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

Current status:
Opinion provided by Committee for Medicinal Products for Human Use

Overview

Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities

Companies that make sartan blood pressure medicines (also known as angiotensin II receptor blockers) are being required to review their manufacturing processes so that they do not produce nitrosamine impurities.

Companies will have a transition period to make any necessary changes, during which strict temporary limits on levels of these impurities will apply. After this period, companies will have to demonstrate that their sartan products have no quantifiable levels of these impurities before they can be used in the EU.

These recommendations follow EMA’s review of N-nitrosodimethylamine (NDMA) and N‑nitrosodiethylamine (NDEA), which are classified as probable human carcinogens (substances that could cause cancer) and have been detected in some sartan medicines.

For the vast majority of sartan medicines, impurities were either not found or were present at very low levels.

The review estimated the highest possible cancer risk with these impurities. It concluded that if 100,000 patients took valsartan from Zhejiang Huahai (where the highest levels of impurities were found) every day for 6 years at the highest dose, there could be 22 extra cases of cancer due to NDMA over the lifetimes of those 100,000 patients. NDEA in these medicines could lead to 8 extra cases in 100,000 patients taking the medicine at the highest dose every day for 4 years.1

The estimates have been extrapolated from animal studies and are very low compared with the lifetime risk of cancer in the EU (1 in 2).


1 The 6 and 4 years refer to the duration of time NDMA and NDEA are believed to have been present in valsartan from Zhejiang Huahai.

How impurities came to be present in sartans

Before June 2018, NDMA and NDEA were not among the impurities identified in sartan medicines and were therefore not detected by routine tests.

It is now known that these impurities can form during the production of sartans that contain a specific ring structure known as a tetrazole ring under certain conditions and when certain solvents, reagents, and other raw materials are used. In addition, it is possible that impurities were present in some sartans because manufacturers had inadvertently used contaminated equipment or reagents in the manufacturing process.

Companies must now take measures to avoid the presence of these impurities and carry out rigorous testing of their products.

Testing during and after the transition period

While the goal is to have no quantifiable nitrosamine impurities in sartans, interim limits have been set for NDMA and NDEA in line with current international guidelines.

Products containing either impurity above these limits or products containing both nitrosamines at whatever level will not be allowed in the EU.

The limits are based on the maximum daily intake for each impurity derived from animal studies: 96.0 nanograms for NDMA and 26.5 nanograms for NDEA. Dividing these by the maximum daily dose for each active substance gives the limit in parts per million (see Table 1).

The transition period, which will last for 2 years, will allow companies to make the necessary changes to their manufacturing processes and to put in place testing regimes able to detect the smallest amounts of these impurities.

After the transition period, companies must exclude the presence of even lower levels of NDEA or NDMA in their products (< 0.03 parts per million).

Table 1. Temporary limits for NDMA and NDEA impurities

 

NDMA

NDEA

Active substance (max daily dose)

Maximum daily intake (ng)

Limit (ppm)

Maximum daily intake (ng)

Limit (ppm)

Candesartan (32 mg)

96.0

3.000

26.5

0.820

Irbesartan (300 mg)

96.0

0.320

26.5

0.088

Losartan (150 mg)

96.0

0.640

26.5

0.177

Olmesartan (40 mg)

96.0

2.400

26.5

0.663

Valsartan (320 mg)

96.0

0.300

26.5

0.082

Investigation continuing

EMA and national authorities will continue investigating the presence of nitrosamine impurities in medicines, including other impurities such as N-nitrosoethylisopropylamine (EIPNA), N-nitrosodiisopropylamine (DIPNA) and N-nitroso-N-methylamino butyric acid (NMBA).

Authorities in the EU will also consider the lessons that can be learned from this review to improve the way impurities in medicines are identified and handled.

EMA’s recommendations for NDMA and NDEA will now be sent to the European Commission for a legally binding decision. An assessment report with further details about the review will be published shortly on EMA’s website.


2 International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidance: M7(R1).

Key facts

Approved name
Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group
International non-proprietary name (INN) or common name

valsartan, candesartan, irbesartan, losartan and 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
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.

Status
Opinion provided by Committee for Medicinal Products for Human Use
Opinion date
31/01/2019

All documents

Document description

  • Questions and answers (Q&A) - easy-to-understand summary of key issues and Committee conclusions
  • Summary of Opinion - contains the CHMP opinion of the referred medicine(s)
  • List of the medicines affected by the referral (Annex I)
  • Scientific conclusions of the Committee (Annex II)

The following two documents are sometimes available:

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