Voluven - Product Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Low Blood Sugar (Hypoglycemia)|
|Form:||Liquid solution, Intravenous (IV)|
|Ingredients:||Poly (O-2-hydroxyethyl) starch, sodium chloride, sodium hydroxide, hydrochloric acid, water for injection, Na +, Cl-|
Summary Product Information
|Route of Administration||Dosage Form / Strength||Non-medicinal Ingredients|
|Intravenous||Solution for infusion / 6% HES 130/0.4 in 0.9% sodium chloride injection||Sodium chloride, Water for injections, pH adjusted with sodium hydroxide or hydrochloric acid|
Indications and Clinical Use
Voluven is indicated for the treatment of hypovolemia when plasma volume expansion is required.
It is not a substitute for red blood cells or coagulation factors in plasma.
Voluven is contraindicated in patients:
- with fluid overload (hyperhydration), especially in cases of pulmonary edema and congestive cardiac failure
- with sepsis.
- with renal impairment with oliguria or anuria not related to hypovolemia.
- with severe liver disease.
- receiving dialysis treatment.
- with severe hypernatremia or severe hyperchloremia.
- with known hypersensitivity to hydroxyethyl starch.
- with intracranial bleeding.
- with pre-existing coagulation or bleeding disorders.
Warnings and Precautions
Serious Warnings and Precautions
The use of hydroxyethyl starch (HES) products, including Voluven, in critically ill adult patients, is associated with increased risk of mortality and renal replacement therapy.In patients with hypovolemia requiring intensive or emergent care, a careful evaluation of the risk of sustaining renal injury or liver failure should be undert aken before instituting treatment with Voluven.
The use of crystalloid solutions in preference to Voluven should be considered in patients deemed at risk of these adverse reactions.
Fluid overload caused by overdose should be avoided in general. Particularly, for patients with cardiac insufficiency or severe kidney dysfunctions the increased risk of hyperhydration must be taken into consideration; posology must be adapted.
Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency or severe kidney dysfunction.
In case of severe dehydration a crystalloid 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 like hypernatremia and hyperchloremia.
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.
Carcinogenesis and Mutagenesis
See PART II: SCIENTIFIC INFORMATION – Toxicology – Mutagenicity study.
Monitor the coagulation status in patients under going 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.
Administration of large volumes of hydroxyethyl starch may transiently alter the coagulation mechanism and decrease hematocrit and plasma proteins due to hemodilution.
Serum amylase can rise during administration of Voluven 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.
Monitor liver function in patients receiving HES products, including Voluven.
Anaphylactic/anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) 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 hould be undertaken until symptoms have resolved (please refer to section 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 hospitalized patients for at least 90 days as use of renal replacement therapy has been recorded up to 90 days after administration of HES products.
Pruritus is a known complication of administration of hydroxyethyl starches, though it is more common with prolonged use of high doses.
HES-induced pruritus may be delayed in onset, typically one to six weeks after exposure, may be severe and may be of protracted (weeks and months) persistence. It is generally unresponsive to therapy.
There are no adequate and well-controlled studies using Voluven in pregnant women. However, animal studies do not indicate harmful effects with respect to embryo/fetal development, pregnancy, parturition or postnatal development. There were no post-marketing reports of harm when Voluven was used in pregnant women.
Embryotoxic effects were observed in rabbits when 10% HES 130/0.4 in 0.9% sodium chloride solution is given at 50 mL/kg BW/day. No evidence of teratogenicity was observed.
Embryotoxic effects were observed in rabbits when 10% HES 130/0.4 in 0.9% sodium chloride solution is given at 50 mL/kg BW/day. No evidence of teratogenicity was observed. Voluven should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Information on the use of Voluven during labour or delivery is unknown. Use if clearly needed.
It is not known whether HES 130/0.4 is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Voluven is administered to a nursing mother.
A decision on whether to continue/discontinue breast-feeding or to discontinue/continue therapy with Voluven should be made taking into account the benefit of breast-feeding to the child and the benefit of Voluven therapy to the nursing mother.
There is limited experience on the use of Voluven in children available. In non-cardiac surgery in 41 children including newborns to infants (< 2 years), a mean dose of 16 ± 9 mL/kg was administered safely and was well tolerated for stabilisation of hemodynamics. The tolerability of this product administered perioperatively was comparable to 5% albumin.
Voluven may be given to premature infants and newborns only after careful risk/benefit evaluation.
Dosage in pediatric patients should be adapted to individual patient colloid needs, taking into account underlying disease, hemodynamics and hydration status.
Of the total number of patients in clinical trials of Voluven (N=471), 25% were 65-75 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.
Adverse reactions with Voluven reported spontaneously, from clinical trials and in the literature include:
Immune system disorders
Rare: Anaphylactic/anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch (see WARNINGS AND PRECAUTIONS).
Abnormal Hematologic and Clinical Chemistry Findings (Investigations)
Common (dose dependent): Increase inserum amylase (see WARNINGS AND PRECAUTIONS).
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 hematocrit.
Skin and subcutaneous tissue disorders
Common (dose dependent):Pruritus, itching (see WARNINGS AND PRECAUTIONS).
Blood and lymphatic system disorders
Rare (in high dose): Blood coagulation disturbances beyond dilution effects can occur depending on the dosage.
|System Organ Class||Adverse Drug Reaction||Frequency of Occurrence|
|Blood and lymphatic system disorders||Coagulation disorders beyond dilution effects||Rare (in high doses) (>0.01% - ≤ 0.1%)|
|Immune system disorders||Anaphylactic/anaphylactoid reactions||Rare (>0.01% - ≤ 0.1%)|
|Skin and subcutaneous tissue disorders||Pruritus||Common (dose dependent) (≥1% - < 10%)|
|Abnormal hematologic and clinical chemistry findings (Investigations)||Increase of serum amylase||Common (dose dependent) (≥1% - < 10%)|
|Decrease of hematocrit||Common (dose dependent) (≥ 1% - < 10%)|
|Decrease of plasma proteins||Common (dose dependent) (≥ 1% - < 10%)|
No interactions of Voluven with other drugs or nutritional products are known or have been reported to date.
However, mixing Voluven with other drugs should be avoided.
Dosage and Administration
Voluven (6% HES 130/0.4 in 0.9% sodium chloride injection) is administered by intravenous infusion only.
Total volume and rate of infusion are dependent on the clinical situation and the individual patient. As with any in travenous fluid, Voluven should be administered in accordance with accepted clinical practices for fluid and electrolyte management.
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.
The initial 10-20 mL is to be infused slowly, keeping the patient under close observation for possible anaphylactic/anaphylactoid reactions.
Voluven can be administered repetitively over several days according to the patient’s needs. The dosage and duration of treatment depends on the duration and extent of hypovolemia, the hemodynamics and on the hemodilution.
There is limited clinical data on the use of Voluven in children. In 41 children including newborns to infants (< 2 years), a mean dose of 16 ± 9 mL/kg was administered safely and well tolerated for stabilization of hemodynamics.
The dosage in children should be adapted to the individual patient colloid needs, taking into account disease state as well as the hemodynamic and hydration status.
As with all volume substitutes, overdose with Voluven can lead to overloading the circulatory system (e.g. pulmonary edema). In this case the infusion should be stopped immediately and if necessary, a diuretic should be administered.
For further information on the management of a suspected drug overdose, contact your regional Poison Control Centre.
Action and Clinical Pharmacology
Voluven contains 6% hydroxyethyl starch (HES 130/0.4), a tetrastarch. HES 130/0.4 is an artificial colloid, third genera tion starch, for volume replacement which is characterized by the molar substitution by hydroxyethyl groups (0.4), the mean molecular weight (130,000 Da), the concentration (6%), and the substitution ratio (C2/C6 ratio) of approximately 9:1. The effect on intravascular volume expansion and hemodilution depends on these parameters as well as on the dosage and infusion rate.
Hydroxyethyl starch 130/0.4 is a derivative of thin boiling waxy maize starch, which mainly consists of a glucose polymer (amylopectin) predominately consisting of ά -1,4-connected glucose units with several ά -1,6-branches. The medium molecular weight (130,000 Da), low degree of substitution (0.4) and narrow molecular weight distribution of hydroxyethyl starch (HES 130/0.4) contained in Voluven contribute to its beneficial effects on pharmacokinetics and intrav ascular volume effect.
Infusion of 500 mL Voluven over 30 minutes in healthy volunt eers results in a plateau-like non-expansive volume increase of approximately 100% of the infused volume which lasts for approximately 4 to 6 hours. Isovolemic exchange of blood with Voluvenmaintains blood volume for at least 6 hours.
The pharmacokinetic profile of HES is complex and largely dependent on its molar substitution as well as its molecular weight. When administered intravenously, molecules smaller than the renal threshold (60,000 - 70,000 Da) are readily and rapidly excreted in the urine, while molecules with higher molecular weights are meta bolised by plasma amylase prior to excretion via the renal route.
The mean in vivo molecular weight of Voluven in plasma is 70,000 - 80,000 Daimmediately following infusion and remains above the renal threshold throughout the treatment period.
The volume of distribution of Voluven after intravenous administration of 500 mL to healthy volunteers is about 5.9 L. Plasma levels of Voluven remain at 75% of peak concentration at 30 minutes post-infusion and decrease rapidly to 14% at 6 hours post-infusion. Plasma levels of Voluven return to baseline levels 24 hours following infusion.
Plasma clearance of Voluven following intravenous administration of 500 mL was 31.4 mL/min with an AUC of 14.3 mg/mL h, following non-linear pharmacokinetics. A single dose of 500 mL of Voluven results in elimination in the urine of approximately 62% within 72 hours. Voluven is eliminated from systemic circulation with a t 1/2 ά of 1.4 h and a terminal half life (t 1/2β) of 12.1 h following administration of a single dose of 500 mL.
The kinetics of Voluven are similar following single and multiple dose administration. No significant plasma accumulation occurred after daily administration of 500 mL of a 10% solution containing HES 130/0.4 over a period of 10 days. Elimination rates in the urine were pproximately 70% within 72 hours.
In an experimental model in rats using repetitive doses of 7 mL/kg BW per day of 10% HES 130/0.4 over 18 days, 52 days after the last administration tissue storage was 0.6% of the total administered dose.
Special Populations and Conditions
Single intravenous administration of VOLUVEN (500 mL) in subjects with mild to severe renal impairment resulted in a moderate increase in AUC by a factor of 1.7 (95% confidence limits 1.44 and 2.07) only in subjects with ClCr < 50 mL/min compared to > 50 mL/min. However, terminal half-life and peak HES concentration were not affected by renal impairment. Plasma levels of Voluven return to baseline levels 24 hours following infusion.
Fifty-nine percent of HES 130/0.4 was recove red in the urine of subjects with ClCr > 30 mL/min versus 51% in those with ClCr between 15 to 30 mL/min.
There is no data available on the use of Voluven in dialysis.
Pharmacokinetic data in patients with hepatic insufficiency are not available.
Pharmacokinetic data in elderly or children are not available.
Storage and Stability
To be used immediately after the bottle or bag is opened.
The solution is intended for intravenous administration using sterile equipment.
Use only clear solutions and undamaged containers.
Parenteral drug products should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. Discard unused portion.
Do not use Voluven after expiry date.
Glass infusion bottle storage: at 15°C - 25 °C for 5 years.
freeflexbag storage: at 15 °C 25 °C for 3 years.
Do not freeze.
Special Handling Instructions
Before administering the product in plastic bags to patient, review these directions:
freeflexIV Solution Container
These instructions are only intended as guidelines for product use. Please refer to your own departmental guidelines.
Check the solution composition, lot number and expiry date, inspect the container for damage or leakage, if damaged do not use.
Use opening aid to remove over-wrap.
Identify the blue infusion (administration) port.
Break off the blue tamper-evident cover from the freeflex infusion port.
- 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.
- Do not remove the freeflex IV container from its overwrap until immediately before use.
- Parenteral drug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.
- Do not administer unless the solution is clear, free from particles and the freeflex IV container is undamaged.
- Voluven should be used immediately after insertion of the administration set.
- Discontinue the infusion if adverse reaction occurs.
- Do not vent.
- It is recommended that administration sets are changed at least once every 24 hours.
- For single use only. Discard unused portion.
Before administering the product in glass infusion bottles to patient, review these directions:
Preparation for Administration
- Check the glass bottle for infusion solution composition, lot number and expiry date.
- Inspect the container for damage or solution leakage at the stopper. If damaged, do not use the solution!
- The infusion solution should be inspected visually for particulate matter and discoloration prior to administration.
- Aseptic technique should be followed during all steps of product preparation and administration.
- Remove the cap from the bottle to expose center portion of the rubber stopper.
- Clean the stopper with germicidal solution such as 70% isopropyl alcohol.
- Use a sterile vented spike (infusion set) for administration.
- Suspend the bottle from the hanger to see the label contents and follow directions for use printed on the administration set container.
- Discontinue administration and notify physician immediately if patients exhibits signs of adverse reactions.
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.
Dosage Forms, Composition and Packaging
Voluven (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is supplied sterile and pyrogen free in 250 and 500 mL plastic bags (freeflex) or in glass infusion bottles for intravenous infusion.
The composition of each 100 mL is as follows:
|Poly (O-2-hydroxyethyl) starch||6.00 g|
|(Molar substitution: 0.4)|
|(Mean molecular weight: 130,000 Da)|
|Sodium chloride||0.90 g|
|pH adjusted with sodium hydroxide or hydrochloric acid 25%||q.s.|
|Water for injection||q.s.|
|Approximate concentration of electrolytes (mmol/L):|
|Theoretical osmolarity (mosmol/L)||308|
|Titratable acidity (mmol NaOH/L)||< 1.0|
|pH||4.0 - 5.5|
Voluven, 6% HES 130/0.4 in 0.9% sodium chloride injection, is supplied in the following primary containers of the following package sizes:
Colourless glass infusion bottle with halobutyl rubber closure and aluminium cap: 10 x 250 mL; 10 x 500 mL
Polyolefin bag (freeflex) with overwrap: 10, 20, 30 x 250 mL; 10, 15, 20 x 500 mL