Data Sheet
VENOFUNDIN 6%
6% hydroxethyl starch (HES) Solution for Infusion
Presentation
Venofundin is a large volume infusion solution containing 6% hydroxyethyl starch (HES) dissolved in an isotonic and iso-oncotic solution consisting of 0.9% sodium chloride.
The sterile parenteral solution does not contain any preservatives or antioxidants.
It is clear, colorless aqueous and solution.
Each 1000 ml contains
| Poly (0-2-hydroxyethyl) starch (HES) (Molar substitution: 0.42 (Mean molecular weight: 130,000 Da) |
60.0g |
| Sodium chloride | 9.0g |
Electrolyte concentration: |
|
| Sodium | 154 mmol/l |
| Chloride | 154 mmol/l |
pH: |
4.0-6.5 |
| Theoretical osmolarity: | 309 m0smol/l |
| Titration acidity: | <1.0 mmol/l |
Uses
Actions
Pharmacotherapeutic group: Blood substitutes and plasma protein fractions, ACT code: B05A A07
Venofundin is a colloidal plasma volume substitute and contains 6% hydroxyethyl starch (HES) in normal saline (sodium chloride 9mg/ml). Its mean molecular weight is 130,000 Dalton and its molar substitution is 0.42
Venofundin is isooncotic, i.e., the intravascular plasma volume increase is equivalent to the infused volume.
The duration of the volume effect depends primarily on molar substitution and to a lesser extent on the mean molecular weight. Intravascular hydrolysis of HES polymers results in the continuous release of smaller molecules which are also oncotically active before being excreted via the kidneys.
Venofundin may reduce hematocrit and plasma viscosity.
Following isovolemic administration, the volume-expanding effect is maintained for at least 6 hours.
Pharmacokinetic properties
Hydroxyethyl starch is a mixture of several molecular species with different degree of substitution and molecular weight. The elimination depends on molecular weight and degree of substitution. Molecules smaller than the renal threshold are eliminated via glomerular filtration. Larger molecules are degraded by α-amylase and are thereafter eliminated renally. The rate of degradation decreases with increased degree of substitution. Approximately 50% if a given dose is excreted into urine within 24 hours.
Following a single infusion of 1000ml of Venofundin, plasma clearance is 19ml/min and the AUC is 58 mgxh/ml, and the terminal serum half-life is about 12 hours.
Indications
Treatment and prophylaxis of hypovolemia and shock
Dosage and Administration
Posology and method of administration
The daily dose and infusion rate depend on the extent of blood loss, maintenance or restoration of hemodynamic parameters.
The first 10-20ml should be infused slowly and with careful patient monitoring so that a possible anaphylactoid reaction can be detected as early as possible.
Maximum infusion rate:
The maximum infusion rate depends on the clinical situation. Patients in acute shock may be administered up to 20 ml per kg of body weight per hour (equivalent to 0.33 ml/kg/min or 1.2 g of hydroxyethyl starch per kg of body weight per hour).
In life-threatening situations, 500 ml may be administered by manual pressure infusion. Also see "Method of administration and duration of therapy".
Maximum daily dose:
Up to 50ml of Venofundin per kg of body weight (equivalent to 3.0 g of hydroxyethyl starch per kg of body weight). This is equivalent to 3,500ml of Venofundin for a 70-kg patient.
The safety and efficacy of Venofundin in children have not been studied. Therefore, Venofundin should be used in children only after careful benefit/risk assessment, and with caution.
Method of administration and duration of therapy:
For intravenous use.
If administration is by rapid infusion under pressure, all air must be withdrawn from the plastic container and infusion set prior to infusion, as otherwise there is a risk of producing air embolism during infusion.
The duration of therapy depends on the duration and extent of hypovolemia, the hemodynamic effects of the administered treatment, and the level of hemodilution.
Overdosage
The greatest risk associated with an acute overdose is hypervolemia. In this case, the infusion must be stopped immediately, and administration of diuretics be considered.
Contraindications
Hyperhydration states including pulmonary edema.
Renal failure with oliguria or anuria.
Intracranial bleeding.
Severe hypernatremia or severe hyperchloremia.
Hypersensitivity to hydroxyethyl starch or to any of the excipients.
Severely impaired hepatic function.
Congestive cardiac failure.
Special Warnings and Precautions
Volume overload from overdosage should always be avoided. Dosage should be carefully adjusted, especially in patients with cardiac insufficiency.
Particular caution should be exercised in patients with renal impairment. The dose may need to be adjusted.
Elderly patients with hypovolaemia should be thoroughly monitored, and the dosage should be adapted, in order to avoid impairment of renal function.
Serum electrolytes, fluid balance, and kidney function should be monitored. Adequate fluid intake must be ensured.
Patients with severe dehydration should first receive intravenous electrolyte solutions.
Particular caution should be exercised in patients with hepatic insufficiency and in those with blood coagulation disorders particularly haemophilia and known or suspected v. Willebrand's disease.
To ensure correct blood typing, a blood sample should be taken prior to the administration of Venofundin.
Because of the possibility of allergic (anaphylactic/anaphylactoïd) reactions, appropriate monitoring of patients is necessary, and a slow infusion rate should be initiated (see adverse effects)
Elevated serum alpha-amylase concentrations may be observed temporarily following administration of HES solutions and must not be considered diagnostic of impaired pancreatic function. (see adverse effects)
Pregnancy and lactation
No adequate data are available for Venofundin from the treatment of pregnant women. Venofundin has not been tested in reproductive toxicology studies in animals, but studies of similar products have revealed vaginal bleeding, embroytoxic and teratogenic effects after repeated treatment of laboratory animals (see section 5.3). HES-related anaphylactic reactions in treated pregnant women may have harmful effects on the fetus. Venofundin should be used in pregnant women only if the anticipated benefits outweigh the potential risk to the fetus; this is especially to be considered when administration of Venofundin in the first three months of pregnancy is planned.
As it is not known whether the modified starch in Venofundin is excreted in breast milk, caution should be exercised when administering this product to breastfeeding mothers. Temporary interruption of breastfeeding may be considered.
Preclinical safety data
Venofundin has not been tested in animal toxicology studies. Published animal toxicology studies of repeated hypervolemic treatment with similar HES products have revealed bleeding and extensive histiocytosis (accumulation of foamy histiocytes/ macrophages) in many organs, along with increased liver, kidney, and spleen weights. Fat deposits and organ vacuolization have been reported along with elevated plasma ASAT and ALAT levels. Some of the described effects have been suggested to be due to hemodilution, circulatory overload, and uptake and accumulation of starch in phagocytic cells.
Similar HES products have been reported to be non-genotoxic in standard tests.
Reproductive toxicity studies of HES products showed vaginal bleeding, embryo-foetotoxic and teratogenic effects after repeated administration to laboratory animals. These effects may be related to hemodilution, leading to fetal hypoxia, and to hypervolemia.
Bleeding may partly also be related to direct effects of HES on the blood coagulation.
Hemodilution from volume overload should always always be avoided when treating the hypovolemic patients
Effects on ability to drive and use machines
Not relevant
Adverse Effects
Adverse reactions have been ranked under headings of frequency using the following convention: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000)
The most commonly reported adverse reactions are directly related to the therapeutic effects of starch solutions and the doses administered, i.e., hemodilution resulting from expansion of the intravascular space without concurrent administration of blood components. Dilution of coagulation factors may also occur.
Hypersensitivity reactions, which are very rare, are not dose-dependent.
Blood and lymphatic system disorders
Very common: Reduced hematocrit and decreased plasma protein concentrations as a result of hemodilution.
Common: (dose-dependent): Higher doses of hydroxyethyl starch cause dilution of coagulation factors and may thus affect blood clotting. Bleeding time and aPTT may be increased and FVII/vWF complex levels may be reduced after administration of high doses. See "Special warnings and special precautions for use".
Immune system disorders
Rare: Anaphylactic reactions of various intensities. For details see "Anaphylactic reactions" below.
General disorders and administration site conditions
Uncommon: Repeated infusions of HES for many days, especially when high cumulative doses are reached, usually lead to pruritus which responds very poorly to therapy. This pruritus may occur many weeks after discontinuing the starch infusions and may persist for months. The likelihood of this adverse effect has not been adequately studied for Venofundin.
Investigations
Very common: The infusion of hydroxyethyl starch produces elevated serum α-amylase concentrations. This effect is the result of the formation of an amylase complex of hydroxyethyl starch with delayed renal and extrarenal elimination. It should not be misinterpreted as evidence of a pancreatic disorder.
Anaphylactic reactions
Anaphylactic reactions of various intensities may occur after administration of hydroxyethyl starch. All patients receiving starch infusions should therefore be closely monitored for anaphylactic reactions. In case of an anaphylactic reaction, the infusion must be stopped immediately and the usual emergency treatment instituted.
There are no tests to identify patients in whom an anaphylactic reaction is likely, nor can the outcome and severity of such a reaction in a given patient be predicted.
The prophylactic use of corticosteroids has not proved effective.
Note:
Patients should inform their doctor or pharmacist if they notice any side effect not mentioned in this leaflet.
Interactions
No interactions with other drugs or nutritional products are known to date. In the absence of compatability studies, this medicinal product must not be mixed with other medicinal products.
Medicine Classification
General sales medicine
Pharmaceutical Precautions
Do not freeze. Protect from light
Single use only
Product has a shelf life of 2 years from date of manufacture.
The product should be used immediately after first opening. Discard any unused product. Use only clear solution, practically free from particles, from intact containers
The product must not be used beyond the expiry date stated on the labeling.
Storage Conditions
It is recommended that the product be stored at or below 25°C
Further Information
List of excipient(s)
Water for Injections
Package Quantities
Venofundin is available in polypropylene bag (Ecobag) with butyl rubber stopper and a polypropylene outer bag.
10 x 500 ml
20 x 500ml
Name and Address of Sponsor
B, Braun New Zealand Pty Ltd
54 Carbine Road
Mt Wellington
Auckland
New Zealand
Date of Preparation
May 2008