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Valsartan / sartan-containing drugs: Pharmaceutical companies should review manufacturing processes to avoid the occurrence of nitrosamine-containing impurities

Safety information | Medicinal products for human use | 02/14/2019

Action at EU level

Pharmaceutical companies that make sartan blood pressure drugs (also known as angiotensin II receptor blockers) need to review their manufacturing processes to ensure that nitrosamine-containing contaminants are avoided in the future. The pharmaceutical companies are given a transition period to make any necessary changes. During this phase, strict temporary limit values ​​apply to these impurities. After this period, companies must demonstrate that their sartan-containing medicines no longer contain any quantifiable amounts of these impurities before they can be used in the EU.

These recommendations follow a risk assessment process carried out by the European Medicines Agency (EMA) on the contamination of some sartans with N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), which have been classified as likely human carcinogens (substances that could cause cancer) . For the vast majority of all sartan-containing drugs, however, these impurities were not detectable or were only present in very small amounts.

In the risk assessment process, an assessment of the highest possible cancer risk was carried out. This estimate showed that if 100,000 patients had taken NDMA-contaminated valsartan from Zhejiang Huahai (the manufacturing site where the highest levels of contaminants were found) every day for 6 years at the highest dose, 22 additional cancer cases could occur over the lifetime of these 100,000 Patients arise. The presence of NDEA in these drugs could also lead to 8 additional cancer cases in 100,000 patients if they had taken the drug at the highest daily dose for 4 years.[1]

The estimates were extrapolated from animal experiments and are very low compared to the normal lifetime risk of developing cancer in the EU (one case per two people).

How the sartans got contaminated

Before June 2018, NDMA and NDEA were not among the contaminants identified in sartans and therefore could not be detected by routine tests.

It is now known that these impurities can form during the production of those sartans with a specific ring structure, a so-called tetrazole ring, under certain conditions and when certain solvents, reagents and other starting materials are used. Additionally, it is possible that contaminants were already present in some sartans due to the fact that manufacturers accidentally used contaminated equipment or reagents in the manufacturing process.

Pharmaceutical companies must now take steps to avoid the presence of these contaminants and subject their medicines to strict controls.

Checks during and after the transition period

While the goal is to no longer have quantifiable amounts of nitrosamine contaminants in sartans, provisional limit values ​​for NDMA and NDEA have been set for the transition period in accordance with current international guidelines.[2]

Medicines that either contain impurities above these limit values ​​or medicinal products that contain both nitrosamines - regardless of the amount - will no longer be marketable in the EU in future.

The limit values ​​are based on maximum daily doses derived from animal experiments: 96.0 nanograms for NDMA and 26.5 nanograms for NDEA. If you divide this amount by the maximum daily dose for each active ingredient, the limit value results in parts per million (ppm) (see Table 1).

The transition period of two years will allow pharmaceutical companies to make the necessary changes in their manufacturing processes and introduce testing procedures that are able to detect minute levels of these impurities.

After this transition period, pharmaceutical companies must then rule out the presence of even lower NDEA or NDMA values ​​in their drugs (<0.03 ppm).

 

 
NDMA

NDEA
Active substance (maximum daily dose)Maximum daily intake (ng)Limit value (ppm)Maximum daily intake (ng)Limit value (ppm)
Candesartan (32 mg)96.03.00026.50.820
Irbesartan (300 mg)96.00.32026.50.088
Losartan (150 mg)96.00.64026.50.177
Olmesartan (40 mg)96.02.40026.50.663
Valsartan (320 mg)96.00.30026.50.082

The investigation continues

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

Competent authorities in the EU will also take appropriate action from the reviews to improve the way in which contaminants in medicines are identified and treated.

The EMA's recommendations on NDMA and NDEA impurities are forwarded to the European Commission for a legally binding decision. An assessment report detailing this review will be published on the EMA website shortly.

Situation in Austria

A large number of medicinal specialties with the following sartan active ingredients are approved in Austria:

An exact list of the products approved in Austria can be made by entering the active ingredient on this page or in the medicinal specialties register:

https://aspregister.basg.gv.at

Recommendations of the BASG

Recommendations for users:

  • Nitrosamines are potent carcinogens in animals and are considered likely carcinogens in humans.
  • These impurities can form during the production of sartans which contain a tetrazole ring, if certain reaction conditions are present or if contaminated materials are used.
  • For NDMA, the critical step is the use of dimethylamine (DMA) in the synthesis, which forms the impurity in the presence of nitrites, usually under acidic conditions. A similar synthetic step - with diethylamine (DEA) - leads to the formation of NDEA.
  • Strict control procedures have been put in place to ensure that drugs containing sartan are reasonably safe.
  • Manufacturers must now review their manufacturing processes in order to avoid the formation of nitrosamines.
  • Should further recalls or other measures be necessary, the national authorities will inform you of the measures to be taken.

Recommendations for patients:

  • There is a very small risk that nitrosamine-containing impurities, in the amounts found in some sartan medicines, can cause cancer in humans.
  • Since the impurities were first detected in some sartan-containing drugs, the regulatory authorities in the EU have been working to protect the health of patients as well as possible. After the tests, some affected drugs were recalled from pharmacies and are no longer used in the EU.
  • The EMA is now taking further measures to prevent such impurities from being contained in batches of sartan-containing drugs in the future.
  • Strict control procedures ensure that drugs containing sartan are sufficiently safe.
  • Patients taking drugs containing valsartan should not stop taking the drug without consulting their doctor.
  • If you have any questions about your current medicine or about a medicine you have taken in the past, ask your doctor or pharmacist.

More about the medicines

The risk assessment procedure concerns the sartan-containing active substances candesartan, irbesartan, losartan, olmesartan and valsartan (also known as angiotensin II receptor antagonists or sartans class).

Some medicines containing sartan have a specific ring structure (tetrazole ring), the synthesis of which could potentially lead to the formation of nitrosamine impurities. Other drugs in the same class that do not have this ring, such as azilsartan, eprosartan, and telmisartan, are not affected by this risk and were not included in the review.

These drugs are used to treat patients with high blood pressure and those with certain heart or kidney diseases. They work by blocking the effects of angiotensin II, a hormone that narrows blood vessels and increases blood pressure.

More about the process

The review of medicinal products with the active substance valsartan was initiated by the European Commission on July 5, 2018 in accordance with Article 31 of Directive 2001/83 / EC. On September 20, 2018, the review was expanded to include medicines containing candesartan, irbesartan, losartan, and olmesartan.

Update April 2019:

The review was carried out by the EMA Committee for Medicinal Products for Human Use (CHMP), which is responsible for questions relating to medicinal products for human use and which subsequently prepared the opinion. The CHMP's opinion was forwarded to the European Commission, which issued a final legally binding decision on April 2nd, 2019, which applies in all EU member states.

Commission implementing decision

http://ec.europa.eu/health/documents/community-register/html/ho26820.htm

Press releases of the CMDh

https://www.hma.eu/249.html

additional Information

Press release of the European Medicines Agency (02/01/2019)
https://www.ema.europa.eu/en/medicines/human/referrals/angiotensin-ii-receptor-antagonists-sartans-containing-tetrazole-group
Warning and safety information from the BASG (05.07.2018):
https://www.basg.gv.at/news-center/news/news-detail/article/rueckruf-von-arzneimittel-mit-ffektstoff-valsartan-vom-chinesischen-steller-zhejiang-huahai-pharma/
BASG safety information, update (03.08.2018):
https://www.basg.gv.at/news-center/news/news-detail/article/ueberpruefung-der-valsartan-medikamente-update-1255/
Safety information of the BASG, NDEA (23.11.2018):
https://www.basg.gv.at/news-center/news/news-detail/article/produktionsbedingte-verunreinigung-mit-n-nitrosodiethylamin-ndea-im-ffektstoff-valsartan-des-herste/

Inquiries (regulatory)

Email: natbasg.gvat

Questions (technical)
Dr. Christoph Baumgärtel, Tel .: 050555/36004
Email: christoph.baumgaertelagesat

Inquiries (for media)
Communication management, Tel .: 050555/25000
Email: presse-basgbasg.gvat

[1] The 6 and 4 year durations refer to the time when NDMA and NDEA were believed to have been present in Valsartan of Zhejiang Huahai.

[2] International Council for Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidance: M7 (R1)

Last change: 02/14/2019