Hydroxyethyl starch solutions for infusion - referral

Current status

European Commission final decision

Overview

 

Hydroxyethyl-starch solutions (HES) no longer to be used in patients with sepsis or burn injuries or in critically ill patients

HES will be available in restricted patient populations

On 23 October 2013, the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)*, endorsed by majority the recommendations of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC), which concluded that HES solutions must no longer be used to treat patients with sepsis (bacterial infection in the blood) or burn injuries or critically ill patients because of an increased risk of kidney injury and mortality.

HES solutions may continue to be used in patients to treat hypovolaemia (low blood volume) caused by acute (sudden) blood loss, where treatment with alternative infusions solutions known as 'crystalloids' alone are not considered to be sufficient. In order to minimise potential risks in these patients, HES solutions should not be used for more than 24 hours and patients' kidney function should be monitored after HES administration. In addition to updating the product information, further studies should be carried out on the use of these medicines in elective surgery and trauma patients.

The review of HES solutions was carried out by the PRAC following the publication of studies showing an increased risk of mortality in patients with sepsis1,2 and an increased risk of kidney injury requiring dialysis in critically ill patients1,2,3 following treatment with HES solutions.

As the CMDh position was adopted by majority vote, it was sent to the European Commission, which endorsed it and, on 19 December 2013, adopted a final legally binding decision valid throughout the European Union (EU).

---

Information for patients

• Because of the risk of kidney injury and mortality, HES solutions must no longer be used in patients with sepsis (bacterial infection in the blood) or burn injuries or critically ill patients.
• HES solutions may continue to be used to treat hypovolaemia (low blood volume) caused by acute (sudden) blood loss. However, the doctor should monitor the patient's kidney function after HES administration.
• Patients who have any questions or concerns should speak to the treating doctor, pharmacist or nurse.

Information for healthcare professionals

• Because of the risk of kidney injury and mortality, HES solutions must no longer be used in patients with sepsis, burn injuries or critically ill patients.
• HES solutions should only be used for the treatment of hypovolaemia due to acute blood loss when crystalloids alone are not considered sufficient.
• There is a lack of robust long-term safety data in patients undergoing surgical procedures and in patients with trauma. The expected benefit of treatment should be carefully weighed against the uncertainties with regard to long-term safety, and other available treatment options should be considered. Additional studies will be performed with HES solutions in patients with trauma and in elective surgery.
• HES solutions should be used at the lowest effective dose for the shortest period of time. Treatment should be guided by continuous haemodynamic monitoring so that the infusion is stopped as soon as appropriate haemodynamic goals have been achieved.
• HES solutions are now contraindicated in patients with renal impairment or renal replacement therapy. The use of HES must be discontinued at the first sign of renal injury. An increased need for renal replacement therapy has been reported up to 90 days after HES administration. Patients' kidney function should be monitored after HES administration.
• HES solutions are contraindicated in severe coagulopathy. HES solutions should be discontinued at the first sign of coagulopathy. Blood coagulation parameters should be monitored carefully in case of repeated administration.
  These recommendations are based on a review of all available safety and efficacy data, including recent data4,5,6, from clinical studies, meta-analyses and post-marketing experience. Healthcare professionals have been informed in writing of the outcome of the review and the changes to the use of HES solutions.

References:

1. Perner A, Haase N, Guttormsen AB et al. Hydroxyethyl starch 130/0.42 versus ringer's acetate in severe sepsis. N Engl J Med 2012;367(2):124-34
2. Brunkhorst FM, Engel C, Bloos F et al. Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis. N Engl J Med 2008; 358(2):125-39
3. Myburgh J, Finder S, Bellomo R et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367:1901-11
4. Annane D. et al. CRISTAL: Colloids Compared to Crystalloids in Fluid Resuscitation of Critically Ill Patients: A Multinational Randomised Controlled Trial. NCT00318942. Available on: http://clinicaltrials.gov/ct2/show/NCT00318942
5. Siegemund M. Firstly presented at European Society of Anaesthesiology conference 2012. Basel Study for Evaluation of Starch (130;0.4) Infusion in Septic Patients:BaSES (130;0.4) Trial, listed at http://clinicaltrials.gov/show/NCT00273728
6. Rational Fluid Therapy in Germany (RaFTinG). Available on ClinicalTrials.gov (NCT01122277) last updated on 07 July 2011: http://clinicaltrials.gov/ct2/show/NCT01122277?term=NCT01122277&rank=1

More about the medicine

Infusion solutions containing HES are frequently used for volume replacement and belong to the class known as colloids. There are two main types of medicines used for volume replacement: crystalloids and colloids. Colloids contain large molecules such as starch, whereas crystalloids, such as saline (salt) solutions or Ringer's acetate, contain smaller molecules.

In the EU, HES-containing solutions for infusion have been approved via national procedures and are available in all Member States under various trade names.

More about the procedure

A review of HES solutions for infusion was initiated on 29 November 2012 at the request of the German medicines agency, under Article 31 of Directive 2001/83/EC. This review, which had been carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), concluded on 13 June 2013, but some of the marketing authorisation holders requested a re-examination.

While the re-examination was ongoing, some Member States decided to suspend or limit the marketing or use of these medicines in their territories. In accordance with EU legislation, this type of action required that an EU review procedure be carried out. Consequently, on 27 June 2013, the UK triggered an EU review of HES solutions under Article 107i of Directive 2001/83/EC. This review procedure ran in parallel with the re-examination of the PRAC's June 2013 recommendation and both procedures were finalised on 10 October 2013. For the re-examination procedure the PRAC confirmed its previous position. However, new evidence was considered in the parallel Article 107i procedure and this was the basis for the PRAC's final recommendation on the use of HES solutions.

As HES-containing solutions for infusion are all authorised nationally, the PRAC recommendations were forwarded to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a final position. The CMDh, a body representing EU Member States, is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

As the CMDh position was adopted by majority vote, it was sent sent to the European Commission, which endorsed it and adopted an EU-wide legally binding decision on 19 December 2013.

Hydroxyethyl-starch solutions (HES) no longer to be used in patients with sepsis or burn injuries or in critically ill patients

Reference Number: EMA/809470/2013

Key facts

About this medicine

• Approved name:
  Hydroxyethyl starch solutions for infusion
• International non-proprietary name (INN) or common name:
  hydroxyethyl starch

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-107i/1376
• Type:
  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 authorisation for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorisation 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 medicines.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  11/07/2013
• PRAC recommendation date:
  10/10/2013
• CHMP opinion date:
  23/10/2013
• EC decision date:
  19/12/2013
• Outcome:
  Risk minimisation measures

Data submission

The Agency invites all stakeholders (e.g. healthcare professionals, patients' organisations and the general public) to submit data relevant to this procedure. This is in accordance with Article 107j(1) of Directive 2001/83/EC.

The following requirements apply for data to be considered:

• Submissions must be accompanied by the submission form below, with all fields completed. The form must be used with Adobe Reader X+ or Adobe Acrobat X+:
  Hydroxyethyl starch Article-107i procedure - Stakeholders' submission form
• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions:
  Hydroxyethyl starch Article-107i procedure - PRAC list of questions to be addressed by the stakeholders
• The submission of all data should take place by 5 August 2013.

Submitting data

Send the completed form electronically to the stakeholders' submission inbox ([e-mail]). Specify the name of the medicine in the subject line of the e-mail.

The size of the submission file should not exceed 25 MB. If your attempt to send your data package to the dedicated e-mail address is unsuccessful, please use alternative submission means.

It is of the utmost importance that data are provided promptly, to avoid undermining the safety review. Due to the urgent nature of the procedure, you are strongly advised to submit your data in English.

Protection of personal data

Personal data submitted are subject to data-protection rules as established by Regulation (EC) 45/2001. They will be treated in accordance with the specific

.

 

Treatment and publication of data

Data submitted will be received and recorded by the Agency.

The Agency will prepare a list of all submissions received, which will be published as an annex to the PRAC assessment report for transparency purposes and public awareness.

Please note that all data submitted in the context of this procedure may be shared and disclosed in the public domain.

All documents

Procedure started

Hydroxyethyl starch Article-107i procedure - Review started

Hydroxyethyl starch Article-107i procedure - PRAC list of questions to be addressed by the stakeholders

Reference Number: EMA/PRAC/411967/2013

Hydroxyethyl starch Article-107i procedure - Annex I

Hydroxyethyl starch Article-107i procedure - Rationale for triggering

Hydroxyethyl starch Article-107i procedure - PRAC list of questions

Hydroxyethyl starch Article-107i procedure - Timetable for the procedure

Hydroxyethyl starch Article-107i procedure - Notification

Hydroxyethyl starch Article-107i procedure - Stakeholders' submission form

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Hydroxyethyl starch Article-107i procedure - PRAC assessment report

AdoptedReference Number: EMA/667553/2013

PRAC confirms that hydroxyethyl-starch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients

Reference Number: EMA/606303/2013

Position provided by CMDh

Hydroxyethyl starch Article-107i procedure - Annex I

Hydroxyethyl starch Article-107i procedure - Annex II

Hydroxyethyl starch Article-107i procedure - CMDh divergent position

Hydroxyethyl starch Article-107i procedure - Annex IV

Hydroxyethyl starch Article-107i procedure - Annex III

Hydroxyethyl-starch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients – CMDh endorses PRAC recommendations

Reference Number: EMA/640658/2013

European Commission final decision

Hydroxyethyl-starch solutions (HES) no longer to be used in patients with sepsis or burn injuries or in critically ill patients

Reference Number: EMA/809470/2013

Hydroxyethyl-starch solutions (HES) no longer to be used in patients with sepsis or burn injuries or in critically ill patients

Reference Number: EMA/809470/2013

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.