On January 12, 2018, the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) recommended the suspension of the marketing authorizations for hydroxyethyl-starch (HES) solutions for infusion across the European Union. These products are used as plasma volume replacement following acute (sudden) blood loss, where treatment with alternative products known as 'crystalloids' alone is not considered to be sufficient47.
The review was triggered by results from two drug utilization studies indicating that HES solutions are being used in critically ill patients and even to those with sepsis and kidney injury despite restrictions introduced in 2013 to reduce the risks of kidney problems and deaths in these patient populations.
Background
In 2013, the PRAC had recommended restrictions on the use of HES solutions, including that they must no longer be used to treat critically ill patients or patients with sepsis, because of an increased risk of kidney injury and mortality seen in clinical trials. The Committee requested that further studies be carried out to verify adherence to these restrictions.
The PRAC reviewed the results from the drug utilization studies of HES solutions for infusion together with the currently available data on benefits and risks from clinical trials and observational studies and feedback received from stakeholders and experts.
Results from these studies show that the implemented restrictions have not been adhered to in practice. Non- adherence to the revised product information was reported to range from 67% - 77%, including 20 – 34% non- adherence to contraindications. On an average, across all EU Member States included in the study, 9% of patients exposed to HES solutions for infusion were critically ill, 5-8% patients had renal impairment and 3- % had sepsis. This raised serious concerns as use of medicinal products containing HES, in patient populations which are contraindicated - those who are critically ill, those with renal impairment, or with sepsis, is associated with a scientifically well-established risk for serious harm including mortality. Recent estimations of patient exposure across the EU indicate approximately 750 000 – 1.5 million patients exposed yearly48.
Based on this review, the PRAC has concluded that the restrictions introduced in 2013 have not been sufficiently effective. The Committee explored the possibility of introducing additional measures but concluded that such measures would be ineffective or insufficient. In view of the serious risks that certain patient populations are exposed to, the PRAChas recommended suspension of the marketing authorizations for HES solutions. Alternative treatment options are available.
PRAC recommendations endorsed by CMDh
The PRAC recommendation was sent to the Coordination Group for Mutual Recognition and Decentralised Procedures–Human (CMDh) for consideration at its meeting held from January 22-25, 2018.
On January 26, 2018, the CMDh endorsed the recommendation to suspend the marketing authorizations of hydroxyethyl-starch (HES) solutions for infusion across the European Union49. The CMDh agreed with the PRAC recommendation that, in view of the serious risks that certain patients are exposed to, HES solutions for infusion should be suspended. Alternative treatment options are available. The CMDh position will now be sent to the European Commission, which will take an EU-wide legally binding decision.
About HES (HydroxyEthyl Starch)
HES solution for infusion is used for the management of hypovolaemia (low blood volume) caused by acute blood loss, where treatment with alternative infusion solutions known as 'crystalloids' alone is not considered to be sufficient. It is given by infusion (drip) into a vein and is used as blood volume expander to prevent shock following acute bleeding. It belongs to the class of medicines known as colloids. Besides blood products, there are two types of medicines used for plasma volume replacement: crystalloids and colloids. Colloids contain large molecules such as starch, whereas crystalloids, such as saline or Ringer's solutions, are pure electrolyte solutions.
About the Procedure
The review of HES solutions for infusion was initiated on October 17, 2017, at the request of the Swedish Medical Products Agency, under Article 107i of Directive 2001/83/EC.
Article 107i procedures:
This type of procedure is triggered when a Member State or the European Commission consider that urgent action is necessary because of a safety issue. Situations that fall under this procedure include consideration for suspension or revocation of the marketing authorization for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorization such as deletion of indications, reduction of the recommended dose or new contraindications. The procedure is also applicable in case of a safety issue with a class of medicines50.
Conclusion:
The suspension of Hydroxyethyl-Starch solutions across European Union is due to serious risks of kidney injury and death in certain patient populations. The safety recommendations from the agency will now be sent to the European Commission, which will take an EU-wide legally binding decision on this matter.
Footnotes
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