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

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 Nitrosamine impurities - Final outcome of Article 5(3) 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.

More about the medicine

The review of sartans concerned candesartan, irbesartan, losartan, olmesartan and valsartan, which belong to a class of medicines called sartans (also known as angiotensin-II-receptor antagonists).

These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities. Other sartan medicines which do not have this ring, such as azilsartan, eprosartan and telmisartan, were not included in this review but are covered by the Nitrosamine impurities - Final outcome of Article 5(3) of other medicines.

Sartans are used to treat patients with hypertension (high blood pressure) and those with certain heart or kidney diseases. They work by blocking the action of angiotensin II, a hormone that constricts blood vessels and causes blood pressure to rise.

More about the procedure

A review of valsartan medicines started on 5 July 2018 at the request of European Commission, under Article 31 of Directive 2001/83/EC. On 20 September 2018, the review was extended to include medicines containing candesartan, irbesartan, losartan and olmesartan.

The review was carried out by EMA’s Committee for Medicinal Products for Human Use (CHMP), which is responsible for questions concerning medicines for human use and adopted the Agency’s opinion. The CHMP opinion was forwarded to the European Commission, which issued legally binding decisions between 2 and 17 April 2019 that are applicable in all EU Member States.

The recommendations from this review have now been updated and aligned with those of the Article 5 (3) procedure, which concluded on June 2020. The updated recommendations were also forwarded to the European Commission, which issued final legally binding decisions between 12 February and 19 February 2021 applicable in all EU Member States.

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

Reference Number: EMA/134937/2021

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

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

Adopted Reference Number: EMA/47245/2021

Angiotensin-II-receptor antagonists (sartans) Article 31 referral - CHMP assessment report

Adopted Reference Number: EMA/217823/2019

Procedure started

Valsartan Art 31 - list NAPs and CAPs

Reference Number: EMA/480845/2018 rev2

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

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

Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Notification

Under evaluation

Olmesartan Art 31 - list of NAPs

Reference Number: EMA/662763/2018

Losartan Art 31 - list of NAPs

Reference Number: EMA/662730/2018

Irbesartan Art 31 - list of NAPs and CAPs

Reference Number: EMA/662946/2018

Candesartan Art 31 - list of NAPs

Reference Number: EMA/662693/2018

Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Notification (extension of scope)

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

Reference Number: EMA/CHMP/668547/2018

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

Reference Number: EMA/CHMP/668548/2018

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

Reference Number: EMA/643116/2018

Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Timetable for the procedure

Reference Number: EMA/CHMP/466973/2018 rev.2

Opinion provided by Committee for Medicinal Products for human Use

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

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

Reference Number: EMA/CHMP/525148/2020

Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Annex I

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

Reference Number: EMA/248364/2019 Rev.1

European Commission final decision

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

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

Angiotensin-II-receptor antagonists (sartans) Article 31 referral - Annex II

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

Reference Number: EMA/134937/2021

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.