Hydroxyethyl starch (HES) containing medicinal products - referral

Current status

European Commission final decision

Overview

Hydroxyethyl starch solutions: CMDh introduces new measures to protect patients

Medicines to remain on the market provided that training, controlled access and warnings on the packaging are implemented

The CMDh¹ has decided that hydroxyethyl starch (HES) solutions for infusion should remain on the market provided that a combination of additional measures to protect patients is implemented. This follows further reflection, in consultation with EU Member States, on whether it would be feasible to introduce new measures that would effectively reduce the risks with these medicines.

HES solutions for infusion are used to replace plasma volume following acute (sudden) blood loss, where treatment with alternative products known as 'crystalloids' alone is not considered sufficient.

In January 2018, EMA's safety committee PRAC recommended suspending the marketing authorisations of these medicines because they continued to be used in critically ill patients and patients with sepsis despite restrictions introduced in 2013 due to the risk of kidney injury and death in these patients.

The CMDh agreed with the PRAC's assessment of the serious risks in critically ill patients and patients with sepsis. However, the CMDh gave further consideration to the place of HES in the clinical practice of some countries, noted that previous risk minimisation measures had some effect, and considered that a combination of new risk minimisation measures would effectively ensure that HES solutions are not used in patients at risk.

The new measures are:

• the implementation of a controlled access programme by the companies holding the marketing authorisations to ensure that only accredited hospitals will be supplied with these medicines. The accreditation would require that relevant healthcare professionals receive training on the safe use of HES solutions for infusion. Further details about the training and the controlled access programme will be provided to hospitals and healthcare professionals in due time;
• warnings in the medicines' packaging and at the top of the summaries of product characteristics (SmPCs) reminding healthcare professionals that these medicines must not be used in patients with sepsis or kidney impairment or in critically ill patients;
• writing directly to healthcare professionals to ensure that they are fully aware of the conditions of use of the medicines and the groups of patients that must not receive them due to an increased risk of kidney injury and death.

The CMDh also requested marketing authorisation holders to conduct studies to check that only patients who should be treated with these medicines are receiving them. This is in addition to ongoing studies on the benefits and risks of HES solutions in patients with trauma and those undergoing elective surgery.

As the CMDh position was adopted by majority vote, the CMDh position was sent back to the European Commission, which took an EU-wide legally binding decision on 17 July 2018.

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¹The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

Information for patients

• HES solutions for infusion are replacement fluids given to patients who have lost blood following injury or surgery.
• EMA is recommending these medicines be removed from the EU market in view of the serious risks (kidney injury and death) in certain patients (for example those who are very ill or have blood poisoning).
• Other treatment options are available.

Information for healthcare professionals

• The marketing authorisations of HES solutions for infusion are being recommended for suspension because of the risk of kidney injury and death in certain patient populations, including critically ill patients and patients with sepsis.
• Despite the introduction of contraindications and warnings in 2013 and further measures in 2018, the latest drug utilisation study shows that HES solutions for infusion continue to be used outside the recommendations included in the product information, which still exposes certain patient populations to serious risks.
• As no other feasible and effective measures to minimise the risks could be identified, EMA is recommending HES solutions for infusion be suspended from the EU market to protect patient health.
• Treatment alternatives are available and should be selected according to relevant clinical guidelines.

If the suspension is confirmed by the European Commission, a direct healthcare professional communication (DHPC) will be sent to relevant healthcare professionals in due course, and published on a dedicated page on the EMA website.

More about the medicine

HES solutions for infusion were authorised 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.

HES solutions belong to a 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 are solutions of low molecular weight substances and include saline and Ringer’s solutions.

In the EU, HES solutions for infusion were authorised via national procedures and are available in several Member States under various trade names.

More about the procedure

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC), responsible for the evaluation of safety issues for human medicines, issued its recommendation after reviewing the results of a drug utilisation study that was requested as part of additional risk minimisation measures resulting from an Article 107i referral procedure concluded in 2018.

The PRAC recommendation was sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). The CMDh, also taking into consideration additional information from the marketing authorisation holders for HES solutions for infusion and external parties, endorsed the PRAC recommendation and adopted its position.

As the CMDh position was adopted by majority vote, it will now be sent to the European Commission, which will take an EU-wide legally binding decision in due course.

The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

Hydroxyethyl starch Article-107i referral - Hydroxyethyl starch solutions: CMDh introduces new measures to protect patients (revised position)

Reference Number: EMA/498908/2018

Key facts

About this medicine

• Approved name:
  Hydroxyethyl starch (HES) containing medicinal products
• 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/1457
• 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:
  26/10/2017
• PRAC recommendation date:
  12/01/2018
• CMDh position date:
  26/10/2017
• EC decision date:
  17/07/2018
• Outcome:
  Risk minimisation measures

Data submission

The Agency invites all stakeholders (e.g. healthcare professionals, patients' organisations, 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 referral - Stakeholder's submission form

• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions:

  Hydroxyethyl starch Article-107i referral - PRAC List of questions to be addressed by the stakeholders

• The submission of all data should take place by 16 November 2017.

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. 

 

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 referral - PRAC List of questions to be addressed by the stakeholders

Hydroxyethyl starch Article-107i referral - Rationale for triggering

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

Reference Number: EMA/PRAC/691228/2017

Hydroxyethyl starch Article-107i referral - Review started

Reference Number: EMA/697706/2017

Hydroxyethyl starch Article-107i referral - Notification

Hydroxyethyl starch Article-107i referral - Stakeholder's submission form

Reference Number: EMEA/H/A-107i/1457

Under evaluation

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

Reference Number: EMA/PRAC/691227/2017 Rev.1

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Hydroxyethyl starch Article-107i referral - Summary of PRAC recommendation

AdoptedReference Number: EMA/4068/2018

Position provided by CMDh

Hydroxyethyl starch Article-107i referral - CMDh endorses PRAC recommendation

Reference Number: EMA/35795/2018

Hydroxyethyl starch Article-107i referral - Hydroxyethyl starch solutions: CMDh introduces new measures to protect patients (revised position)

Reference Number: EMA/498908/2018

European Commission final decision

Hydroxyethyl starch Article-107i referral - Annex II

Hydroxyethyl starch Article-107i referral - Annex IV

Hydroxyethyl starch Article-107i referral - Assessment report

AdoptedReference Number: EMA/171888/2018

Hydroxyethyl starch Article-107i referral - CMDh divergent positions

Hydroxyethyl starch Article-107i referral - Annex III

Hydroxyethyl starch Article-107i referral - Annex I

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.