Consumer medicine information

Voluven 6%

Hydroxyethyl starch

BRAND INFORMATION

Brand name

Voluven 6%

Active ingredient

Hydroxyethyl starch

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Voluven 6%.

What is in this leaflet

This leaflet answers some common questions about Voluven. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you given Voluven against any benefits they expect it will have for you.

Please read this leaflet carefully. If you have any questions or are unsure about anything, please ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What is Voluven used for

Voluven is a plasma volume substitute that is used to restore the blood volume when you have lost blood when other products called crystalloids are not considered sufficient alone. It is not a substitute for blood or blood containing products.

Before you are given Voluven

You must NOT use this product if you:

  • are critically ill to be admitted to intensive care unit.
  • are allergic to hydroxyethyl starches or any of the other ingredients as listed at the end of this leaflet.
  • have bleeding of the brain (cerebral haemorrhage)
  • have too high sodium or chloride levels in your blood
  • have a severe blood infection
  • have severe liver disease
  • have coagulation or bleeding disorder
  • have been told that you have pulmonary oedema where too much fluid is in your lungs
  • have been told that you have a congestive heart failure (a condition in which your heart cannot pump enough blood to other organs of your body)
  • have kidney failure and you produce little or no urine and if this is not caused by low blood volumes (hypovolemia)
  • are receiving dialysis treatment (an artificial kidney treatment)

Before you use Voluven, you must also tell your doctor if you have problems with your heart, liver, lung or have severe lack of fluid (dehydration). Special care has to be taken while this product is given to you. Infusion of large quantities of plasma substitutes may cause too much dilution of blood components or blood clotting factors and blood samples may be taken to check this.

If you have impaired kidney function, your doctor will need to adjust the dosage since Voluven is excreted by the kidneys.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

The safety of the product in pregnant and breast-feeding women has not been investigated.

How Voluven is given

How much will be given

Your doctor will determine the amount of Voluven that is appropriate for you.

How is it given

Voluven should be administered by continuous drip into the vein using a sterile tubing and needle. It should only be administered to you by qualified medical staff. You will be kept under close observation by a health professional at the beginning of Voluven infusion to ensure that you do not have an allergic reaction as all plasma substitutes carry a slight risk of allergic reactions that can be mild or severe.

If you are given too much (overdose)

This rarely happens as Voluven is usually administered under the care of a trained health care professional in a hospital or clinic setting.

Your doctor has information on how to recognise and treat an overdose. Ask your doctor if you have any concerns.

Otherwise immediately telephone your doctor or contact the Poisons Information Centre in your country.

Australia: 13 11 26
New Zealand: 0800 764 766.

Side Effects

Voluven, like all other medicine which are given intravenously, may cause unwanted effects in some people.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • mild flu-like symptoms
  • itching of the skin

Tell your doctor as soon as possible if you notice any of the following:

  • serious allergic reactions (skin rash and hives)
  • breathing difficulties (wheezing or coughing)
  • effects on heart beat (slower or faster than normal)

Please tell your doctor or your health professional if you feel unwell during treatment.

Storage

Voluven should be stored below 25°C and not be frozen. As with any medicine, Voluven should be stored out of the reach of children. Do not use injections that have been used, have expired or the container is damaged.

Product Description

What it looks like

Voluven 6% is a clear, colourless solution which comes in a glass bottle or plastic bag.

Ingredients

Voluven contains hydroxyethyl starch 130/0.4 and also contains excipients sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.

Voluven does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Voluven does not contain any preservative.

Voluven comes in 2 different containers and 2 pack sizes. They can be identified by the following AUST R numbers:

Glass bottles 250ml
AUST R 120276

Glass bottles 500ml
AUST R 120358

Freeflex® bags with overwrap 250 mL
AUST R 120359

Freeflex® bags with overwrap 500 mL
AUST R 120361

Further Information
More detailed information is available from your doctor or pharmacist.

Sponsor

Fresenius Kabi Australia Pty Limited
Level 2, 2 Woodland Way, Mount Kuring-gai
NSW 2080
Australia
Telephone: 1300 361 004

Fresenius Kabi New Zealand Limited
60 Pavilion Drive
Airport Oaks, Auckland 2022
New Zealand
Freecall: 0800 144 892

® = Registered Trademark

Date of information

This information leaflet was prepared in August 2016.

Published by MIMS February 2017

BRAND INFORMATION

Brand name

Voluven 6%

Active ingredient

Hydroxyethyl starch

Schedule

Unscheduled

 

1 Name of Medicine

Hydroxyethyl starch 130/0.4.

2 Qualitative and Quantitative Composition

Active.

Hydroxyethyl starch 130/0.4. Amount (L): 60 g.

Excipient.

NaCl (Na+ 154 mmol, Cl- 154 mmol). Amount (L): 9 g.
Hydroxyethyl starch is characterised by its molar substitution, molecular weight and the C2/C6 ratio. See Section 5.2 Pharmacokinetic Properties; Section 6.7 Physicochemical Properties.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Voluven 6% isotonic solution is colourless, clear and slightly acidic (pH 4.0-5.5).
Osmolality approx 304 mOsm/kg water.
Theoretical osmolarity 308 mOsm/L.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypovolaemia due to acute blood loss when crystalloids alone are not considered sufficient. The use of Voluven is not a substitute for the appropriate use of packed red blood cells or fresh frozen plasma.

4.2 Dose and Method of Administration

For intravenous infusion.
Use of Voluven should be restricted to the initial phase of volume resuscitation with a maximum duration of use of 24 hours.
Administration of Voluven may cause anaphylactic reactions that may manifest as acute hypotension. In all patients, the initial 10-20 mL of Voluven should be infused slowly, keeping the patient under close observation for anaphylactic/ anaphylactoid reactions manifesting as unexpected hypotension, or the development of wheeze or rash. (Please also see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
The daily dose and rate of infusion depend on the patient's blood loss, on the maintenance or restoration of haemodynamics and on the haemodilution (dilution effect).
In clinical trials, infusions up to 33 mL/kg/day were most commonly used. There is limited experience with infusions between 33 mL/kg/day and 50 mL/kg/day.
Hepatic and renal monitoring is necessary at higher doses. (Please also see Section 4.4 Special Warnings and Precautions for Use).

Treatment of children.

Data are limited in children. It is therefore recommended not to use HES products in paediatric patients. (Please also see Section 4.4 Special Warnings and Precautions for Use).

Instructions for use/ handling.

Each container should be used in one patient and on one occasion only. It should be used immediately after the bottle or bag is opened and any unused solution must be discarded. The solution contains no antimicrobial preservatives. Do not use if the solution is not clear or if the container is damaged.

Special handling instructions.

Before administering the product in plastic bags to the patient, review these directions: Freeflex IV solution container.
(1) Check the expiry date and the solution for visible particles or cloudiness, do not use unless the solution is clear. Inspect the container for damage or leakage, if damaged do not use.
(2) Using the pre-cut corner tabs, peel open and remove the over-wrap.
(3) Identify the blue infusion (administration) port. Use the blue port only to administer solution. Never use the white port.
(4) Break off the blue tamper-evident cover from the Freeflex blue infusion port.
(5) Close roller clamp. Insert the spike until the clear plastic collar of the port meets the shoulder of the spike. Use a non-vented standard infusion set and close air inlet. Hang the bag on the infusion stand. Press drip chamber to get fluid level. Prime infusion set. Connect and adjust the flow rate.

Warnings.

1. Do not remove the Freeflex IV container from its overwrap until immediately before use.
2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
3. Do not administer unless the solution is clear, free from particles and the Freeflex IV container is undamaged.
4. Voluven should be used immediately after insertion of the administration set.
5. Use the blue port only to administer solution. Never use the white port.
6. Do not vent.
7. If administered by pressure infusion, air should be withdrawn or expelled from the bag through the medication/ administration port prior to infusion.
8. Discontinue the infusion if an adverse reaction occurs.
9. It is recommended that administration sets are changed at least once every 24 hours.
10. For single use only. Discard unused portion.

4.3 Contraindications

Voluven should not be used, if any one or more of the following clinical conditions apply.
Critically ill patients (typically admitted to intensive care unit), including those with sepsis.
Fluid overload (hyperhydration), especially in cases of pulmonary oedema and congestive cardiac failure.
Patients with pre-existing coagulation or bleeding disorders.
Renal failure with oliguria or anuria not related to hypovolaemia.
Patients receiving dialysis treatment.
Intracranial bleeding.
Severe hypernatraemia or severe hyperchloraemia.
Known hypersensitivity to hydroxyethyl starches.
Patients with severe liver disease.

4.4 Special Warnings and Precautions for Use

Voluven is not a substitute for red blood cells or coagulation factors in plasma.

Fluid overload.

Administration of Voluven may cause fluid overload, resulting in cardiac and pulmonary failure. Administration should be carefully titrated to relevant physiological endpoints. Particular care must be taken in patients with cardiac insufficiency or severe renal dysfunction.

Dehydration.

Intravenous fluid resuscitation in cases of severe dehydration should be through the use of crystalloid solutions.

Bleeding risk.

Voluven administration may cause coagulopathy, either through a direct effect; or indirectly through the dilution effect. This will increase the risk of bleeding. Administration should be ceased if a coagulopathy develops or excessive bleeding occurs.

Cardiopulmonary bypass.

Coagulation status must be closely monitored during cardiopulmonary bypass in patients receiving Voluven because of the bleeding risk.

Surgery and trauma.

There is a lack of robust, long-term safety data in patients undergoing surgical procedures and in patients with trauma. The expected benefit of treatment should be carefully weighed against uncertainty with regard to this long-term safety. Other available treatment options should be considered.

Use in renal impairment.

It is important to supply sufficient fluid and to regularly monitor kidney function and fluid balance. Avoid use in patients with pre-existing renal dysfunction.
Serum electrolytes should be monitored.
Discontinue use of HES at the first sign of renal injury. A need for renal replacement therapy has been reported up to 90 days after HES administration. Continue to monitor renal function for at least 90 days in any case of deterioration of renal function.

Liver function.

Monitor liver function in patients receiving HES products, including Voluven 6%.

Anaphylactic/ anaphylactoid reactions.

Regarding the occurrence of anaphylactic/ anaphylactoid reactions, please see Section 4.8 Adverse Effects (Undesirable Effects).

Laboratory assessments.

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.

Use in the elderly.

Clinical experience (including published trials) has included elderly populations, some exclusively with patients of 70 years and above. Dose reduction was not required and safety has been comparable to control treatments (gelatin or albumin) in elderly patients.

Paediatric use.

There is lack of robust, long-term safety data in children undergoing surgical procedures. The expected benefit of treatment should be carefully weighed against uncertainty with regard to this long-term safety and informed consent obtained from the patient/ parent where possible. Other available treatment options should be considered.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interactions with other drugs or nutritional products are known to date.
Please see Section 4.8 Adverse Effects (Undesirable Effects) concerning the concentration of serum amylase which can rise during administration of hydroxyethyl starch and can interfere with the diagnosis of pancreatitis.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

HES 130/0.4 10% solution in 0.9% sodium chloride did not impair fertility in male rats at IV doses up to 5 g/kg/day. In female rats, no adverse effects on fertility were observed at doses up to 2.5 g/kg/day. Slight inhibition of ovulation, evident as a decrease in corpora lutea and resulting in a reduced number of fetuses, was observed at a maternotoxic dose of 5 g/kg/day IV.
(Category B3)
No clinical data are currently available on the use of Voluven during pregnancy. Studies in pregnant rats and rabbits showed that the type of hydroxyethyl starch present in Voluven was associated with embryofoetal toxicity following IV administration at 5 g/kg/day. The embryofoetal toxicity included resorption, stillbirths, reduced foetal weight and delayed foetal development.
Voluven should not be used during pregnancy, unless the expected therapeutic benefit clearly outweighs the potential risk to the foetus.
 There are currently no clinical data on the use of Voluven in breastfeeding women. A study in lactating rats showed that the type of hydroxyethyl starch present in Voluven was associated with decreased postnatal growth and development following IV administration at 5 g/kg/day. It is not known whether the hydroxyethyl starch is excreted into human milk. As many drugs are excreted into human milk, Voluven should not be used in breastfeeding women.

4.7 Effects on Ability to Drive and Use Machines

Not applicable.

4.8 Adverse Effects (Undesirable Effects)

Medicinal products containing hydroxyethyl starch may rarely lead to anaphylactic/ anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, noncardiac pulmonary oedema). In the event of an intolerance reaction occurring, the infusion should be discontinued immediately and the appropriate emergency medical treatment initiated.
Prolonged administration of high doses of hydroxyethyl starch commonly causes pruritus (itching), which is a known undesirable effect of hydroxyethyl starches.
Commonly, the concentration of serum amylase can rise during administration of hydroxyethyl starch and can interfere with the diagnosis of pancreatitis.
At high dosages the dilution effects may result commonly in a corresponding dilution of blood components such as coagulation factors and other plasma proteins and a decrease in haematocrit.
With the administration of Voluven, disturbances of blood coagulation beyond dilution effects can occur rarely, depending on the dosage. See Table 1.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Excessive or rapid administration of volume expanders such as Voluven may result in fluid overload with resulting cardiac and pulmonary failure. If this occurs, volume replacement should be ceased and supportive care provided. Use of diuretics may be required.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Voluven is an artificial colloid for volume replacement whose effect in intravascular volume expansion and haemodilution depends on the molar substitution by hydroxyethyl groups (0.4), the mean molecular weight (130,000 Da), the concentration (6%), the degree of substitution (C2/C6 ratio) of approximately 9:1, as well as the dosage and infusion rate.
Infusion of 500 mL Voluven 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 Voluven maintains blood volume for at least 6 hours.

Clinical trials.

In 21 randomised controlled clinical trials a total of 1315 subjects have been studied; 768 receiving Voluven and 547 receiving another colloid or crystalloid solution. These trials have been conducted in order to evaluate the efficacy and safety of Voluven. Adult and paediatric surgical patients and ICU patients treated for volume replacement make up 705 subjects (355 receiving Voluven).
The patient population of the primary efficacy clinical studies (clinical settings of volume replacement therapy) included various types of surgery (orthopaedic, urologic, cardiac, paediatric and aortic surgery), trauma, intensive care, situations in which hypovolaemia is treated (pre-, intra-, and postoperative) or prevented (autologous blood donation, acute normovolaemic haemodilution). The comparators for these controlled studies were HES 200/0.5, HES 450/0.7 (hetastarch), gelatin, human serum albumin and crystalloids.
197 patients received infusions from 30 to > 50 mL/kg of Voluven. This dose range is supported by experience in the published literature.
Analysis of coagulation parameters revealed significant differences between Voluven and HES 200/0.5: significantly higher levels of von Willebrand factor, factor VIII, and Ristocetin cofactor with Voluven compared to HES 200/0.5. Furthermore, there were reduced blood loss and transfusion requirements in the Voluven treated patients compared to the HES 200/0.5 treated patients.
Clinical trials demonstrated comparable efficacy of Voluven with the control colloids to maintain or restore haemodynamics as shown by comparable volume of colloid administration (primary efficacy endpoint) and similar stabilisation of haemodynamics (secondary endpoints). There was no difference in mortality between groups. Regarding safety, Voluven proved to be at least as safe as the comparators.
Published clinical trials conducted in elderly populations have included two studies in which 90 elderly patients (age range 70 to 86 years) were studied. In both trials, the analysed kidney function did not differ between Voluven and gelatin or human albumin. No specific dosage adjustments were required in these elderly patients.
Of the total number of patients in clinical trials of Voluven (n = 471), 25% were 65 to 75 years old, while 7% were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported experience has not identified specific risks for the application of Voluven in this patient group.

5.2 Pharmacokinetic Properties

The pharmacokinetics of hydroxyethyl starch is complex and depends on the molecular weight and mainly on the molar substitution degree. 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 Voluven 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 Voluven 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 Voluven was administered, with an AUC of 14.3 mg/mL.h, which shows non-linear pharmacokinetics. 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 of 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, versus 51% at ClCr 15 to 30 mL/min. Plasma levels of Voluven 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 bodyweight/day of Voluven over 18 days, 52 days after the last administration tissue storage was 0.6% of the total administered dose.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro genotoxicity studies revealed no evidence for mutagenicity or clastogenicity for the type of hydroxyethyl starch present in Voluven. An in vivo chromosomal aberration study in rats was also negative at the tested dose of 5 g/kg/day IV.

Carcinogenicity.

The carcinogenic potential of Voluven has not been investigated in animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Table 2.

6.2 Incompatibilities

The mixing with other drugs should be avoided.

6.3 Shelf Life

Approved shelf life as packaged for sale Australia.

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

New Zealand.

Freeflex bag: 36 months.
Plastic PE bottle: 36 months.
Glass bottle: 60 months.

6.4 Special Precautions for Storage

Store below 25°C. Do not freeze.

6.5 Nature and Contents of Container

Polyolefin bag (Freeflex) with overwrap.
All packaging components for the Freeflex bag are latex- and PVC-free.
Colourless type II glass bottle with halobutyl rubber closure and aluminium cap.

Pack sizes in Australia.

Glass bottles 250 mL (cartons of 10 bottles) AUST R 120276.
Glass bottles 500 mL (cartons of 10 bottles) AUST R 120358.
Freeflex bags with overwrap 250 mL (cartons of 10/20/30/ bags) AUST R 120359.
Freeflex bags with overwrap 500 mL (cartons of 10/15/20 bags) AUST R 120361.

In New Zealand.

Glass bottles 250 mL (cartons of 10 bottles).
Glass bottles 500 mL (cartons of 10 bottles).
Plastic PE Bottle 500mL (cartons of 10 bottles).
Freeflex bags with overwrap 250 mL (cartons of 10/20/30/35/40 bags).
Freeflex bags with overwrap 500 mL (cartons of 10/15/20 bags).
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Hydroxyethyl starch (HES) is a derivative of amylopectin, which is a highly branched compound of starch. In humans and animals, amylopectin is rapidly hydrolysed 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 determines the enzymatic degradation of HES. Voluven is characterised by its molar substitution, by its molecular weight and the C2/C6 ratio.
Molecular weight (MW): The molecular weight indicates the weight average and it is 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 (range 0.38-0.45) 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.
Hydroxyethyl starch 130/0.4 is a white to yellowish white, odourless and tasteless amorphous powder, readily soluble in water at room temperature, soluble in DMSO, practically insoluble in most organic solvents. The solution is slightly acidic (pH 4.0-5.5).

Chemical structure.


Molar substitution: 0.38 - 0.45.
Average molecular weight: 110,000 - 150,000 Dalton.
Mean molecular weight (MW): 130,000.
Chemical name: poly (O-2 hydroxyethyl) starch.

CAS number.

Active substance: Hydroxyethyl starch 130/0.4.
CAS number: 9005-27-0.

7 Medicine Schedule (Poisons Standard)

Australia: Not Scheduled.
New Zealand: General Sale Medicine.

Summary Table of Changes