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Pharmacotherapeutic Group: Plasma substitutes and plasma protein fractions. ATC Code: B05AA07.
Pharmacology: Pharmacodynamics: The active ingredient hydroxyethyl starch 130/0.4 is a derivative of waxy maize starch mainly consisting of a glucose polymer (amylopectin) predominately composed of α-1,4-connected glucose units with several α-1,6-branches.
Volulyte is an artificial colloid for volume replacement. Its pharmacological properties depend on the molar substitution by hydroxyethyl groups (0.4), the mean molecular weight (130,000 Da), the concentration (6%), the substitution ratio (C2/C6 ratio) of approximately 9:1 as well as the dosage and infusion rate.
To describe the molecular weight and molar substitution characteristics of the hydroxyethyl starch in Volulyte, the compound is designated as hydroxyethyl starch 130/0.4. The low molar substitution, medium molecular weight, and narrow molecular weight distribution of HES 130/0.4 contained in Volulyte contribute to its beneficial effects on pharmacokinetics and intravascular volume effect.
Infusion of 500 ml of a similar product containing HES 130/0.4 (6%) in 0.9% sodium chloride solution in 30 minutes in volunteers results in a plateau-like non-expansive volume increase of approximately 100% of the infused volume which lasts for approximately 4 to 6 hours.
Isovolaemic exchange of blood with HES 130/0.4 in 0.9% sodium chloride solution maintains blood volume for at least 6 hours.
Volulyte contains the electrolytes sodium (Na+), potassium (K+), magnesium (Mg++), chloride (Cl-) and acetate (CH3COO-) in an isotonic composition. Acetate is a metabolisable anion which is oxidised in different organs and has an alkalising effect.
Volulyte contains a reduced amount of chloride and therefore counteracts the development of hyperchloraemic metabolic acidosis, especially when large dose infusions are required or in patients at risk for the development of metabolic acidosis.
In cardiac surgery, chloride levels were significantly lower and base excess levels were seen to be less negative for Volulyte in comparison to HES 130/0.4 (6%) in 0.9% sodium chloride solution.
Paediatric use: No clinical trials have been performed with the product in paediatric patients. However, clinical data on the use of a similar product containing HES 130/0.4 (6%) in 0.9% sodium chloride solution in paediatric patients is available. In one trial with a similar product containing HES 130/0.4 (6%) in 0.9% sodium chloride solution, newborns and infants (< 2 years) of age undergoing elective surgery were randomised to receive HES 130/0.4 in 0.9% sodium chloride (N=41) or 5% albumin (N=41). The mean dose of 16 ± 9 ml/kg.
In an additional trial, children from 2 - 12 years of age undergoing cardiac surgery were randomised to receive HES 130/0.4 in 0.9% sodium chloride (N=31) or 5% albumin (N=30). The mean dose administered was 36 ± 11 ml/kg.
The product may be given to children after careful benefit/risk evaluation (in particular in children below one year of age who independently of the product have a potential to develop lactic acidosis) taking into account the disease state, as well as the haemodynamics and hydration status (see Dosage & Administration).
Treatment of pregnant women undergoing caesarian section: There are limited clinical study data available from the use of a single dose of HES 130/0.4 (6%) in 0.9% sodium chloride in pregnant women undergoing caesarean section with spinal anaesthesia. The occurrence of hypotension was significantly lower for HES 130/0.4 (6%) in combination with crystalloid compared to crystalloid control alone (36.6% vs. 55.3%). Overall efficacy evaluation showed significant benefits for HES 130/0.4 (6%) in the prevention of hypotension and in the occurrence of severe hypotension compared to crystalloid control.
Pharmacokinetics: The pharmacokinetics of hydroxyethyl starch is complex and depends on the molecular weight and mainly on the molar substitution degree and the substitution pattern (C2/C6 ratio). When applied intravenously, molecules smaller than the renal threshold (60,000 - 70,000 Da) are readily excreted in the urine while larger ones are metabolised by plasma α-amylase before the degradation products are renally excreted.
The mean in vivo molecular weight of HES 130/0.4 in the plasma is 70,000 - 80,000 Da immediately after infusion and remains above the renal threshold throughout the therapeutic period.
The volume of distribution is about 5.9 litres. Within 30 minutes of infusion the plasma level of HES 130/0.4 (6%) is still 75% of the maximum concentration. After 6 hours the plasma level has decreased to 14%. Following a single dose of 500 ml hydroxyethyl starch plasma levels almost return to baseline after 24 hours.
Plasma clearance was 31.4 ml/min when 500 ml of HES 130/0.4 (6%) was administered, with an AUC of 14.3 mg/ml x h, which shows a non-linear pharmacokinetic. Plasma half-lives were t1/2α = 1.4 h and t1/2β = 12.1 h when 500 ml were administered on a single occasion.
Using the same dose (500 ml) in subjects with stable mild to severe renal impairment, the AUC moderately increased by a factor of 1.7 (95% confidence limits 1.44 and 2.07) in subjects with ClCr < 50 ml/min compared to > 50 ml/min. Terminal half life and peak HES concentration were not affected by renal impairment. At ClCr ≥ 30 ml/min, 59% of the drug could be retrieved in the urine, vs 51% at ClCr 15 to 30 ml/min. Plasma levels of HES 130/0.4 almost returned to baseline levels 24 hours following infusion.
No significant plasma accumulation occurred even after a daily administration of 500 ml of a 10% solution to volunteers containing HES 130/0.4 over a period of 10 days. In an experimental model in rats using repetitive doses of 0.7 g/kg BW per day of HES 130/0.4 over 18 days, 52 days after the last administration tissue storage was 0.6% of the total administered dose.
In a further pharmacokinetic study, eight stable patients with end stage renal disease (ESRD) requiring haemodialysis received a single dose of 250 ml (15 g) of HES 130/0.4 (6%). 3.6 g (24%) of the HES dose was eliminated during a 2-hour haemodialysis session (500 mL dialysate per minute, Filter HD Highflux FX 50, Fresenius Medical Care, Germany). After 24 hours the mean HES plasma concentration was 0.7 mg/ml. After 96 hours the mean plasma concentration of HES was 0.25 mg/ml. HES 130/0.4 (6%) is contraindicated in patients receiving dialysis treatment (see Contraindications).
Pharmacokinetic data in patients with hepatic insufficiency or in paediatric or geriatric patients are not available. Effects of gender on the pharmacokinetics of Volulyte 6% have not been studied.
Toxicology: Preclinical safety data: All non-clinical safety studies have been performed with a similar product containing HES 130/0.4 (10%) in 0.9% sodium chloride solution.
Repeat dose toxicity: Three-month repeat infusion toxicology studies were conducted in rats and dogs in which three groups of animals were administered daily intravenous infusion over three hours. Dosing volumes of either 60 or 90 ml/kg body weight of HES 130/0.4 (10% solution) or 90 ml/kg 0.9% sodium chloride injection were studied. Observed toxicity following repeat infusion of hydroxyethyl starch is consistent with the oncotic properties of the solution resulting in hypervolaemia in the animals. No HES specific toxicity was detected up to doses of 9 g/kg which is at least 3 times the human dose. There were no gender-related effects on toxicity following repeat administration of HES 130/0.4 in rats or dogs.
Mutagenesis and carcinogenesis: No mutagenic effects were observed with HES 130/0.4 (10%) solution in the following tests on mutagenic activity: Salmonella typhimurium reverse mutation assay (in vitro), mammalian cells in the in vitro gene mutation assay, assessment of the clastogenic activity in cultured human peripheral lymphocytes (in vitro), bone marrow cytogenetic test in Sprague-Dawley rats. Long-term studies in animals to evaluate the carcinogenic potential of HES 130/0.4 (10%) in 0.9% sodium chloride solution have not been performed.
Reproductive toxicity: In reproduction studies in rats and rabbits, HES 130/0.4 (10% solution) had no teratogenic properties. Embryo-foetotoxicity in rats and rabbits was only observed at maternal-toxic dose levels. Embryolethal effects were observed in rabbits at 5 g/kg body weight/day. In rats, bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays. Signs of fluid overload were seen in the dams. HES 130/0.4 (10% solution) had no effect in studies assessing skin sensitization, antigenicity, and blood compatibility.
In a rat fertility study no influence on male and female fertility parameters were observed.
