Volulyte - Scientific Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Anaphylactic Shock (Anaphylaxis), Fainting (Syncope), Hypovolemia, Low Blood Sugar (Hypoglycemia)|
|Form:||Liquid solution, Intravenous (IV)|
|Ingredients:||6% hydroxyethyl starch 130/0.4 in an isotonic electrolyte injection, magnesium chloride hexahydrate, potassium chloride, sodium acetate trihydrate, sodium chloride, water for injections|
Description of Drug Substance
Hydroxyethyl starch is a derivative of amylopectin, which is a highly branched compound of starch. In humans and animals amylopectin is rapidly hydrolyzed by amylase. In order to reduce the metabolic degradation, glucose residues of the amylopectin are reacted with ethylene oxide. The hydroxyethyl groups can be introduced at three positions (C2, C3, C6) of the glucose residues. The degree of substitution and the substitution pattern, expressed by the C2/C6 ratio, determine the enzymatic degradation of HES. HES 130/0.4 contained in Volulyte is characterized by its molar substitution, molecular weight and the C2/C6 ratio.
|Proper or common name||Hydroxyethyl Starch (HES) (130/0.4)|
|Chemical name||Poly (O-2 hydroxyethyl) starch|
|Molecular weight (Mw)||The molecular weight indicates the weight average. The Mw of HES 130/0.4 lies between 110,000 and 150,000 Dalton, which corresponds approximately to 609 to 830 partially hydroxyethylated glucose units.|
|Molar substitution (MS)||The ratio of hydroxyethyl groups to glucose units is called the molar substitution (MS). The MS for this substance is 0.4 (0.38 – 0.45), tetrastarch, and determines the molar ratio of hydroxyethyl ether groups to glucose units.|
|C2/C6 ratio||This parameter gives information about the preferred position of hydroxyethylation and reflects the different intrinsic reactivity of the secondary and the primary alcohol functionality at the respective positions of the glucose ring. The value of the C2/C6 ratio should be higher than 8 for HES 130/0.4.|
|Product Characteristics||Hydroxyethyl starch (6% HES 130/0.4, a tetrastarch) in an isotonic electrolyte solution is a clear to slightly opalescent solution, colourless to slightly yellow.|
A prospective, randomized, double-blinded, multicentre, parallel group study in 81 patients undergoing cardiac surgery compared the efficacy and safety of two different 6% HES 130/0.4 formulations: Volulyte and Voluven. The results showed that Volulyte and Voluven were therapeutically equivalent regarding the volume of each product needed for adequate plasma volume expansion.
The safety of Volulyte was not significantly different from that observed with Voluven. There was no evidence that the addition of Mg++, K+, and acetate in the solvent of Volulyte in comparison to saline solutions influences coagulation parameters or bleeding events, as both the measured and calculated red blood cell loss showed no differences between treatment groups in this study.
Groups were comparable with regard to overall safety.
The pharmacodynamic effect of 6% HES 130/0.4 was examined in a shock model in conscious rats and an exchange model in dogs. In both studies the control group received 6% HES 200/0.5 (pentastarch).
Six percent HES 130/0.4 solution was as effective as 6% HES 200/0.5 solution in maintaining cardio-pulmonary functions during isovolemic hemodilution in Beagle dogs. In the 3-hour follow-up period no additional administration of colloid was necessary.
There were no differences in long-term survival of rats after a single administration of 6% HES 130/0.4 and 6% HES 200/0.5 solution following an induced hemorrhagic shock (67% and 50% blood loss). In the 6% HES 130/0.4 group bled at 67%, the survival rate was 83% since one animal died. However, non-survival of one animal lies within the normal range for this type of experiment. In the corresponding 6% HES 200/0.5 group survival was 100%. Infusion of Ringer's lactate resulted in a 50% survival rate after a 50% blood loss and a 0% survival after a 67% blood loss. In conclusion, 6% HES 130/0.4 had a life saving effect equivalent to 6% HES 200/0.5 in this rat model.
After multiple I.V. administration of 0.7 g per kg BW per day of 10% HES 130/0.4 or 10% HES 200/0.5 solution during 18 consecutive days, the plasma HES concentration in rats treated with 10% HES 130/0.4 was lower compared to rats treated with 10% HES 200/0.5. Ten percent HES 130/0.4 was eliminated faster than 10% HES 200/0.5. In both groups, clear signs of HES tissue storage were detected in lymph nodes and spleen. Numerous empty vacuoles in macrophages were observed. Only a minimal cellular vacuolization was found in the liver and kidney. Histochemical differences between the groups were not observed.
Therefore, a study with radio-labelled 10% 14C-HES 130/0.4 and 10% 14C-HES 200/0.5 solutions was carried out. In animals treated with HES 130 radioactivity decreased from 4.3% of the total administered dose (2.6 g HES 130/animal) on day 3 to 0.6% on day 52. In animals treated with HES 200/0.5 the 14C-activity decreased from 7.7% of the total administered dose (2.7 g HES 200/animal) on day 3 to 2.45% on day 52. These results confirm the faster elimination and lower persistence of HES 130/0.4 in tissue.
The intravenous infusion of 90 mL of 10% HES 130/0.4 per kg BW/day infused over 3 hours each day in rats and dogs for 3 months resulted in no signs of overt toxicity, except for an increased workload on the kidney and the liver, uptake and metabolism of hydroxyethyl starch in the reticulo-endothelial system, hepatic parenchyma, and other tissues associated with the animals´ unphysiological state during the test period.
HES 130/0.4 had no teratogenic properties in rats or rabbits. Embryolethal effects were observed in rabbits at 50 mL/kg BW/day of 10% HES 130/0.4. In rats, bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays. However, embryo-feto-toxicity in rats and rabbits was only observed at maternal-toxic dose levels. Signs of fluid overloading were seen in the dams. Fertility studies on directly exposed animals have not been conducted.
No mutagenic effects were observed with HES 130/0.4 10% solution according to the following tests on mutagenic activity: Salmonella typhimurium reverse mutation assay (in vitro), mammalian cells in the in vitro gene mutation assay (HPRT), assessment of the clastogenic activity in cultured human peripheral lymphocytes (in vitro), bone marrow cytogenetic test in Sprague-Dawley rats.
In a skin sensitization study, 30 male Dunkin-Hartley guinea pigs were treated intracutaneously and topically with undiluted HES 130/0.4 10% to examine the local irritation. Animals of the control group were treated with isotonic NaCl solution (negative control). The positive control group was treated with potassium dichromate.
No skin irritation after application of HES 130/0.4 10% solution was observed. HES 130/0.4 10% has no sensitizing properties.
A study in 5 female Dunkin-Hartley guinea pigs was done to demonstrate non-antigenicity of HES 130/0.4 10% in sensitized guinea pigs. After the 48-day sensitization period the animals received 3 mL of HES 130/0.4 10% intravenously.
No sensitizing properties of HES 130/0.4 10% were observed in this animal model.
Blood Compatibility Study
A study to examine the hemolytic properties of HES 130/0.4 10% solution on human red blood cells was performed. Undiluted HES 130/0.4 10% solution was shown to have no hemolytic effect on human red blood cells.
In an in vitro study, both Volulyte and 6% HES 130/0.4 in 0.9% sodium chloride solution did not cause hemolysis in human whole blood.
In a local tolerance study in 12 Himalayan rabbits (6 males and 6 females) were administered a single intravenous infusion (300 mL 10% HES 130/0.4 / 3 hours / animal), intra-arterially (300 mL 10% HES 130/0.4 / 3 hours / animal), paravenously (0.5 mL 10% HES 130/0.4 / animal), and subcutaneously (1 mL 10% HES 130/0.4 / animal). Isotonic saline (NaCl 0.9%) served as a negative control.
Under these test conditions 10% HES 130/0.4 showed good local tolerance in rabbits after intravenous infusion at a dose level that corresponded to 4-5 fold the level used in man. Microscopic investigations did not show any substance-related local changes.
In a further local tolerance test in New Zealand White rabbits, both Volulyte and 6% HES 130/0.4 in 0.9% sodium chloride solution were administered in intended intravenous administration site as well as in unintended injection sites (intraarterial, paravenous, subcutaneous and intramuscular). Both Volulyte and 6% HES 130/0.4 in 0.9% sodium chloride solution showed good local tolerance in rabbits after intravenous infusion and also indicated no difference between both HES solutions.