Questions and Answers: NDMA impurities in metformin products
Answers to questions about NDMA impurities found in metformin and FDA’s actions to address the issue
Important information about the NDMA impurity in metformin products
- The U.S. Food and Drug Administration has recommended recalls of certain metformin products that may contain the impurity N-nitrosodimethylamine (NDMA) above the acceptable intake limit.
- Patients taking recalled metformin should continue taking it until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking their metformin without first talking to their health care professional.
- The agency is also asking all manufacturers of extended release versions of metformin to evaluate their risk of excessive NDMA and to test at-risk product before each batch is released onto the U.S. market. If testing shows NDMA above the acceptable intake limit, the manufacturer must inform the agency and should not release the batch to the U.S. market.
- FDA’s testing has shown elevated levels of NDMA in some extended release (ER) metformin formulation but not in the immediate release (IR) formulation or in the active pharmaceutical ingredient.
A: FDA does not have scientific evidence to determine how long NDMA has been present in metformin products and we are investigating the root cause of its presence.
A: We do not know how long patients may have been exposed to higher NDMA levels in ER metformin. FDA does not expect nitrosamines to cause harm when ingested at or below the acceptable intake limit levels (such low levels of nitrosamines are present in foods in low levels and ingested as part of usual diets) even over a long period of time (such as a 70-year lifespan). Nitrosamine impurities may increase the risk of cancer if people are exposed to them at above acceptable levels over long periods of time, but we do not anticipate that shorter term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer. We are working to ensure medicines on the U.S. market do not exceed the acceptable intake limit.
A: Please see the FDA’s Drug Recalls page for information about any recalled metformin products.
A: Patients taking recalled metformin should continue taking it until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking their metformin without first talking to their health care professional. Patients should return unused recalled metformin to their pharmacist when they get their new medication.
A: FDA has recommended five manufacturers of metformin ER recall lots of their metformin ER tablets. There are additional manufacturers of the metformin ER formulation that supply the bulk of the US market, and their products are not being recalled. The agency will work closely with manufacturers to prevent or reduce any potential impact of shortages.
Q: Does the agency believe manufacturers can make ER metformin without NDMA, or is it like ranitidine and will always be there?
A: Because the agency has tested samples of ER metformin and found no NDMA in many samples, we believe it is possible to manufacture metformin without the NDMA impurity. FDA reminds manufacturers that it is their responsibility to develop and use suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects new or higher levels of impurities, they should fully evaluate the impurities and take action to ensure the product is safe for patients.
A: This is an ongoing investigation. The agency does not believe the metformin active pharmaceutical ingredient is a primary source of NDMA but is investigating the root cause of the impurity.
A: No. The agency has only detected levels of NDMA above the acceptable intake limit in some extended release metformin but not in any tested immediate release metformin.
A: Yes. The agency has posted its testing method on the public website for use by industry, third party laboratories and our international regulatory partners. Manufacturers may use their own testing method or use the FDA’s posted method, but any testing method should be validated by the user if the resulting data are used to support a required quality assessment of the active pharmaceutical ingredient or drug product, or if the results are used in a regulatory submission.