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(6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride) Injection
RENAL REPLACEMENT THERAPY
In critically ill adult patients, including patients with sepsis, use of hydroxyethyl starch
(HES) products, including Voluven®, increases risk of
Renal replacement therapy
Do not use HES products, including Voluven®, in critically ill adult patients, including
patients with sepsis.
Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is a clear to slightly
opalescent, colorless to slightly yellow, sterile, non-pyrogenic, isotonic solution for intravenous
administration using sterile equipment.
Each 100 mL of the solution contains: 6 g of Hydroxyethyl Starch 130/0.4 and 900 mg of Sodium
Chloride USP in Water for Injection USP.
In addition, sodium hydroxide, USP, or Hydrochloric acid, USP, has been added to adjust the final pH
so the final solution pH is 4.0 to 5.5.
The electrolyte composition is as follows (mEq/L): Sodium 154, Chloride 154.
The calculated osmolarity is 308 mOsmol/L.
The hydroxyethyl starch contained in Voluven® is a synthetic colloid for use in plasma volume
replacement. The chemical name of hydroxyethyl starch is poly(O-2-hydroxyethyl) starch. The
structural formula of hydroxyethyl starch is
R = -H, -CH2CH2OH
R1 = -H, -CH2CH2OH or glucose units
Voluven® is packaged in 500 mL flexible plastic containers (freeflex®). Freeflex® is a flexible container
made from coextruded polyolefin and is free of PVC, plasticizers, adhesives or latex (Non-DEHP,
Latex-free). The freeflex® container offers an air-closed system and can be used with non-vented IV
sets which prevent external air contamination. Freeflex® is collapsible and can be used in emergency
cases for pressure infusion.
Indications & Dosage
Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the
treatment and prophylaxis of hypovolemia in adults and children. It is not a substitute for red blood
cells or coagulation factors in plasma.
DOSAGE AND ADMINISTRATION
Voluven® is administered by intravenous infusion only. The daily dose and rate of infusion
depend on the patient’s blood loss, on the maintenance or restoration of hemodynamics and on the
hemodilution (dilution effect). Voluven® can be administered repetitively over several days. [see WARNINGS AND PRECAUTIONS]
The initial 10 to 20 mL should be infused slowly, keeping the patient under close observation due to
possible anaphylactoid reactions. [see General WARNINGS AND PRECAUTIONS]
Up to 50 mL of Voluven® per kg of body weight per day (equivalent to 3 g hydroxyethyl starch and
7.7 mEq sodium per kg of body weight). This dose is equivalent to 3500 mL of Voluven® for a 70 kg
The dosage in children should be adapted to the individual patient colloid needs, taking into account
the disease state, as well as the hemodynamic and hydration status.
In 41 newborns to infants (< 2 years), a mean dose of 16 ± 9 mL/kg was administered. In 31 children
from 2 – 12 years of age a mean dose of 36 ± 11 mL/kg was administered. The dose in adolescents
> 12 is the same as the adult dose. [see Pediatric Use]
Directions Of Use for Voluven®
Check the solution composition, lot number and expiry date, inspect the container for damage or leakage, if damaged do not use.
Identify the blue infusion (administration) port.
Use opening aid to remove over-wrap.
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.
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 discoloration prior
to administration, whenever solution and container permit.
Do not administer unless the solution is clear, free from particles and the freeflex® IV container is
Voluven® should be used immediately after insertion of the administration set.
Do not vent.
If administered by pressure infusion, air should be withdrawn or expelled from the bag through the
medication/administration port prior to infusion.
Discontinue the infusion if an adverse reaction occurs.
It is recommended that administration sets be changed at least once every 24 hours.
For single use only. Discard unused portion.
Doage Forms And Strengths
500 mL freeflex® flexible plastic intravenous solution container are available. Each 100 mL contains 6 g
hydroxyethyl starch 130/0.4 in isotonic sodium chloride injection.
Storage And Handling
Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for intravenous infusion is
supplied in the following primary container and carton sizes:
Polyolefin bag (freeflex®) with overwrap: 500 mL
Carton of 15 x 500 mL NDC 0409-1029-01
Carton of 20 x 500 mL NDC 0409-1029-02
Store at 15° to 25°C (59° to 77°F). Do not freeze.
Neff TA, Doelberg M, Jungheinrich C, et al. Repetitive large-dose infusion of the novel hydroxyethyl
starch HES 130/0.4 in patients with severe head injury. Anest Analg 2003; 96 (5): 1453–9.
Kozek-Langenecker S. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology
2005; 103 (3): 654-60.
Standl T, Lochbuehler H, Galli C, et al. HES 130/0.4 (Voluven®) or human albumin in children
younger than 2 yr undergoing non-cardiac surgery. A prospective, randomized, open label,
multicentre trial. Eur J Anaesthesiol 2008; 25(6): 437-45.
Jungheinrich C, Neff T. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinetik 2005;
44 (7): 681-99.
Jungheinrich C, Scharpf R, Wargenau M, et al. The pharmacokinetics and tolerability of an
intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal
impairment. Anesth Analg 2002; 95 (3): 544 – 51.
Leuschner J, Opitz J, Winkler A, Scharpf R, Bepperling F. Tissue storage of 14C-labeled
hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to
rats. Drugs R D 2003; 4 (6): 331-8.
Gandhi SD, Weiskopf RB, Jungheinrich C et al. Volume replacement therapy during major
orthopedic surgery using Voluven® (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology
Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl Starch 130/0.4 versus Ringer’s Acetate in
Severe Sepsis. N Eng J Med 2012; 367(2): 124-34.
Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6%
hydroxyethylstarch 130/0.4 versus 0.9% NaCl fluid replacement in patients with severe sepsis:
The CRYSTMAS study. Crit Care 2012; 16(3): R94.
Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in
intensive care. N Engl J Med 2012; 367(20): 1901-11.
Manufactured by: Distributed by: Fresenius Kabi Norge AS, P.O. Box 430, NO-1753 Halden, Norway. Revised: Oct 2013.
What is hemophilia?See Answer
Side Effects & Drug Interactions
Overall Adverse Reaction Profile
Serious adverse reactions reported in clinical trials were increased mortality and need for renal
replacement therapy in critically ill patients including sepsis.
The most common adverse reactions after administration of Voluven® occurring in more than 1%
of patients are: pruritus (itching; ≥1% to <10%), elevation of serum amylase (≥1% to <10%; can
interfere with the diagnosis of pancreatitis), and dilutional effects that may result in decreased levels of
coagulation factors and other plasma proteins and in a decrease of
hematocrit (≥1% to <10%).
Anaphylactoid reactions occur rarely in <0.1% after administration of hydroxyethyl starch solutions.
Disturbances of blood coagulation beyond dilution effects can occur rarely in <0.1% depending on the
dosage with the administration of hydroxyethyl starch solutions2.
Adverse Reactions In Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
or another patient population and may not reflect the rates observed in clinical practice.
During clinical development, a total of 899 subjects received the hydroxyethyl starch 130/0.4 drug
substance contained in Voluven® at different concentrations (2%, 4%, 6%, or 10%) and at cumulative
doses of several mL up to 66 L1. Of these 899 subjects, 602 were exposed to Voluven® (i.e., 6%
hydroxyethyl starch 130/0.4). The mean duration of treatment with hydroxyethyl starch 130/0.4 was
3.7 ± 3.1 days, mean cumulative doses were 3185 ± 3498 mL, and the longest follow-up period was
In 100 subjects undergoing elective orthopedic surgery Voluven® was administered in 49 subjects and
hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) in 51 subjects for intraoperative
volume replacement7. Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL
Adverse reactions observed in at least 1% of subjects: In the orthopedic surgery trial conducted in
the US, no significant differences in serious adverse reactions were noted overall between the two
treatment arms. A possible relationship to Voluven® was reported in five cases among three subjects
(aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus). A possible relationship to
hetastarch was reported in five subjects (three cases of coagulopathy; two cases of pruritus). The
three coagulopathy cases in the hetastarch group were serious and occurred in subjects receiving
more than the labeled ceiling dose (20 mL/kg), which is known to increase the risk of bleeding,
whereas no serious coagulopathy occurred in the Voluven® group. Since EBL for the two treatment
arms was not statistically different (95% confidence interval included unity), the difference observed
for Factor VIII (see Table 1, below) must be interpreted with caution. An exploratory analysis of total
erythrocyte volume transfused (8.0 mL/kg vs. 13.8 mL/kg, Voluven® vs. hetastarch, respectively) must
also be viewed with caution.
Table 1: Safety Variables for the Orthopedic Surgery Trial conducted in the US
Ratio VOLUVEN / Hetastarch
Calculated red blood cell loss [L]*
Factor VIII [%]*
von Willebrand factor [%]*
Fresh frozen plasma [mL]*
A safety profile of Voluven® at least as favorable as for pentastarch was also demonstrated in studies
where Voluven® was administered at doses higher (up to 50 mL/kg or 3 g/kg) than for pentastarch (up
to 33 mL/kg or 2 g/kg) in clinical settings where large or repetitive doses were administered.
Three randomized controlled trials (RCTs) followed critically ill adult patients treated with different HES
products for 90 days.
One trial (N=804) in severe sepsis patients using an HES product not licensed in the U.S. reported
increased mortality (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03) and RRT (relative risk, 1.35; 95%
CI, 1.01 to 1.80; p=0.04) in the HES treatment arm8.
Another trial (N=196) using Voluven® in severe sepsis patients reported no difference in mortality
(relative risk, 1.20; 95% CI, 0.83 to 1.74; p=0.33) and a trend for RRT (relative risk, 1.83; 95% CI, 0.93
to 3.59; p=0.06) in HES patients9.
A third trial (N=7000) using Voluven® in a heterogeneous population of critically ill patients admitted
to the ICU reported no difference in mortality (relative risk, 1.06; 95% CI, 0.96 to 1.18; p=0.26) but
increased use of RRT (relative risk, 1.21; 95% CI, 1.00 to 1.45; p=0.04) in HES patients10.
Because adverse reactions are reported voluntarily post-approval from a population of uncertain size,
it is not always possible to reliably estimate the frequency or establish a causal relationship to product
Among the very rarely occurring serious adverse drug reactions in patients treated with Voluven®,
anaphylactic/anaphylactoid/hypersensitivity reactions or hypotension/shock/circulatory collapse were
most frequently reported.
The following adverse reactions have been identified and reported during the post-approval use of
different HES products in critically ill adult patients, including patients with sepsis:
Renal: need for renal replacement therapy.
The safety and compatibility of other additives have not been established.
Warnings & Precautions
Included as part of the "PRECAUTIONS" Section
Anaphylactoid reactions (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 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 renal injury.
Continue to monitor renal function in hospitalized patients for at least 90 days as use of RRT has been
reported up to 90 days after administration of HES products.
Monitor the coagulation status of patients undergoing open heart surgery in association with
cardiopulmonary bypass as excess bleeding has been reported with HES solutions in this population.
Discontinue use of Voluven® at the first sign of coagulopathy.
Avoid fluid overload; adjust dosage in patients with cardiac or renal dysfunction.
Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients
with cardiac insufficiency or severe kidney dysfunction.
In cases of severe dehydration, a crystalloid solution should be given first. Generally, sufficient fluid
should be administered in order to avoid dehydration.
Monitoring: Laboratory Tests
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®.
Interference With Laboratory Tests
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 hematocrit.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of Voluven® have not been
performed. No mutagenic effects were observed with hydroxyethyl starch 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.
Fertility studies on directly exposed animals have not been performed.
Use In Specific Populations
Pregnancy Category C. Voluven® has been shown to cause embryocidal or other adverse effects in
rats and rabbits when given in doses 1.7 times the human dose.
The type of hydroxyethyl starch present in Voluven® had no teratogenic properties in rats or rabbits. At
5 g/kg of body weight per day, administered as a bolus injection, fetal retardations and embryolethal
effects were observed in rats and rabbits, respectively. In rats, a bolus injection of this dose during
pregnancy and lactation reduced body weight of offspring and induced developmental delays. All
adverse effects were seen exclusively at maternal toxic doses due to fluid overload. [see Animal
Pharmacology and/or Toxicology, Toxicology]
Fertility studies on directly exposed animals have not been conducted.
There are no adequate and well-controlled studies in pregnant women. Voluven® should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor And Delivery
Information on the use of Voluven® during labor or delivery is unknown. 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 Voluven® is administered to a nursing woman.
In one trial, newborns and infants < 2 years of age undergoing elective surgery were randomized to
receive Voluven® (N=41) or 5% albumin (N=41). The mean dose of Voluven® administered was
16 ± 9 mL/kg.
In an additional trial, children from 2 – 12 years of age undergoing cardiac surgery were randomized
to receive Voluven® (N=31) or 5% albumin (N=30). The mean dose administered was 36 ± 11 mL/kg.
Use of Voluven® in adolescents > 12 years is supported by evidence from adequate and wellcontrolled
studies of Voluven® in adults.
Dosage in children should be adapted to individual patient colloid needs, taking into account
underlying disease, hemodynamics and hydration status. [see Pediatric Dose]
Of the total number of subjects in clinical studies of Voluven® (N= 471), 32% were ≥ 65 years old while
7% were ≥ 75 years old. No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but greater sensitivity of some
older individuals cannot be ruled out.
Voluven® is mainly excreted by the kidneys, and the risk of adverse reactions to this drug may be
greater in patients with impaired renal function. Volume status, infusion rate, and urine output should
be closely monitored. Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection. [see Pharmacokinetics]
Overdosage & Contraindications
Overdosage can lead to overloading of the circulatory system (e.g., pulmonary edema). In this case,
the infusion should be stopped immediately and if necessary, a diuretic should be administered. [see General WARNINGS AND PRECAUTIONS]
Do not use hydroxyethyl starch (HES) products, including Voluven®, in critically ill adult patients,
including patients with sepsis, due to increased risk of mortality and renal replacement therapy.
Do not use HES products, including Voluven®, in patients with severe liver disease.
Do not use HES products, including Voluven®, in patients with known hypersensitivity to
hydroxyethyl starch. [see General WARNINGS AND PRECAUTIONS]
Do not use HES products in clinical conditions with volume overload.
Do not use HES products in patients with pre-existing coagulation or bleeding disorders.
Do not use HES products in patients with renal failure with oliguria or anuria not related to
Do not use HES products in patients receiving dialysis treatment.
Do not use HES products in patients with severe hypernatremia or severe hyperchloremia.
Do not use HES products in patients with intracranial bleeding.
Mechanism Of Action
Voluven® contains hydroxyethyl starch in a colloidal solution which expands plasma volume when
administered intravenously. This effect depends on the mean molecular weight (130,000 daltons;
range 110,000 – 150,000 daltons), the molar substitution by hydroxyethyl groups (0.4; range 0.38
– 0.45) on glucose units of the starch, the pattern of hydroxyethyl substitution (C2/C6 ratio) of
approximately 9:1, and the concentration (6%), as well as the dosage and infusion rate.
Hydroxyethyl starch is a derivative of thin boiling waxy corn starch, which mainly consists of a glucose
polymer (amylopectin) predominantly composed of α-1-4-connected glucose units with several α-1-6-
branches. Substitution of hydroxyethyl groups on the glucose units of the polymer reduces the normal
degradation of amylopectin by α-amylase in the body. The low molar substitution (0.4) is the main
pharmacological determinant for the beneficial effects of Voluven® on pharmacokinetics, intravascular
volume and hemodilution4. To describe the molecular weight and molar substitution characteristics of
the hydroxyethyl starch in Voluven®, the compound is designated as hydroxyethyl starch 130/0.4.
After isovolemic exchange of blood with 500 mL of Voluven® in healthy volunteers, blood volume is
maintained for at least 6 hours.
The pharmacokinetic profile of hydroxyethyl starch is complex and largely dependent on its molar
substitution as well as its molecular weight4. When administered intravenously, molecules smaller
than the renal threshold (60,000-70,000 daltons) are readily and rapidly excreted in the urine, while
molecules with higher molecular weights are metabolized by plasma α-amylase prior to excretion via
the renal route.
The mean in vivo molecular weight of Voluven® in plasma is 70,000 – 80,000 daltons immediately
following infusion and remains above the renal threshold throughout the treatment period.
Following intravenous administration of 500 mL Voluven® to healthy volunteers, plasma levels of
Voluven® remain at 75% of peak concentration at 30 minutes post-infusion and decrease to 14% at 6
hours post-infusion. Plasma levels of Voluven® return to baseline levels 24 hours following infusion.
Plasma clearance, volume of distribution, and elimination half-life of Voluven® in healthy volunteers
following IV administration of 500 mL were 31.4 mL/min, 5.9 liters, and 12 hours, respectively.
Approximately 62 % of Voluven® was excreted as hydroxyethyl starch molecules in urine within 72 hours.
The pharmacokinetics 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 hydroxyethyl starch 130/0.4 over a period of 10 days. Approximately 70% of Voluven®
was excreted as hydroxyethyl starch molecules in urine within 72 hours.
Following a single intravenous administration of Voluven® (500 mL) in subjects with varying degrees
of renal dysfunction, the AUC and clearance of Voluven® increased by 73% and decreased by 42% in
subjects, respectively, with creatinine clearance <50 mL/min as compared to subjects with creatinine
clearance >50 mL/min. However, terminal half-life and peak hydroxyethyl starch concentration were
not affected by renal impairment. Plasma levels of Voluven® returned to baseline levels 24 hours
following infusion. Approximately 59 % and 51 % of Voluven® were excreted as hydroxyethyl starch
molecules in urine within 72 hours in subjects with creatinine clearance ≥30 mL/min and <30 mL/min,
There are no data available on the use of Voluven® in subjects undergoing hemodialysis.
Pharmacokinetic data in patients with hepatic insufficiency or in pediatric or geriatric patients are not
available. Effects of gender or race on the pharmacokinetics of Voluven® have not been studied.
Animal Pharmacology And/Or Toxicology
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 hydroxyethyl starch 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 hypervolemia in the animals. There
were no gender-related effects on toxicity following repeat administration of hydroxyethyl starch
130/0.4 in rats or dogs.
In reproduction studies in rats and rabbits, hydroxyethyl starch 130/0.4 (10% solution) had no
teratogenic properties. 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. Hydroxyethyl starch
130/0.4 (10% solution) had no effect in studies assessing skin sensitization, antigenicity, and blood
The pharmacodynamic effect of Voluven® was examined in a hemorrhagic shock model in conscious
rats and a hemodilution model in dogs. In both studies the control group received pentastarch (6%
hydroxyethyl starch 200/0.5).
Voluven® was as effective as pentastarch in maintaining cardiopulmonary function during isovolemic
hemodilution in beagle dogs. In the three-hour follow-up period no additional administration of colloid
There were no differences in long-term survival of rats after a single administration of Voluven® and
pentastarch solutions following induced hemorrhagic shock (67% and 50% blood loss). In the 67%
induced bleeding group receiving Voluven® (N=6), the survival rate was 83% which is within the
normal range for this type of experiment. In the corresponding pentastarch group, survival was 100%.
Infusion of Ringer’s lactate resulted in a 50% survival rate after a 50% blood loss and a 0% survival
after a 67% blood loss.
After multiple intravenous infusions of 0.7 g per kg body weight per day of 10% hydroxyethyl starch
130/0.4 or 10% hydroxyethyl starch 200/0.5 solution during 18 consecutive days, the plasma
hydroxyethyl starch concentration in rats treated with hydroxyethyl starch 130/0.4 was lower compared
to rats treated with hydroxyethyl starch 200/0.5. Hydroxyethyl starch 130/0.4 was eliminated faster
than hydroxyethyl starch 200/0.5. In both groups, clear signs of hydroxyethyl starch tissue storage
were detected in lymph nodes and spleen. Numerous empty vacuoles in macrophages were
observed. Only minimal cellular vacuolization was found in the liver and kidney. Histochemical
differences between the groups were not observed.
A study with 10% radiolabeled 14C-hydroxyethyl starch 130/0.4 and 10% 14C- hydroxyethyl starch
200/0.5 solutions was carried out6. In animals treated with hydroxyethyl starch 130/0.4, radioactivity
decreased from 4.3% of the total administered dose (2.6 g hydroxyethyl starch 130/0.4 per animal)
on day 3 to 0.65% on day 52. In animals treated with hydroxyethyl starch 200/0.5, the 14C-activity
decreased from 7.7% of the total administered dose (2.7 g hydroxyethyl starch 200/0.5 per animal)
on day 3 to 2.45% on day 52. These results confirm the faster elimination and lower persistence of
hydroxyethyl starch 130/0.4 in tissue.
Voluven® was studied in controlled clinical trials among adult and pediatric subjects undergoing
various types of surgery (orthopedic, urologic, cardiac) in which hypovolemia is treated (pre-, intra-,
and postoperative) or prevented (autologous blood donation, acute normovolemic hemodilution,
hypervolemic hemodilution before cardiac surgery). Adult subjects in intensive care units also were
studied. The safety and efficacy of Voluven® were compared to other colloidal plasma substitutes
[pentastarch (6% hydroxyethyl starch 200/0.5), hetastarch (6% hydroxyethyl starch 450/0.7), gelatin
solution or human serum albumin]. Perioperative fluid administration of Voluven® ranged from 500 to
4500 mL/day in surgical subjects, and cumulatively, from 6 to 66 L in intensive care subjects following
traumatic brain injury.
Orthopedic Surgery Trial
A prospective, controlled, randomized, double-blind, multi-center trial of 100 subjects undergoing
elective orthopedic surgery was conducted in the US evaluating Voluven® (N=49) compared to
hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N=51) for intraoperative
volume replacement therapy7. The primary efficacy variable, total volume of colloid solution required
for intraoperative volume replacement therapy, was equivalent for the two treatment groups. Mean
volume infused was 1613 ± 778 mL for Voluven® and 1584 ± 958.4 mL for hetastarch. The ratio
Voluven®/hetastarch was estimated as 1.024 with a 95% confidence interval (0.84, 1.25), which was
included within the equivalence range of (0.55, 1.82) prespecified in the study protocol. This indicated
that Voluven® and hetastarch have similar efficacy as intraoperative volume replacement therapy in
major orthopedic surgery.
A second objective of the trial was to show superiority for safety between Voluven® and hetastarch.
Four safety endpoints were prospectively defined and compared in a sequential manner (in order to
preserve the type-1 error rate, i.e., observing a difference where none actually exists). Per protocol,
if there was no difference found between treatment arms for the first safety endpoint (EBL), the
remaining endpoints were to be considered exploratory analyses requiring additional studies for
confirmation. [see ADVERSE REACTIONS in Clinical Trials]
There was no statistically significant difference between the two treatment groups with respect to the
secondary efficacy endpoints of hemodynamic stability, body temperature, hemodynamic parameters,
blood pressure, central venous pressure, heart rate, fibrinogen and platelet count.
In addition to the US trial, three non-US trials were conducted with the primary objective of showing
equivalency (based on mean difference rather than mean ratio as in the US study) between Voluven®
and pentastarch in maintaining or restoring hemodynamic parameters. The largest of the three trials
(N=100) met the prespecified boundary (-500 mL, 500 mL), but the two smaller studies (N=52 and
N=59) did not.
In exploratory analyses, the effect of Voluven® on coagulation parameters (von Willebrand factor,
Factor VIII, and Ristocetin cofactor) was shown to be significantly lower than pentastarch at one
or more time points (US and non-US trials). These findings are consistent with the lower molar
substitution, lower average molecular weight and narrower molecular weight distribution of Voluven®
as compared to pentastarch resulting in a lower in vivo molecular weight and increased elimination
from the circulation.
Severe Sepsis Trial
A randomized, double-blind, multicenter study of subjects with severe sepsis ≥ 18 years old compared
Voluven® (n=100) vs. normal saline (n=96) infused over a maximum of 4 days for the treatment
of hypovolemia9. The primary endpoint was volume of study drug (mL) required to achieve initial
hemodynamic stabilization (HDS), defined as MAP ≥ 65 mmHg, CVP 8-12 mmHg, urine output
≥ 2 mL/kg over 4 h, and central venous oxygen saturation ≥ 70% maintained for four hours with no
increase in the infusion rate of vasopressors or inotropic support and ≤ 1 L of additional study drug
administration. Safety parameters included the incidence of acute renal failure, prospectively defined
as need for renal replacement therapy (RRT) or doubling of baseline serum creatinine at some point
during the 90-day observation period. AKIN and RIFLE criteria also were evaluated.
Baseline characteristics for the two treatment arms were 24.0% vs. 18.8% for intra-abdominal sepsis,
53.0% vs. 60.4% for pulmonary sepsis, and 8.0% vs. 14.6% for urogenital sepsis, Voluven® vs. normal
Subjects achieving HDS (N=88 vs. 86) required less Voluven® compared to control: 1379 mL ±
886 (Voluven®) vs. 1709 ± 1164 mL (normal saline), representing a mean difference of 331 mL
(95% confidence interval: -640 mL to -21 mL). Less time was needed from start of study drug to
achievement of HDS in the Voluven® group compared to the normal saline group (11.8 hours ± 10.1
hours vs. 14.3 hours ± 11.1 hours; mean ± SD).
A post hoc sensitivity analysis was performed to determine the number of subjects not achieving HDS
as a result of a change made to the protocol definition of HDS after enrollment had commenced, i.e.,
from requiring all four hemodynamic criteria to requiring normalization of MAP and two of the three
remaining hemodynamic criteria. Approach 1 used the original definition of HDS for subjects enrolled
prior to the protocol change and the revised definition of HDS for subjects enrolled subsequently;
Approach 2 used the revised definition of HDS for all enrolled subjects. More Voluven® subjects than
control subjects were declared to have achieved HDS, although not all the requirements for HDS had
been fulfilled (see Table 2).
Table 2: Post Hoc Sensitivity Analysis
Number of subjects without declaration of HDS
Number of subjects without declaration of HDS plus
number of subjects with HDS declared by Approach 1
Number of subjects without declaration of HDS plus
number of subjects with HDS declared by Approach 2
The number of treatment emergent serious adverse events (SAEs) and number of treatment
emergent SAEs leading to death in the Voluven® and normal saline treatment arms during the 90-day
observation period were 53 vs. 44 and 38 vs. 32, respectively.
Acute kidney injury scores (AKIN and RIFLE classifications) were comparable between groups (see
Table 3, below). The number of subjects undergoing RRT was 21 vs. 11 for the 90-day observation
period and 17 vs. 8 for the first 7 days of treatment. Mean duration of RRT was 9.1 days in the
Voluven® arm vs. 4.3 days in the normal saline arm.
Kaplan-Meier curves for time to RRT (Figure 1, below) showed a trend against Voluven® (p=0.06, logrank
test) [see ADVERSE REACTIONS].
Table 3: Evaluation of Subjects According to the AKIN Classification
Normal saline (N=96)
Worst AKIN Stage
AKIN Stage 1
AKIN Stage 2
AKIN Stage 3
p-value of test for trend
AKIN classification was based on serum creatinine values and renal replacement therapy. Urine output criteria were
ignored. Percentages are based on the number of evaluable subjects (m), i.e., the number of subjects for whom an
AKIN score could be determined.
Figure 1: Kaplan-Meier Curves for time to RRT
In a randomized, controlled trial among a heterogeneous adult ICU population (N=7000) that included
subjects with sepsis as well as trauma subjects and postoperative elective surgery subjects, Voluven®
was compared against 0.9% NaCl for volume replacement therapy10. The primary endpoint was
death within 90 days. Secondary endpoints included renal risk (RIFLE-R), injury (RIFLE-I) and
failure (RIFLE-F) until day 7 of product exposure, and use of RRT within 90 days. Mortality was not
significantly different overall [597 of 3315 (18%) Voluven® subjects vs. 566 of 3336 (17%) control
subjects; p=0.26] or in six pre-defined subgroups including patients with sepsis. RIFLE-R occurred in
54% (Voluven®) and 57.3% (0.9% NaCl, p=0.007), RIFLE-I occurred in 34.6% and 38.0% of subjects
(p=0.005) and RIFLE-F occurred in 10.4% and 9.2% of subjects (p=0.12), respectively. RRT was used
in 235 (7.0%) Voluven® subjects compared to 196 (5.8%) normal saline subjects (relative risk, 1.21;
95% CI, 1.00 to 1.45; p=0.04; p=0.05 after adjustment for baseline). No loss of renal function or end
stage renal disease (RIFLE-L and RIFLE-E) was reported. [see ADVERSE REACTIONS in Clinical Trials]
In another RCT performed in 804 severe sepsis patients using a different HES type, HES 130/0.42
in Ringer’s acetate injection (not approved in the U.S.), mortality rate in patients with severe sepsis
treated with HES 130/0.42 was higher (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03), and the
frequency of patients who received RRT was also higher (relative risk, 1.35; 95% CI, 1.01 to 1.80;
p=0.04) compared to those who received modified acetated Ringer’s solution8. [see ADVERSE REACTIONS in Clinical Trials]
Because this product is not used directly by patients, patient counseling or instructions for use by
patients is not considered necessary.