Renin-angiotensin-system (RAS)-acting agents
- Procedure started
- Under evaluation
- PRAC recommendation
- CHMP opinion
- European Commission final decision
Table of contents
Overview
Restriction of combined use of medicines affecting the renin-angiotensin system (RAS)
On 23 May 2014 the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) endorsed restrictions on combining different classes of medicines that act on the renin-angiotensin system (RAS), a hormone system that controls blood pressure and the volume of fluids in the body.
These medicines (called RAS-acting agents) belong to three main classes: angiotensin-receptor blockers (ARBs, sometimes known as sartans), angiotensin-converting enzyme inhibitors (ACE-inhibitors) and direct renin inhibitors such as aliskiren. Combination of medicines from any two of these classes is not recommended and, in particular, patients with diabetes-related kidney problems (diabetic nephropathy) should not be given an ARB with an ACE-inhibitor.
Where combination of these medicines (dual blockade) is considered absolutely necessary, it must be carried out under specialist supervision with close monitoring of kidney function, fluid and salt balance and blood pressure. This would include the licensed use of the ARBs candesartan or valsartan as add-on therapy to ACE-inhibitors in patients with heart failure who require such a combination. The combination of aliskiren with an ARB or ACE-inhibitor is strictly contraindicated in those with kidney impairment or diabetes.
The CHMP opinion confirmed recommendations made by the Agency's Pharmacovigilance Risk Assessment Committee (PRAC) in April 2014, following assessment of evidence from several large studies in patients with various pre-existing heart and circulatory disorders, or with type 2 diabetes. These studies found that combination of an ARB with an ACE-inhibitor was associated with an increased risk of hyperkalaemia (increased potassium in the blood), kidney damage or low blood pressure compared with using either medicine alone. Furthermore, no significant benefits from dual blockade were seen in patients without heart failure and benefits were thought to outweigh risk only in a selected group of patients with heart failure in whom other treatments were unsuitable. This broad review of evidence relating to all RAS-acting agents supported the conclusions of a previous EMA review relating specifically to medicines containing aliskiren.1
The CHMP opinion was forwarded to the European Commission, which issued final decisions valid throughout the EU in September 2014.
Key facts
About this medicine
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Approved name |
Renin-angiotensin-system (RAS)-acting agents
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International non-proprietary name (INN) or common name |
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Associated names |
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Class |
angiotensin-receptor blockers (ARBs), angiotensin-converting-enzyme inhibitors (ACEIs), direct renin inhibitors (aliskiren)
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About this procedure
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Current status |
European Commission final decision
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Reference number |
EMEA/H/A-31/1370
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Type | |
Authorisation model |
Centrally and nationally authorised products (mixed)
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Decision making model |
PRAC-CHMP-EC
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Key dates and outcomes
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Procedure start date |
16/05/2013
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PRAC recommendation date |
10/04/2014
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CHMP opinion/CMDh position date |
22/05/2014
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EC decision date |
04/09/2014
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Outcome |
Risk minimisation measures
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All documents
Procedure started
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - Annex I (PDF/21.1 MB)
First published: 14/06/2013
Last updated: 14/07/2014
EMA/353230/2013
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - Notification (PDF/140.63 KB)
First published: 17/05/2013
Last updated: 17/05/2013
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - Timetable for the procedure (PDF/64.7 KB)
First published: 17/05/2013
Last updated: 07/03/2014
EMA/PRAC/290691/2013 rev. 3
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - PRAC list of questions (PDF/76.37 KB)
First published: 17/05/2013
Last updated: 17/05/2013
EMA/PRAC/290692/2013
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - Review started (PDF/65.7 KB)
First published: 17/05/2013
Last updated: 17/05/2013
EMA/291202/2013
Recommendation provided by Pharmacovigilance Risk Assessment Committee
Opinion provided by Committee for Medicinal Products for Human Use
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - Assessment report (PDF/278.67 KB)
First published: 05/06/2014
Last updated: 05/06/2014
EMA/PRAC/294920/2014
Combined use of medicines affecting the renin-angiotensin system (RAS) to be restricted – CHMP endorses PRAC recommendation (PDF/83.26 KB)
First published: 23/05/2014
Last updated: 23/05/2014
EMA/294911/2014
European Commission final decision
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - Scientific conclusion - Annex I (PDF/54.97 KB)
First published: 08/10/2014
Last updated: 08/10/2014
Renin-angiotensin-system (RAS)-acting agents Article-31 referral - Annex II (PDF/152 KB)
First published: 23/05/2014
Last updated: 08/10/2014
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.
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