July 23, 2016
Recommended Topic Related To:


"The U.S. Food and Drug Administration yesterday approved Rixubis [Coagulation Factor IX (Recombinant)] for use in people with hemophilia B who are 16 years of age and older. Rixubis is indicated for the control and prevention of bleeding episodes"...



Side Effects


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 90 days.

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 for hetastarch.

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

  Mean Ratio VOLUVEN / Hetastarch
Variable VOLUVEN
Estimate 95% Cl
Calculated red blood cell loss [L]* 1.17 1.31 0.910 [0.720; 1.141]
Factor VIII [%]* 100.5 81.4 1.244 [1.000; 1.563]
von Willebrand factor [%]* 97.7 88.7 1.128 [0.991; 1.285]
Fresh frozen plasma [mL]* 72 144 0.723 [0.000; 2.437]
*Exploratory analyses

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.

Postmarketing Experience

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 exposure.

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.

Read the Voluven (hydroxyethyl starch in sodium chloride injection) Side Effects Center for a complete guide to possible side effects


The safety and compatibility of other additives have not been established.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 7/13/2016

Side Effects

Report Problems to the Food and Drug Administration


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

Women's Health

Find out what women really need.