FDA Adds Serious New Warnings to Hydroxyethyl Starch Products, but Falls Short of EMA's Restrictions

US regulators are joining their EU counterparts in issuing a warning about the use of hydroxyethyl starch (HES) solutions, a product used to stabilize patients experiencing severe blood loss and commonly used by the military, saying it has several side effects that are more prominent than previously known.

Background

HES has been in the crosshairs of regulators for more than a year now. The product, usually in the form of hydroxyethyl starch 6.0%, is used to prevent the onset of hypovolemia-also known as low blood volume-which can come about through trauma, sepsis, burns or anaphylaxis.

A website for one of the largest manufacturers of HES products, BioTime, explains that the product "creates oncotic pressure, which would normally be provided by blood proteins, and permits retention of intravascular fluid."  FDA notes it has approved three HES products-manufactured by Fresnius Kabi (Voluven), BioTime, Inc. (Hextend) and  B. Braun Medical (Hespan)-the first of which was licensed before 1985.

The products are used in hospital environments in both civilian and military settings, which may have explained the Department of Defense's interest in co-sponsoring a July 2013 meeting with the US Food and Drug Administration (FDA). That meeting was intended to launch a process of reassessing the safety risks of HES products, including skin and tissue irritation and disorders, anaphylaxis, and a decrease in blood coagulation factors.

In June 2013, the European Medicines Agency (EMA) announced that its Pharmacovigilance Risk Assessment Committee (PRAC) had recommended suspending marketing authorizations for HES products in light of their conclusion that the benefits of the products "no longer outweigh their risks."

Explained EMA: "The review of infusion solutions containing HES was triggered … following three recent studies that compared HES with other products used for volume replacement called crystalloids in critically ill patients. The studies showed that patients with severe sepsis treated with HES were at a greater risk of kidney injury requiring dialysis. Two of the studies also showed that in patients treated with HES, there was a greater risk of mortality."

FDA Restrictions Mirror PRAC's Logic

Now FDA is moving to restrict HES solutions as well, issuing a MedWatch warning that "patients should be aware of the risks associated with the use of HES solutions and discuss these risks with their healthcare provider (refer to the FDA Safety Communication for detailed recommendations for patients)."

"FDA has concluded that HES solutions should not be used in critically ill adult patients, including patients with sepsis and those admitted to the ICU, and a Boxed Warning to include the risk of mortality and severe renal injury is warranted."

Regulators added that they had determined a need for additional warnings to be added to the package insert (PI) of the product in light of risks to open heart surgery patients, who could experience "excessive bleeding" according to a meta-analysis by FDA.

Additional recommendations from FDA include:

• Do not use HES solutions in critically ill adult patients, including those with sepsis, and those admitted to the ICU.
• Avoid use in patients with pre-existing renal dysfunction.
• Discontinue use of HES at the first sign of renal injury.
• 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 all patients.
• Avoid use in patients undergoing open heart surgery in association with cardiopulmonary bypass due to excess bleeding.
• Discontinue use of HES at the first sign of coagulopathy.

The recommendations may be welcomed to an extent by HES manufacturers, as FDA's restrictions fall far short of the outright ban called for by EMA regulators.

FDA Safety Communication - Boxed Warning on Increased Mortality and Severe Renal Injury and Risk of Bleeding