Renin-angiotensin-system (RAS)-acting agents

  • Procedure started
  • Under evaluation
  • PRAC recommendation
  • CHMP opinion
  • European Commission final decision
Current status:
European Commission final decision

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.


1 European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines.

Key facts

About this medicine
Approved name
Renin-angiotensin-system (RAS)-acting agents
International non-proprietary name (INN) or common name
  • captopril
  • imidapril
  • zofenopril
  • candesartan
  • delapril
  • telmisartan
  • aliskiren
  • moexipril
  • enalapril
  • valsartan
  • fosinopril
  • irbesartan
  • perindopril
  • quinapril
  • ramipril
  • eprosartan
  • olmesartan
  • trandolapril
  • losartan
  • azilsartan
  • lisinopril
  • spirapril
  • benazepril
  • cilazapril
Associated names
  • Tolucombi
  • Telmisartan Teva
  • Telmisartan Teva Pharma
  • Tolura
  • Onduarp
  • Twynsta
  • Actelsar HCT
  • Kinzalkomb
  • MicardisPlus
  • PritorPlus
  • Copalia HCT
  • Dafiro HCT
  • Exforge HCT
  • Rasilamlo
  • Rasilez
  • Rasilez HCT
  • Rasitrio
  • Edarbi
  • Ipreziv
  • Aprovel
  • Ifirmasta (previously Irbesartan Krka)
  • Irbesartan Teva
  • Irbesartan Zentiva (previously Irbesartan Winthrop)
  • Karvea
  • Sabervel
  • CoAprovel
  • Ifirmacombi
  • Irbesartan/Hydrochlorothiazide Teva
  • Irbesartan Hydrochlorothiazide Zentiva (previously Irbesartan Hydrochlorothiazide Winthrop)
  • Karvezide
  • Kinzalmono (previously Telmisartan Boehringer Ingelheim Pharma KG)
  • Micardis
  • Pritor
  • Telmisartan Actavis
Class
angiotensin-receptor blockers (ARBs), angiotensin-converting-enzyme inhibitors (ACEIs), direct renin inhibitors (aliskiren)
About this procedure
Current status
European Commission final decision
Reference number
EMEA/H/A-31/1370
Type
Article 31 referrals

This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Decision making model
PRAC-CHMP-EC
Authorisation model
Centrally and nationally authorised products (mixed)
Key dates and outcomes
Procedure start date
16/05/2013
PRAC recommendation date
10/04/2014
CHMP opinion/CMDh position date
22/05/2014
EC decision date
04/09/2014
Outcome
Risk minimisation measures

All documents

Procedure started

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Opinion provided by Committee for Medicinal Products for Human Use

European Commission final decision

  • List item

    Restriction of combined use of medicines affecting the renin-angiotensin system (RAS) (PDF/84.41 KB)


    First published: 08/10/2014
    Last updated: 08/10/2014
    EMA/554928/2014

  • List item

    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

  • List item

    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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