Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies.
Regulators in the European Union (EU) first became aware of nitrosamines in medicines in mid-2018 when nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were detected in blood pressure medicines known as 'sartans'.
There is a very low risk that nitrosamine impurities at the levels found in medicines could cause cancer in humans.
The information below outlines the actions taken by the European medicines regulatory network between 2018 and 2021 to manage the risk of impurities detected in certain types of EU medicines.
The requirements that marketing authorisation holders for sartan medicines need to follow to avoid the presence of nitrosamine impurities in their products are the same as for all human medicines.
The CHMP updated the requirements for sartans in November 2020, bringing them in line with the outcome of its Article 5(3) opinion. It first issued recommendations for sartans in January 2019.
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In June 2020, the European medicines regulatory network published the outcome of a lessons learnt exercise on the presence of nitrosamines in sartan medicines (also known as angiotensin II receptor antagonists). This includes recommendations to help reduce the risk of impurities in medicines and ensure that regulators are better prepared to manage cases of unexpected impurities:
The recommendations apply to all medicines. They include:
An implementation plan agreed in October 2020 sets out how the European medicines regulatory network intends to address each recommendation. It identifies lead responsibilities and indicative timelines.
The recommendations were relevant for the Article 5(3) procedure.
A stakeholder consultation process fed into the lessons learned exercise, including a meeting with stakeholders in November 2019:
Authorities in the EU worked closely with companies and the official medicines control laboratories (OMCLs) on the investigations following the presence of a nitrosamine impurity, 1-nitroso-4-methyl piperazine, in rifampicin medicines.
As a precautionary step, national competent authorities asked marketing authorisation holders for rifampicin-containing medicines to test their medicines before releasing them onto the market while the investigations and implementation of any corrective measures are ongoing.
This is in line with the measures introduced by EMA's Article 5(3) review to limit the presence of nitrosamines in human medicines.
Rifampicin is a first-line treatment for tuberculosis. It is also used for management of other serious infections, including blood infections and leprosy.
The risk to patients from not taking their rifampicin medicines far outweighs any potential risk from nitrosamine impurity.
Healthcare professionals should therefore continue to prescribe rifampicin medicines as normal in accordance with the product information.
EMA's review of ranitidine medicines led it to recommend their suspension after tests showed that some of these products contained NDMA. For more information, see:
EMA and the national competent authorities worked closely with companies and the official medicines control laboratories (OMCLs) on the investigations following tests in 2019 which detected NDMA in some EU batches of metformin-containing medicines, used for the treatment of diabetes.
As a precautionary step, EMA and the national competent authorities asked marketing authorisation holders for metformin-containing medicines to test their medicines before releasing them onto the market while the investigations and implementation of any corrective measures were ongoing.
This is in line with the measures introduced by EMA's Article 5(3) review to limit the presence of nitrosamines in human medicines.
EMA advises patients in the EU to continue to take metformin medication as the risks from not treating diabetes far outweigh any possible effects of the low levels of NDMA seen in tests.
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In February 2025, EMA's CHMP adopted a positive opinion approving changes to the manufacturing process for Champix, a smoking cessation medicine.
These changes ensure that the levels of nitrosamine impurity N-nitroso-varenicline present in Champix stay below the acceptable intake limit during manufacture and throughout the product’s shelf-life.
In 2021, the CHMP carried out a review of the presence of N nitroso-varenicline in Champix.
The CHMP concluded that the marketing authorisation holder should make changes to Champix's authorisation to ensure that it conforms to acceptable nitrosamine intake limits for EU medicines. These limits are calculated in line with the ICH M7 guideline.
As a precaution, the marketing authorisation holder recalled several batches and paused distribution of Champix as of June 2021.
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