hydroxyethyl starch solution for 10 consecutive days in healthy volunteers, no significant accumulation of the drug in plasma occurred.

After repeated administration of HES 130/0.4 solution at a dose of 0.7 g/kg body weight per day for 18 days in animal experiments (rats), tissue accumulation of 0.6% of the total administered dose was observed 52 days after the last dose.

In another pharmacokinetic study, a single dose of 250 mL (15 g) of HES 130/0.4 (6%) was administered to 8 stable patients with end-stage renal disease requiring dialysis. During a 2-hour dialysis session, 3.6 g (24%) of the HES dose was removed. The mean plasma concentration of HES was 0.7 mg/mL at 24 hours and 0.25 mg/mL at 96 hours. The use of HES 130/0.4 (6%) is contraindicated in patients requiring dialysis.

Toxicity with Long-Term Administration

Intravenous infusion of hydroxyethyl starch at a dose of 9 g per kg of body weight per day administered to rats and dogs over 3 months did not reveal any toxic effects.

Increased load on the kidneys, liver, and metabolism of hydroxyethyl starch in the reticuloendothelial system led to non-physiological states in animals during the testing period.

The lowest observed toxic dose of hydroxyethyl starch exceeds 9 g per kg body weight per day and is therefore at least 5 times higher than the maximum therapeutic dose.

Reproductive Toxicity

Hydroxyethyl starch showed no teratogenic effects in rats and rabbits. Embryo-lethal effects were observed in rabbits at a dose of 5 g active substance per kg body weight per day. Treatment during pregnancy and lactation resulted in weight loss and developmental delay in offspring of rats receiving this dose as a bolus injection. Signs of volume overload were observed in maternal animals. Fertility studies in animals directly exposed to the drug have not been conducted.

Pharmacokinetic data in patients with hepatic insufficiency, pediatric, or geriatric patients are lacking. The influence of sex on the pharmacokinetics of the drug has not been studied.

Clinical characteristics.

Indications.

Hypovolemia caused by acute blood loss in cases where the use of crystalloids alone is considered insufficient.

Contraindications.

Do not use in sepsis, renal failure, or critically ill patients.

• Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition"
• Sepsis
• Burns
• Impaired kidney function or ongoing renal replacement therapy
• Intracranial or intracerebral hemorrhage
• Critically ill patients (typically those requiring hospitalization in intensive care and resuscitation units)
• Hyperhydration
• Pulmonary edema
• Dehydration
• Severe hypernatremia or severe hyperchloremia
• Severe hepatic dysfunction
• Decompensated heart failure
• Severe coagulation disorders
• Patients with transplanted organs

Interaction with other medicinal products and other forms of interaction.

Studies on interactions with other medicinal products have not been conducted.

Whenever possible, mixing with other medicinal products should be avoided. If in exceptional cases mixing cannot be avoided, attention must be paid to their compatibility (no cloudiness or precipitation should be observed), adherence to hygiene standards during administration, and thorough mixing.

Special precautions for use.

Due to the risk of allergic reactions, frequent monitoring of the patient's condition is required. Moreover, infusion of the drug should be initiated at a low rate. Anaphylactic/anaphylactoid reactions such as hypersensitivity, influenza-like symptoms, bradycardia, tachycardia, bronchospasm, and non-cardiogenic pulmonary edema have been associated with hydroxyethyl starch (HES) solutions. If hypersensitivity reactions occur, administration of the drug should be stopped immediately, and appropriate therapeutic and supportive measures should be initiated until symptoms resolve.

Surgical procedures and trauma

Currently, there are no reliable long-term safety data on the use of HES in patients undergoing surgical procedures or in patients with trauma.

Before prescribing HES to such patients, the expected benefit should be carefully weighed against the uncertainty regarding long-term safety, and alternative treatment options should be considered.

Indications for HES use for volume replacement should be carefully evaluated. Hemodynamic parameters should also be monitored to control and adjust volume and dosage.

In all cases, volume overload (hypervolemia) due to overdose or excessively high infusion rate should be avoided. The drug dosage should be selected with caution, especially in patients with lung or cardiovascular diseases. Frequent monitoring of serum electrolyte levels, fluid balance, and renal function is required.

HES-containing drugs are contraindicated in patients with impaired renal function and in patients receiving renal replacement therapy. HES administration should be discontinued at the first signs of kidney injury.

Cases of increased need for renal replacement therapy within 90 days after HES solution administration have been reported. Therefore, monitoring of renal function in patients for at least 90 days is recommended.

Particular caution should be exercised when treating patients with impaired liver function or patients with coagulation disorders.

Marked hemodilution associated with high-dose HES solutions should be avoided, especially in the treatment of patients with hypovolemia.

In case of repeated administration, coagulation parameters should be closely monitored. HES solution therapy should be discontinued at the first signs of coagulation abnormalities.

If a patient requires open-heart surgery with cardiopulmonary bypass, HES solutions are not recommended due to the risk of severe bleeding.

In cases of severe dehydration, crystalloid solutions should be administered first. Adequate fluid should generally be administered to prevent dehydration. Particular attention should be paid to patients with electrolyte imbalances.

Clinical assessment and periodic laboratory tests are necessary to monitor fluid balance, serum electrolyte concentrations, renal function, acid-base balance, and coagulation parameters during prolonged parenteral therapy and whenever the patient's condition requires such monitoring.

Currently, there are no reliable data on the long-term safety of HES use in patients after surgical procedures or in patients with trauma. Before prescribing HES to such patients, the expected benefit should be carefully weighed against the uncertainty regarding long-term safety, and alternative treatment options should be considered.

The daily dose of the drug Hekoven may contain more than 1 mmol (more than 23 mg) of sodium, depending on the patient's body weight. This should be taken into account if the patient is on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

There are some clinical data on the use of a single dose of HES in pregnant women undergoing cesarean section under spinal anesthesia. The incidence of arterial hypotension in the HES group was significantly lower compared to the crystalloid group (36.6% vs. 55.3%, respectively). Overall, efficacy parameters indicated a significant benefit of HES in preventing arterial hypotension and in preventing severe arterial hypotension compared to the control group receiving crystalloids.

Regarding safety, no negative effects of HES on pregnant women were observed, nor were any negative effects on newborns detected.

Animal studies did not reveal any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. No signs of teratogenicity were observed.

Hekoven may be used during pregnancy only if the expected benefit of treatment outweighs the potential risk to the fetus.

Except for cesarean section, there is no information on the use of HES during labor. Hekoven should be used only if clearly needed.

It is unknown whether the drug passes into breast milk. Excretion of HES into breast milk has not been studied in animals. The decision on continuing/discontinuing breastfeeding or continuing/discontinuing therapy with Hekoven should be made considering the benefit of breastfeeding for the child and the benefit of Hekoven therapy for the mother. Currently, there are no clinical data on the use of HES during lactation.

Ability to affect reaction speed when driving vehicles or operating machinery.

Hekoven does not affect reaction speed when driving vehicles or operating machinery.

Method of Administration and Dosage

For intravenous use only.

Dosage for adults

The maximum daily dose of Hekoven is 30 ml/kg body weight.

The use of HES should be limited to the initial phase of hemodynamic stabilization and should not exceed 24 hours.

The first 10–20 ml of the solution should be administered slowly. The patient must be under close monitoring due to possible anaphylactic/anaphylactoid reactions.

The daily dose and infusion rate depend on the volume of blood loss, hemodynamic support or restoration, and on hemodilution (dilution effect).

The lowest effective dose of the drug should be used. During treatment, monitoring of hemodynamic parameters should be performed, and once target hemodynamic parameters are achieved, the infusion should be discontinued. The recommended maximum daily dose must not be exceeded.

From a microbiological standpoint, the medicinal product should be used immediately. If the product is not used immediately, the responsibility for storage conditions and duration after opening lies with the user. The product should be used immediately after opening.

Children.

Data on the use of HES in children are limited. Therefore, the use of HES-containing products in this patient group is not recommended.

Overdose.

As with other plasma volume expanders, overdose of Hekoven may lead to circulatory overload (e.g., pulmonary edema). In such cases, the infusion must be stopped immediately, and if necessary, a diuretic should be administered.

Adverse Reactions

The following classification is used to assess the frequency of adverse reactions: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1,000 and < 1/100; rare: ≥ 1/10,000 and < 1/1,000; very rare: < 1/10,000; frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders.
Rare (at high doses): administration of hydroxyethyl starch may lead to dose-dependent coagulation disorders due to dilution effects.

Immune system disorders.
Rare: medicinal products containing HES may cause anaphylactic/anaphylactoid reactions (hypersensitivity, mild flu-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiogenic pulmonary edema). If hypersensitivity reactions occur, infusion must be stopped immediately and appropriate therapeutic and supportive measures should be initiated until symptoms resolve.

Skin and subcutaneous tissue disorders.
Common (dose-dependent): prolonged administration of high doses of hydroxyethyl starch may cause pruritus. Pruritus may develop several weeks after the last infusion and may persist for several months.

Hepatobiliary disorders.
Frequency not known: liver injury.

Renal and urinary disorders.
Frequency not known: kidney injury.

Investigations.
Common (dose-dependent): during HES administration, serum amylase levels may increase, which may interfere with the diagnosis of pancreatitis.

The increase in amylase levels is due to formation of an amylase–HES complex, resulting in slow elimination and should not be considered a diagnostic criterion for pancreatitis.

Common (dose-dependent): at high doses, dilution effects may lead to corresponding dilution of blood components such as coagulation factors and other plasma proteins, and decreased hematocrit.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions in accordance with pharmacovigilance legislation.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C in a place inaccessible to children. Do not freeze during storage.

Packaging. 200 ml, 250 ml, 400 ml or 500 ml in a bottle; 1 bottle in a carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and site of operations.
84A Nemyrivske Highway, Vinnytski Khuhtory, Vinnytsia district, Vinnytsia region, 23219, Ukraine.