Safety update on hydroxyethyl starch (HES)-containing products

HSA would like to inform healthcare professionals about a new safety update regarding the use of hydroxyethyl starch (HES)-containing products, and recommends that HES-containing products should not be used in septic patients, critically ill patients and patients with renal failure and/or severe hepatic impairment. This recommendation is made in consultation with its Product Vigilance Advisory Committee (PVAC) based on information from reviews by the Cochrane Collaboration and two major regulatory agencies, which revealed increased mortality and renal injury requiring renal replacement therapy in these patients who were treated with HES-containing products.

HES-containing products are colloid solutions mainly used for fluid resuscitation in patients with hypovolaemia. There are five HES-containing products registered in Singapore: Tetraspan® Solution for Infusion 6% & 10%, HAES-Steril® Infusion 6%, Voluven® Solution for Infusion 6%, and Volulyte® Solution for Infusion 6%. Tetraspan® is marketed by B. Braun Singapore Pte Ltd, whereas the remaining three products are marketed by Fresenius Kabi (Singapore) Pte Ltd.

Background

HES solutions are known to be associated with potential safety concerns such as anaphylaxis, coagulopathy, bleeding, and renal failure. However, recent reviews by the Cochrane Collaboration, the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC), as well as the US Food and Drug Administration (FDA) triggered HSA to conduct a safety assessment of the local use of starch-based colloids in critically ill patients.

In March 2013, the Cochrane Collaboration conducted a review investigating the effects of colloids compared to crystalloids on mortality in critically ill patients when used for fluid resuscitation.¹ This updated meta-analysis of 25 studies (n=9147) showed an increased risk of death in patients treated with HES solutions. The results were primarily driven by three recent studies in septic^2,3 and critically ill⁴ patients,which demonstrated a higher risk of deaths (6–17% increased risk) and renal failure requiring renal replacement therapy (20–35% increased risk) in these patients following HES treatment.

In June 2013, the EMA's PRAC concluded that the benefits of infusion solutions containing HES no longer outweigh their risks and recommended the suspension of marketing authorisations of these medicines.⁵ Following an appeal by the companies, the EMA conducted a re-evaluation and concluded in October 2013 that the marketing of HES-containing products can be continued, however these products should no longer be used to treat critically ill patients or patients with sepsis or burn injuries due to an increased risk of renal injury and mortality.⁶

The US FDA announced in June 2013 that HES-containing products should not be used in critically ill adult patients, including patients with sepsis and those admitted to the intensive care unit (ICU).⁷ HES-containing products should also be avoided in patients with pre-existing renal disease. These recommendations were made following the FDA's analyses of available data, which showed increased mortality and renal injury requiring renal replacement therapy in these patient populations who were treated with HES-containing products.

HSA's advisory

• HSA has reviewed the available information and assessments conducted by the EMA and US FDA. Although no local adverse events associated with HES-containing products have been reported to-date, HSA, in consultation with its PVAC, recommends the following in the use of these products:

• HES-containing products should not be used in patients with sepsis or critically ill patients, and in patients with renal failure and/or severe hepatic impairment.

• HES-containing products should only be used to treat hypovolaemia when crystalloids alone are not sufficient, provided appropriate measures are taken to reduce potential risk. Positive fluid responsiveness must be confirmed after the administration of HES-containing products, and the lowest possible effective dose should be used.

• HSA will be working with the companies to update the above information in the local package inserts of HES-containing products. Healthcare professionals are encouraged to report adverse events associated with the use of HES-containing products to the Vigilance Branch of HSA.References

1. Cochrane Database Syst Rev 2013; 2: CD000567

2. N Engl J Med 2012; 367: 124-34

3. N Engl J Med 2008; 358: 125-39

4. N Engl J Med 2012; 367: 1901-11

5. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001814.jsp&mid=WC0b01ac058004d5c1 ↗ (opens in new tab)

6. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/10/news_detail_001917.jsp&mid=WC0b01ac058004d5c1 ↗ (opens in new tab)

7. http://www.fda.gov/biologicsbloodvaccines/safetyavailability/ucm358271.htm ↗ (opens in new tab)