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
  • Rasilamlo
  • Rasilez
  • Rasilez HCT
  • Rasitrio
  • Edarbi
  • Ipreziv
  • Aprovel
  • Ifirmasta
  • Irbesartan Teva
  • Irbesartan Zentiva
  • Karvea
  • Sabervel
  • CoAprovel
  • Ifirmacombi
  • Irbesartan Hydrochlorothiazide Teva
  • Irbesartan Hydrochlorothiazide Zentiva
  • Karvezide
  • Kinzalmono
  • 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

    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 - Annex II (PDF/152 KB)


    First published: 23/05/2014
    Last updated: 08/10/2014

  • Document description

    • Annex I - List of the medicines affected by the referral
    • Annex II - Scientific conclusions of the CHMP or CMDh
    • Annex III - Changes to the summary of product characteristics, labelling or package leaflet - available when the CHMP or CMDh recommends changes to the product information. Also includes conditions for lifting of suspensions, if applicable
    • Annex IV - Conditions of the marketing authorisation - available when the CHMP or CMDh recommends other measures to be taken for the marketing authorisation such as safety measures or additional studies
    • Notification - A letter from a Member State, the European Commission or a marketing-authorisation holder requesting the initiation of a referral procedure
    • Rationale for triggering - Background provided by the party triggering the referral explaining the issues leading to the initiation of the procedure
    • PRAC list of questions - Questions agreed by the PRAC requesting further information to evaluate the issues identified
    • PRAC timetable - Timeframe agreed by the PRAC to receive information, assess the issues and adopt a recommendation
    • PRAC / CHMP or CMDh assessment report - The assessment and conclusions of the PRAC and CHMP or CMDh on the issues investigated

    How useful was this page?

    Add your rating