Poly(O-2-hydroxyethyl) starch, sodium acetate trihydrate, sodium chloride, potassium chloride, magnesium chloride hexahydrate and electrolytes.
1000 mL solution for infusion contains Poly (O-2-hydroxyethyl) starch 60.00 g (Molar substitution: 0.38-0.45, mean molecular weight: 130,000 Da), sodium acetate trihydrate 4.63 g, sodium chloride 6.02 g, potassium chloride 0.30 g, magnesium chloride hexahydrate 0.30 g.
Electrolytes (Na+=137.0 mmol/l; K+=4.0 mmol/l, Mg++=1.5 mmol/l, Cl-=110 mmol/l, CH3COO-=34.0 mmol/l).
The solution has a theoretical osmolarity of 286.5 mOsmol/l, pH 5.7-6.5 and titratable acidity of <2.5 mmol NaOH/l.
Excipients/Inactive Ingredients: Sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment), water for injection.
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.
Treatment of hypovolaemia caused by acute blood loss.
For use in elective surgery patients, trauma patients, patients undergoing open-heart surgery in association with cardiopulmonary bypass, where alternative infusion solutions are not considered to be sufficient.
Kidney function should be monitored at least 90 days and blood coagulation parameter should be closely monitored.
Volulyte is administered by intravenous infusion only.
The daily dose and rate of infusion depends on the patient's blood loss, on the maintenance or restoration of haemodynamics and on the haemodilution (dilution effect).
Use at the lowest effective dose for the shortest period of time. Should not be used for more than 24 hours.
The initial 10 to 20 ml should be infused slowly, keeping the patient under close observation due to possible anaphylactic/anaphylactoid reactions.
Adult dose: Up to 50 ml of Volulyte per kg of body weight per day (equivalent to 3.0 g hydroxyethyl starch, 6.85 mEq sodium and 0.2 mEq potassium per kg of body weight). This dose is equivalent to 3,500 mL Volulyte for a 70 kg patient.
Paediatric dose: The dosage in children should be adapted to the individual patient colloid needs, taking into account the basic disease state, as well as the haemodynamics and hydration status (see Pharmacology: Pharmacodynamics under Actions).
As with all volume substitutes, overdose can lead to overloading of the circulatory system (e.g. pulmonary oedema). In this case, the infusion should be stopped immediately and if necessary, a diuretic should be administered.
Do not use HES products in: patients with severe sepsis; critically ill patients; patients with severe liver disease; patients with known hypersensitivity to hydroxyethyl starch; clinical conditions where volume overload is a potential problem, especially in cases of pulmonary oedema and congestive cardiac failure; patients with pre-existing coagulation or bleeding disorders; patients with renal impairment; patients receiving dialysis treatment; patients with severe hyperkalaemia, severe hypernatraemia or severe hyperchloraemia; patients with intracranial bleeding; patients with blood coagulation disorders; patients with burns, scalds.
(Based on Notification of the Ministry of Public Health.)
Do not use in patients with severe sepsis, critically ill patients, patients with renal impairment, patients with blood coagulation disorders and patients with burns, scalds.
Use with caution in elective surgery patients, trauma patients, patients undergoing open heart surgery in association with cardiopulmonary bypass.
Use at the lowest effective dose for the shortest period of time. Should not use for more than 24 hours.
Kidney function should be monitored at least 90 days and blood coagulation parameter should be closely monitored.
Use with caution in elective surgery patients, trauma patients, patients undergoing open heart surgery in association with cardiopulmonary bypass.
Anaphylactic/anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary oedema) have been reported with solutions containing hydroxyethyl starch. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved. (See Adverse Reactions.)
Avoid use in patients with pre-existing renal dysfunction.
Discontinue use of Voluven at the first sign of clinically relevant renal injury.
Continue to monitor renal function in hospitalised patients for at least 90 days as use of renal replacement therapy has been recorded up to 90 days after administration of HES products.
Monitor the coagulation status in patients undergoing open heart surgery in association with cardiopulmonary bypass as excess bleeding has been reported with other HES solutions in this population. Discontinue the use of Voluven at the first sign of clinically relevant coagulopathy.
Avoid fluid overload; adjust dosage in patients with cardiac dysfunction. Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency.
In cases of severe dehydration a crystalloid solution should be given first. Generally, sufficient fluid should be administered in order to avoid dehydration.
Particular care must be taken in patients with electrolyte abnormalities.
In metabolic alkalosis and clinical situations where alkalisation should be avoided, saline based solutions like a similar product containing HES 130/0.4 in 0.9% sodium chloride solution should be preferred over alkalising solutions like Volulyte.
Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, serum electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient's condition warrants such evaluation. Monitor liver function in patients receiving HES products, including Voluven.
Effects on ability to drive and use machines: Volulyte has no influence on the ability to drive and use machines.
For Volulyte no clinical data on exposed pregnancies are available.
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 anesthesia. No negative influence of HES on patient safety could be detected; a negative influence on the neonate could also not be detected (see Pharmacology: Pharmacodynamics under Actions).
Animal studies with a similar product containing HES 130/0.4 in 0.9% sodium chloride solution do not indicate harmful effects with respect to pregnancy, embryo/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical Safety data under Actions).
No evidence of teratogenicity was seen.
Volulyte should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Information on the use of Volulyte during labour or delivery is unknown with the exception of caesarean section (see above). Use if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Volulyte is administered to a nursing woman.
The undesirable effects are defined as follows:
Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10, 000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: Rare (in high doses): With the administration of hydroxyethyl starch disturbances of blood coagulation beyond dilution effects can occur depending on the dosage.
Immune system disorders: Rare: Medicinal products containing hydroxyethyl starch may lead to anaphylactic/anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary oedema). If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved.
Skin and subcutaneous tissue disorders: Common (dose dependent): Prolonged administration of high dosages of hydroxyethyl starch may cause pruritus (itching) which is a known undesirable effect of hydroxyethyl starches.
Investigations: Common (dose dependent): The concentration of serum amylase level can rise during administration of hydroxyethyl starch and can interfere with the diagnosis of pancreatitis. The elevated amylase is due to the formation of an enzyme-substrate complex of amylase and hydroxyethyl starch subject to slow elimination and must not be considered diagnostic of pancreatitis.
Common (dose dependent): At high dosages the dilution effects may result in a corresponding dilution of blood components such as coagulation factors and other plasma proteins and in a decrease of haematocrit.
No interactions with other drugs or nutritional products are known to date.
Consideration should be given to the concomitant administration of medicinal products that can cause potassium or sodium retention.
Elevated serum amylase levels may be observed temporarily following administration of the product and can interfere with the diagnosis of pancreatitis.
At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in haematocrit.
Special precautions for disposal and other handling: For single use only.
To be used immediately after the bottle or bag is opened.
Do not use Voluven after expiry date. Any unused solution should be discarded. Any unused solution should be disposed of in accordance with local requirements.
Use only clear, particle-free solutions and undamaged containers.
Remove the overwrap from the Polyolefine (freeflex) bag and PVC bag prior to use.
Incompatibilities: The mixing with other drugs should be avoided. If, in exceptional cases, a mixture with other drugs is required, care should be taken with the compatibility (clouding or precipitation), hygienic injection and a good admixture.
Do not freeze.
Do not store above 30°C.
Shelf-Life of the product as packaged for sale: Freeflex bag: 3 years.
Shelf-Life after first opening of the container: The product should be used immediately after opening.
V06DE - Amino acids/carbohydrates/minerals/vitamins, combinations ; Used as general nutrients.
Volulyte 6% soln for infusion
500 mL x 1's
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