Pharmacological properties of the drug Voluven
Voluven is a solution of hydroxyethyl starch (HES), which is obtained from amylopectin and is characterized by molecular weight and degree of substitution. For Voluven, the average molecular weight is 130,000 Da and the degree of substitution is 0.38–0.45 (this means that for every 10 glucose residues of amylopectin there are about 4 hydroxyethyl groups). Hydroxyethyl starch is structurally related to glycogen, which explains its high tolerance and low risk of anaphylactic reactions. Voluven is characterized by high stability of the solution and does not flocculate during temperature fluctuations. The pharmacokinetics of hydroxyethyl starches is complex and depends on the molecular weight and degree of molecular substitution of the substance. After intravenous administration of hydroxyethyl starches, molecules smaller than 60,000–70,000 Da (the threshold for renal filtration) are quickly excreted in the urine, and larger molecules, including Voluven, are broken down by plasma α-amylase, after which they are also excreted by the kidneys. The average molecular weight of Voluven in the first minutes after infusion in blood plasma in vivo 70,000–80,000 Da and remains above the renal filtration threshold throughout the entire treatment period. 30 minutes after the end of the Voluven infusion, its concentration in the blood plasma is 75% of the maximum, and after 6 hours it decreases to 14%. With a single administration of 500 ml of Voluven, hydroxyethyl starch molecules are completely eliminated from the body after 24 hours. With daily administration of 500 ml of 10% HES 130/0.4 solution to volunteers for 10 days, no significant accumulation of the substance in the blood plasma was detected. Impaired renal function did not affect the half-life in the final elimination phase and the maximum concentration of HES in the blood plasma. With a CC of 30 ml/min, 59% of the administered dose of the drug was excreted in the urine, and with a CC of 15–30 ml/min - 51%. Compared to HES 200/0.5, Voluven has improved pharmacokinetics (metabolism and excretion are optimized) while maintaining its plasma replacement effect. Improved pharmacokinetic characteristics make it possible to weaken the effect of the drug on the hemostatic system with repeated administration of high doses and reduce the accumulation of hydroxyethyl starch in tissues.
Voluven instructions for use
Release form Solution for infusion 6% transparent or slightly opalescent, colorless or slightly yellow. Composition 1 l contains active substances poly(O-2-hydroxyethyl) starch* 60 g sodium chloride 9 g electrolytes: Na+ 154 mmol/l Cl- 154 mmol/l theoretical osmolarity 308 mOsm/l titratable acidity less than 1 mmol NaOH/l pH 4.0 -5.5 * with a degree of molar substitution of 0.4; average molecular weight 130,000 Da. Excipients: sodium hydroxide - qs for pH correction, hydrochloric acid - qs for pH correction, water for pH correction - up to 1 liter.
Pharmacological action Plasma replacement drug. Voluven is a solution of hydroxyethyl starch (HES) that is obtained from waxy corn amylopectin and is characterized by molecular weight and degree of substitution. For Voluven, the average molecular weight is 130,000 Da and the degree of substitution is 0.4, which means that for every 10 glucose residues of amylopectin there are 4 hydroxyethyl groups. HES is structurally related to glycogen, which explains its high tolerance and low risk of anaphylactic reactions. Voluven is highly stable solution and does not flocculate when temperature fluctuates. Voluven is an iso-oncotic plasma replacement solution, due to which, when administered, the volume of intravascular fluid increases in proportion to the injected volume of Voluven. The persistent volemic effect of Voluven is 100% within 4 hours from the moment of administration of the drug into the vascular bed. The therapeutic effect lasts up to 6 hours.
Pharmacokinetics The pharmacokinetics of HES is complex and depends on the molecular weight of HES, the degree of molar substitution of the substance and the nature of the molar substitution of C2/C6 hydroxyl groups. After intravenous administration of HES, molecules weighing less than 60,000-70,000 Da (renal filtration threshold) are quickly excreted in the urine, and larger molecules are broken down by plasma α-amylase, after which they are also excreted through the kidneys. The lower the degree of substitution of HES, the faster the drug is hydrolyzed by α-amylase and excreted from the body, the less accumulation in tissues (in particular, in cells of the immune system) and blood plasma. The nature of C2/C6 substitution affects the volemic effect of the drug. This figure for Voluven is 9:1, i.e. hydroxyl groups are located in the more stable position C2, 9 times more than in C6. If there are ≥ 8 hydroxyl groups in the C2 position, then the volemic effect of HES is more stable than that of HES with this indicator less than 8. The average molecular weight of Voluven in vivo in the first minutes after infusion is 70,000-80,000 Da in blood plasma and remains above the threshold renal filtration during the entire treatment period. After administration of 500 ml of Voluven, its plasma clearance is 31.4 ml/min. After a single administration of 500 ml of the drug, T1/2 in the blood plasma in the first phase of elimination is 1.4 hours, and in the second phase - 12.1 hours. With a single administration of 500 ml of Voluven, HES molecules are completely eliminated from the body after 24 hours. With repeated administration of 500 ml of solution HES 130/0.4 did not reveal any significant accumulation of the substance in the blood plasma within 10 days. Pharmacokinetics in special clinical situations In patients with stable renal impairment (from mild to severe) and CC < 50 ml/min, Cmax of HES in the blood was slightly higher than in patients with CC > 50 ml/min at the same administered dose drug (500 ml). Impaired renal function did not affect T1/2 in the final elimination phase and the Cmax value of HES in the blood plasma. When CC > 30 ml/min, 59% of the administered dose of the drug was excreted in the urine, and with CC 15-30 ml/min - 51%. Compared to HES 200/0.5, Voluven has improved pharmacokinetics (metabolism and excretion are optimized), while maintaining its plasma replacement effect. At the same time, the drug has maximum safety compared to previous generations of HES, because has a minimal effect on the hemostatic system even with repeated administration of high doses, and there is virtually no accumulation in tissues.
Voluven, indications for use treatment and prevention of hypovolemia of any origin and shock (due to trauma, including spinal injury with spinal cord damage, blood loss, burns, sepsis, multiple organ failure, in the postoperative period, acute adrenal insufficiency, anaphylaxis and other conditions , accompanied by the development of collapse); acute normovolemic hemodilution; therapeutic hemodilution; filling the extracorporeal circulation apparatus.
Contraindications : hyperhydration; hypervolemia; congestive heart failure; severe blood clotting disorders; intracranial bleeding; state of dehydration, when correction of water and electrolyte balance is required; severe renal failure with oliguria or anuria; use in patients on hemodialysis; hyperchloremia; hypernatremia; hypersensitivity to the drug.
Use for liver dysfunction Particular caution is required in severe liver failure.
Use for impaired renal function The drug is contraindicated for use in severe renal failure with oliguria or anuria and in patients on hemodialysis;
Use in children: In children under 2 years of age who have undergone surgery (excluding cardiac surgery), the tolerability of Voluven during surgery was comparable to that of 5% albumin.
Method of administration and dosage The drug is administered by long-term intravenous infusion. The first 10-20 ml of solution should be administered slowly, with careful monitoring of the patient's condition, due to the risk of anaphylactoid reactions. The daily dose and infusion rate depend on the degree of blood loss, maintenance or restoration of hemodynamics and the degree of hemodilution (blood dilution). In situations requiring rapid compensation of hypovolemia and emergency replenishment of blood volume, you can use 500 ml of solution in plastic containers under pressure. In this case, before administering Voluven, it is necessary to remove air from the container in order to prevent the occurrence of air embolism. The maximum daily dose is 50 ml/kg body weight/day, which corresponds to 3750 ml/day for a patient with a body weight of 75 kg. In children under 2 years of age who underwent surgery (excluding cardiac surgery), the tolerability of Voluven during surgery was comparable to that of 5% albumin. To replenish blood volume in adults, the maximum dose is 50 ml/kg/day; children and adolescents aged 10-18 years - 33 ml/kg/day; in children aged 2-10 years - 25 ml/kg/day; in newborns and children under 2 years of age - 25 ml/kg/day. Voluven can be administered repeatedly over several days, depending on the clinical situation. The duration of treatment depends on the duration and severity of hypovolemia, the hemodynamic effectiveness of the drug and hemodilution.
Use during pregnancy and lactation There are no clinical data on the use of Voluven during pregnancy and lactation. The use of the drug during pregnancy is possible only if the potential benefit to the mother outweighs the possible risk to the fetus. Experimental studies on animals did not reveal any direct or indirect adverse effects on pregnancy, embryo/fetal development, childbirth or postnatal development. No evidence of teratogenicity was observed.
Side effects Dermatological reactions: with prolonged administration in high doses - skin itching. From the laboratory parameters: an increase in the concentration of serum amylase is possible. When using the drug in high doses, due to the dilution effect, dilution of blood components, a decrease in hematocrit, as well as coagulation factors and plasma proteins, is possible. In this regard, the activity of blood coagulation factor VIII (von Willebrand) may be reduced during infusion. Bleeding time and other indicators of blood clotting may increase. However, these changes are significantly reduced compared to those with the infusion of previous generations of HES, and are restored to the initial level 6 hours after stopping the drug infusion. Other: allergic reactions of varying severity.
Special instructions As with the use of other solutions, when carrying out plasma replacement therapy, it is necessary to avoid fluid overload. The risk of overhydration is particularly increased in patients with heart failure or severe renal impairment. In this case, the indications for infusion should be clarified. In cases of severe dehydration, saline solutions should be preferred. Particular caution is required in case of severe liver failure or blood clotting disorders, incl. in severe cases of von Willebrand disease. It is important to ensure sufficient fluid intake, regular monitoring of kidney function and fluid balance. Serum electrolytes should be monitored. When treating patients whose blood type is not determined, it should be borne in mind that the administration of Voluven in high doses may affect the agglutination reaction and give false positive results when determining the blood group. Administration of HES may lead to an increase in serum amylase levels. This effect should not be considered as a violation of pancreatic function, but as a result of the formation of a complex of HES with amylase with a subsequent delay in its excretion through the kidneys. Currently, cases of such interaction are unknown. The drug does not affect the increase in serum glucose levels after hydrolysis by α-amylase and can be used in patients with diabetes mellitus.
Use in pediatrics The dose for children should be selected individually in accordance with the need for colloids and taking into account the severity of the underlying disease, hemodynamic parameters, and water balance.
Drug interactions Avoid mixing Voluven with other drugs. If this is required in exceptional cases, then the compatibility of the drugs should be checked (turbidity, precipitation), aseptic rules should be observed when mixing and good mixing should be ensured.
Overdose Symptoms: overload of the circulatory system (for example, pulmonary edema). Treatment: stop administering the drug; if necessary, prescribe a diuretic.
Storage conditions The drug should be stored out of the reach of children, in a dry place, protected from light at a temperature not exceeding 25°C; do not freeze. Only use clear solutions in undamaged containers. Once the vial or container is opened, the solution should be used immediately. Unused solution must be destroyed.
Shelf life In freeflex containers - 3 years In bottles - 5 years.
Use of the drug Voluven
The drug is intended for long-term intravenous infusion for adults and children of any age, starting from the neonatal period. An initial dose of 10–20 ml should be administered slowly and the patient should be closely monitored due to the possibility of anaphylactoid reactions. The daily dose and infusion rate depend on blood loss, maintenance or restoration of hemodynamics, and blood dilution (hemodilution). The maximum daily dose is 50 ml/kg body weight per day, which corresponds to 3g/kg/day (about 3500 ml/day for a body weight of 70 kg). Voluven is used to replenish blood volume:
- in adults, the maximum daily dose is 50 ml/kg body weight;
- for children aged 10–18 years, the daily dose is 33 ml/kg;
- in children aged 2–10 years, the daily dose is 25 ml/kg;
- in newborns and children under 2 years of age, the daily dose is 25 ml/kg.
Voluven can be administered repeatedly over several days depending on the patient's needs. The duration of treatment depends on the duration and severity of hypovolemia, hemodynamics and hemodilution. Avoid mixing the drug with other substances. If in exceptional cases this is required, then the compatibility of the drugs should be checked (based on the appearance of turbidity or sediment), observe aseptic rules when mixing and ensure good mixing. Use the drug immediately after opening the bottle. Application is possible if the solution is transparent and the packaging is intact.
VOLUVEN solution for infusion 6% plastic. container 500 ml No. 10
special instructions
Due to the possible risk of allergic (anaphylactic/anaphylactoid) reactions, it is necessary to closely monitor the patient's condition and begin infusion of the drug at a low rate.
There are no adequate long-term data on the use of hydroxyethyl starch in patients undergoing surgery or trauma. The expected benefit of treatment must be carefully weighed against the uncertain long-term safety. Other available therapeutic measures should be considered.
The appropriateness of using hydroxyethyl starch for the treatment of hypovolemia should be carefully assessed and hemodynamic parameters should be monitored to monitor the achievement of the desired effect and determine the dose of the drug.
Volume overload associated with drug overdose or high infusion rates should be avoided. The dose of the drug must be selected with caution, especially in patients with diseases of the lungs and cardiovascular system. Serum electrolytes, fluid balance, and renal function should be carefully monitored.
The use of HES-based products is contraindicated in patients with renal failure or receiving renal replacement therapy. At the first signs of renal dysfunction, the use of hydroxyethyl starch should be discontinued.
Studies have shown that there may be an increased need for renal replacement therapy up to 90 days after HES use. It is recommended to monitor renal function in hospitalized patients for a minimum of 90 days.
Caution should be exercised when using the drug in patients with impaired liver function or in patients with coagulopathy.
In patients with hypovolemia, severe hemodilution associated with the use of high doses of HES solutions should be avoided.
When HES is reintroduced, blood coagulation parameters must be carefully monitored. When the first signs of coagulopathy appear, the use of the drug should be discontinued.
When performing open heart surgery in combination with extracorporeal circulation, the use of HES drugs is not recommended due to the risk of increased bleeding.
For single use only.
The outer protective bag should be removed before use.
Use the solution immediately after opening the package. Use only clear solution from undamaged packaging. Any remaining unused solution should be destroyed.
Special instructions for the use of Voluven
As with the introduction of other solutions, when carrying out plasma replacement therapy, it is necessary to avoid fluid overload. The risk of overhydration especially increases in the case of heart failure or severe renal impairment. When treating such patients, the indications for infusion should be clarified. In cases of severe dehydration, preference should be given to saline solutions. It is important to administer adequate fluids and regularly monitor kidney function and fluid balance. Plasma electrolytes should be monitored. Doses for children should be selected individually in accordance with the child's needs for colloids and taking into account the severity of the underlying disease, hemodynamic parameters and water balance. During pregnancy and breastfeeding. Animal studies have not revealed direct or indirect adverse effects on pregnancy, embryo/fetal development, childbirth and postnatal development. Also, no evidence of teratogenicity was observed. Voluven can be used during pregnancy only in cases where the expected benefit from treatment outweighs the possible risk to the fetus.
