Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group

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

Overview

Nitrosamines: EMA aligns recommendations for sartans with those for other medicines

On 12 November 2020, EMA’s human medicines committee (CHMP) aligned recommendations for limiting nitrosamine impurities in sartan medicines with previous recommendations it issued for other classes of medicines.

The main change concerns the limits for nitrosamines, which previously applied to the active ingredients but will now apply instead to the finished products (e.g. tablets). These limits, based on internationally agreed standards (ICH M7(R1)), should ensure that the excess risk of cancer from nitrosamines in any sartan medicines is below 1 in 100,000 for a person taking the medicine for lifelong treatment.

In line with previous recommendations, companies should have appropriate control strategies to prevent or limit the presence of nitrosamine impurities as much as possible and, where necessary, improve their manufacturing processes. Companies should also evaluate the risk of nitrosamines being present in their medicines and carry out appropriate tests.

Nitrosamines are classified as probable human carcinogens (substances that could cause cancer). In the vast majority of sartan medicines, these impurities were either not found or were present at very low levels.

The CHMP concluded its review of sartan medicines in January 2019. The committee subsequently conducted a wider review, taking into account the experience from sartans and other medicines where nitrosamines were detected. The revised conditions companies need to fulfil for sartans brings them in line with those for other classes of medicines issued in June 2020.

EMA will continue working with national authorities and the European Commission to ensure that companies are taking all necessary measures. EMA will also continue its close cooperation with the European Directorate for the Quality of Medicines & HealthCare and international partner agencies.

Key facts

About this medicine
Approved name
Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group
International non-proprietary name (INN) or common name
  • valsartan
  • candesartan
  • irbesartan
  • losartan
  • olmesartan
Associated names
  • Karvezide
  • Karvea
  • Irbesartan/Hydrochlorothiazide Teva
  • Irbesartan Zentiva (previously Irbesartan Winthrop)
  • Irbesartan Teva
  • Irbesartan Hydrochlorothiazide Zentiva (previously Irbesartan Hydrochlorothiazide Winthrop)
  • Ifirmasta (previously Irbesartan Krka)
  • Ifirmacombi
  • Aprovel
  • Neparvis
  • Exforge
  • Exforge HCT
  • Entresto
  • Dafiro HCT
  • Dafiro
  • Copalia HCT
  • Copalia
  • Amlodipine / Valsartan Mylan
  • CoAprovel
Class
angiotensin-II-receptor antagonist
About this procedure
Current status
European Commission final decision
Reference number
EMEA/H/A-31/1471
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.

Authorisation model
Centrally and nationally authorised products (mixed)
Key dates and outcomes
CHMP opinion date
12/11/2020
EC decision date
19/02/2021

All documents

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - CHMP assessment report - Impact of the Article 5(3) scientific opinion on nitrosamines (PDF/362.31 KB)

    Adopted

    First published: 02/03/2021
    EMA/47245/2021

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Annex I (PDF/83.35 KB)


    First published: 17/05/2019

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - CHMP assessment report (PDF/531.32 KB)

    Adopted

    First published: 02/05/2019
    EMA/217823/2019

  • Procedure started

    Under evaluation

  • List item

    Olmesartan Art 31 - list of NAPs (PDF/1.89 MB)


    First published: 04/10/2018
    Last updated: 17/05/2019
    EMA/662763/2018

  • List item

    Losartan Art 31 - list of NAPs (PDF/1.73 MB)


    First published: 04/10/2018
    Last updated: 17/05/2019
    EMA/662730/2018

  • List item

    Irbesartan Art 31 - list of NAPs and CAPs (PDF/1.38 MB)


    First published: 04/10/2018
    Last updated: 17/05/2019
    EMA/662946/2018

  • List item

    Candesartan Art 31 - list of NAPs (PDF/1.66 MB)


    First published: 04/10/2018
    Last updated: 17/05/2019
    EMA/662693/2018

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Notification (extension of scope) (PDF/66.56 KB)


    First published: 04/10/2018

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - CHMP list of questions to be addressed by the marketing authorisation holders for valsartan-containing medicinal products (PDF/92.74 KB)


    First published: 04/10/2018
    EMA/CHMP/668547/2018

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - CHMP list of questions to be addressed by the API manufacturers for valsartan-containing medicinal products (PDF/92.74 KB)


    First published: 04/10/2018
    EMA/CHMP/668548/2018

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - EMA review of impurities in sartan medicines (PDF/66.76 KB)


    First published: 21/09/2018
    EMA/643116/2018

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Timetable for the procedure (PDF/74.28 KB)


    First published: 17/07/2018
    Last updated: 18/12/2018
    EMA/CHMP/466973/2018 rev.2

  • Opinion provided by Committee for Medicinal Products for Human Use

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Nitrosamines: EMA aligns recommendations for sartans with those for other medicines (PDF/117.21 KB)


    First published: 13/11/2020

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Timetable for the procedure - CHMP Opinion on the impact of the Article 5(3) referral on nitrosamines in human medicinal products on the referral (PDF/115.46 KB)


    First published: 20/10/2020
    EMA/CHMP/525148/2020

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities (PDF/99.94 KB)


    First published: 01/02/2019
    Last updated: 28/05/2019
    EMA/248364/2019 Rev.1

  • European Commission final decision

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Nitrosamines: EMA aligns recommendations for sartans with those for other medicines (PDF/142.85 KB)


    First published: 19/03/2021
    EMA/134937/2021

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral – Annex II – Impact of the Article 5(3) scientific opinion on nitrosamines (PDF/122.17 KB)


    First published: 19/03/2021

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral – Annex I – Impact of the Article 5(3) scientific opinion on nitrosamines (PDF/95.85 KB)


    First published: 19/03/2021

  • List item

    Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Annex II (PDF/59.81 KB)


    First published: 17/05/2019

  • 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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