Special Warning : אזהרת שימוש

5     WARNINGS AND PRECAUTIONS

5.1   Anaphylactoid Reactions
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 (6)] 
5.2   Renal Dysfunction
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.

5.3   Coagulopathy
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.

5.4   Fluid Equilibrium
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.


5.5   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.

5.6   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.

6     ADVERSE REACTIONS

6.1   Overall Adverse Reaction Profile
Serious adverse reactions reported in clinical trials include increased mortality and increased use of RRT in critically ill subjects, including subjects with 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%; interference 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 solutions.

6.2   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 L. 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 a randomized controlled trial (RCT) of subjects (N=100) undergoing elective orthopedic surgery, Voluven (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection; N=51) were administered for intraoperative volume replacement. 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 U.S., 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 calculated red blood cell loss for the two treatment arms was not statistically different (95% confidence interval included unity), differences 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) also must be viewed with caution.

Table 1: Safety Variables for the Orthopedic Surgery Trial conducted in the US 
Mean                     Ratio
Voluven /Hetastarch
Variable                  Voluven         Hetastarch   Estimate      95% Cl N=49             N=51
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 for 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.

Trials in critically ill adult subjects
Three RCTs followed critically ill adult subjects treated with different HES products for 90 days.

One trial using Voluven in severe sepsis subjects (N=196) reported no difference in mortality (relative risk, 1.20; 95% CI, 0.83 to 1.74; p=0.33) and a trend for increased use of RRT (relative risk, 1.83; 95% CI, 0.93 to 3.59; p=0.06) in HES subjects.

Another trial using Voluven in a heterogeneous population of critically ill subjects admitted to the ICU (N=7000) 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 subjects.
A third trial in severe sepsis subjects (N=804) using an HES product not licensed in the U.S.
(HES 130/0.42) reported increased mortality (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03) and increased use of RRT (relative risk, 1.35; 95% CI, 1.01 to 1.80; p=0.04) in HES subjects.


6.3   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: 
Mortality
Renal: use of RRT

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com

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