EMA and EU national competent authorities will be contacting all marketing authorisation holders of metformin-containing medicines to request they implement testing of the medicines for the presence of nitrosamines before they are released onto the market.

This is a precautionary step to ensure patient safety while ongoing investigations on these medicines are being finalised. The request is in line with this year’s Article 5(3) review, which introduced measures for companies to take to limit the presence of nitrosamines in medicines. Regulatory authorities will carefully monitor the responses to this request and take appropriate action where necessary.

The presence of nitrosamine in metformin medicines is under ongoing investigation since a nitrosamine called N-nitrosodimethylamine (NDMA) was found in some EU batches earlier this year. For more information, please see below or the EMA website.

EMA and national competent authorities advise 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.

Although NDMA is classified as a probable human carcinogen (a substance that could cause cancer) on the basis of animal studies, it is not expected to cause harm when ingested in very low levels.

EMA and national competent authorities will continue to provide updates as necessary.

2020.07.30 - EMA Update on metformin diabetes medicines

Update on nitrosamines in medicines containing metformin (CMDh press release July 2020)

As announced in the CMDh press release of February and May 2020, national authorities continue with the assessment of the impact of recent tests, which found NDMA in some EU batches of metformin medicines, used for diabetes.

While further results from tests on metformin in the EU are being awaited, the CMDh re-enforces its message to MAHs given in the May 2020 press release and requests that MAHs proactively accelerate ongoing work and submit the test results of batches of API and finished products (marketed and awaiting release) and the investigation report comprehensive of corrective actions and preventive actions at the latest by 1 October 2020, if not already done so. All known and potential root causes, including packaging materials utilised and any source of nitrosating agents, should be taken into account in the investigation.

In line with previous advice (see below - 06th December 2020), patients should continue taking their metformin medicines as normal. The risk from not having adequate diabetes treatment far outweighs possible risks from low levels of NDMA found in some batches of metformin.

As metformin is considered a critical medicine, EMA and national authorities are cooperating closely to avoid possible shortages so patients can continue to get the treatments they need.

2019.12.06 - EMA update on metformin diabetes medicines

EMA is aware that trace amounts of an impurity, N-nitrosodimethylamine (NDMA), have been found in a small number of metformin diabetes medicines outside the EU.

The levels of NDMA in the affected non-EU metformin medicines are very low and appear to be within or even below the range that people can be exposed to from other sources, including certain foods and water.

At this point, there are no data indicating that EU metformin medicines are affected. Authorities in the EU are in the process of working with companies to test EU medicines and will provide further updates as more information becomes available.

Patients in the EU should continue taking their metformin medicines as normal. The risk from not having adequate diabetes treatment far outweighs possible effects of the low levels of NDMA seen in tests. Healthcare professionals should remind patients of the importance of keeping their diabetes under control.

Metformin is widely used alone or in combination with other medicines to treat type 2 diabetes. It is usually the first-line treatment, and it works by reducing the production of glucose in the body and reducing its absorption from the gut.

Information for patients

• Metformin is an effective medicine for controlling blood sugar.

• Continue taking your metformin medicine to keep your diabetes under control.

• Stopping treatment could make your diabetes become uncontrolled and leave you open to symptoms caused by high blood sugar, including thirst, drowsiness and blurred vision.

• Long-term complications of uncontrolled diabetes include heart disease, nerve problems, kidney damage, eye problems and damage to the foot that can lead to amputation.

Information for healthcare professionals

• Continue prescribing metformin medicines as normal and await further information from authorities in the EU.

• Advise your patients against stopping their diabetes treatment.

• Remind your patients of the importance of keeping their diabetes under control.

NDMA is classified as a probable human carcinogen (a substance that could cause cancer) on the basis of animal studies. It is present in some foods and in water supplies, but it is not expected to cause harm when ingested in very low levels.

Last year, NDMA and other impurities of the same class (nitrosamines) were found in some blood pressure medicines known as sartans. Subsequently, EMA started a review of ranitidine medicines and launched a procedure to request companies to take specific measures to avoid the presence of nitrosamines in human medicines, including metformin.

This procedure, known as an Article 5 (3) procedure, is still ongoing and will be used to provide guidance to companies and support the evaluation of data on nitrosamines. The expedited testing of metformin medicines in the EU is part of this procedure.

EMA and national authorities together with international partners and the European Directorate for the Quality of Medicines & HealthCare (EDQM) are continuously sharing information about impurities such as NDMA and are taking action to protect patients and reassure them about the quality of their medicines.