Shandong Qidu Pharmaceutical Co.,Ltd.

[Indications and Clinical use]: For treatment and prevention of hypovolemia.

[Strength]: 250ml: 15g hydroxyethyl starch 130/0.4 and 2.25g sodium chloride

[Pharmacological Actions]

Hydroxyethyl starch (130/0.4) 6% is a synthetic colloid for use in plasma volume replacement. The plasma expansion effects of the product are determined by its mean molecular weight (130kDa), the molar substitution by hydroxyethyl groups (0.4) on glucose units of the starch, the pattern of hydroxyethyl substitution (C₂/C₆ ratio) of approximately 9:1, and the concentration (6%), as well as the dosage and infusion rate.1. The 130/0.4 designation refers to the molecular weight and molar substitution characteristic of this formulation of hydroxyethyl 6% starch. In general, the higher the molar substitution and the C₂/C₆ratio, the slower the starch is metabolized. Hydroxyethyl starch is a derivative of thin boiling waxy corn starch, which mainly consists of a glucose polymer (amylopectin) predominantly, composed of alpha-1-4-connected glucose units with several alpha-1-6-branches. Substitution of hydroxyethyl groups on the glucose units of the polymer reduces the normal degradation of amylopectin by alphaamylase in the body. The low molar substitution (0.4) is the main pharmacological determinant for the beneficial effects of this product on pharmacokinetics, intravascular volume, and hemodilution.

After isovolemic exchange of blood with 500mL hydroxyethyl starch (130/0.4) 6% in healthy volunteers, blood volume was maintained for at least 6 hours.1 The volume expansion effects of hydroxyethyl starch 6% 130/0.4 (voluven) has been compared with that of hydroxyethyl starch (670/0.75) 6% (Hextend) in 20 volunteers bled 10% of their total blood volume in a randomized, double-blind study.

[Indications]

Hydroxyethyl starch (130/0.4) 6% is indicated for the treatment and prophylaxis of hypovolemia. It is not a substitute for red blood cells (RBCs) or coagulation factors in plasma.1

[Dosage and Administration]

Hydroxyethyl starch (130/0.4) 6% should be administered by IV infusion only. The initial 10 to 20mL should be infused slowly with close observation because of the potential for anaphylactoid reactions. The daily dose and rate of infusion is dependent upon the patient’s blood loss and hemodynamics, and the hemodilution effects. The product can be administered repetitively over several days.

In adults, the usual dose is up to 50mL/kg/day (equivalent to 3g hydroxyethyl starch and 7.7mEq of sodium per kg of body weight). This dose is equivalent to 3,500mL for a 70 kg patient.1 Doses as high as 70mL/kg/day have been administered in the study setting.20 Limited data are available to guide dosing in children. In 41 children, including newborns and infants (less than 2 years of age), a mean dose of 16 ± 9mL/kg was administered. The dosage in children should be adapted to the individual patient’s colloid needs, taking into account the disease state as well as the hemodynamic and hydration status. No data are available for children 2 to 12 years of age. In adolescents, use is supported by data from adults and children younger than 2 years of age.

[Adverse Reactions]

The most common adverse reactions (occurring in 1% to 10% of patients) include pruritus, elevated serum amylase, and hemodilution (resulting in dilution of blood components, including coagulation factors and other plasma proteins and a decrease in hematocrit). Anaphylactoid reactions have been observed in fewer than 0.1% of patients treated with products containing hydroxyethyl starch. In a study comparing hydroxyethyl starch (130/0.4) 6% (Voluven) and hetastarch (hydroxyethyl starch 6% in sodium chloride 0.9%), single cases of elevated APTT, prolonged PT, wound hemorrhage, anemia, and pruritus in a total of 3 patients were possibly associated with Voluven, while 3 cases of coagulopathy and 2 cases of pruritus were possibly associated with hetastarch. The 3 coagulopathy cases observed with hetastarch were serious and occurred in patients receiving more than the maximum labeled dose of 20mL/kg; no serious coagulopathy occurred in the Voluven group. The effects of Voluven on von Willebrand factor, factor VIII, and Ristocetin cofactor (von Willebrand factor activity) were less than those of pentastarch in several studies, consistent with the lower molecular weight and increased elimination.

[Precautions]

Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, noncardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch. If a hypersensitivity reaction occurs, administration should be immediately discontinued and treatment and supportive measures undertaken until symptoms have resolved.

Fluid status and rate of infusion should be assessed regularly during treatment to avoid fluid overload with the administration of hydroxyethyl starch (130/0.4) 6%. The dosage should be adjusted in patients with cardiac or renal function impairment. Hydroxyethyl starch is excreted renally and the risk of adverse reactions may be greater in patients with renal function impairment. Volume status, infusion rate, and urine output should be closely monitored. In patients with severe dehydration, a crystalloid solution should be given first. Sufficient fluid should be administered to avoid dehydration. Caution is advised with administration in patients with severe liver disease or bleeding disorders. Hespan labeling contains a warning regarding use in cardiopulmonary bypass and an increased risk of bleeding. This warning was prompted by 2 randomized studies and an epidemiologic study that demonstrated increased blood loss in this population. Following publication of these data and the labeling change, a number of other retrospective analyses appeared to confirm the findings. No studies have specifically assessed hextend in cardiac surgery studies; therefore, it is not known if the bleeding risk differs between hespan and Hextend.30

Other studies have observed patients with type O blood may have reduced factor VIII/von willebrand factor levels compared with patients with other blood types and may be more likely to develop changes in hemostatic factors after hemodilution with hydroxyethyl starch, including hydroxyethyl starch (130/0.4) 6%.31 No overall differences in safety or effectiveness were noted between subjects older than 65 years of age and younger subjects. Because elderly patients are more likely to have decreased renal function, care is advised in dosage selection.

In children, the dose should be adjusted to individual patient needs taking into account the disease state as well as the hemodynamic and hydration status. Limited data are available to guide dosing in children. In 41 newborns-toinfants (younger than 2 years of age) enrolled in a study and a mean dose of 16 ± 9 mL/kg was administered. The product may be given to premature infants and newborns only after a careful risk/benefit evaluation. No data are available for children 2 to 12 years of age. In adolescents, use is supported by data from adults and children younger than 2 years of age. Hydroxyethyl starch (130/0.4) 6% is in Pregnancy Category C.