FDA: Unacceptable NDMA Levels Identified in Certain Metformin ER Products

Specifically, unacceptable levels of this potentially carcinogenic impurity have been identified in products manufactured by 5 different firms.

Levels of N-Nitrosodimethylamine (NDMA) above the Food and Drug Administration (FDA)’s acceptable intake limit have been identified in several lots of metformin extended-release (ER), a prescription drug used in the treatment of type 2 diabetes.

Specifically, unacceptable levels of this potentially carcinogenic impurity have been identified in products manufactured by 5 different firms; the Agency is currently working with these manufacturers to begin recalls. Although not present in samples of the metformin active pharmaceutical ingredient, elevated levels of NDMA were found in finished-dose tablets of the ER formulation. 

While a significant number of companies manufacture metformin ER, and their products are currently not subject to recall, the potential for shortages does exist. In a press statement, the FDA noted that “the Agency will work closely with manufacturers to prevent or reduce any impact of shortages.”

At this time, the FDA recommends that healthcare professionals continue to prescribe metformin when clinically indicated. Recent testing of metformin immediate-release tablets showed that these products contained undetectable levels of NDMA. The Agency is also calling upon manufacturers to test their products for NDMA before releasing it into the US market. Recall notices related to metformin ER products with levels above acceptable limits will be posted here.

“We understand that patients may have concerns about possible impurities in their medicines, and want to assure the public that we have been looking closely at this problem over many months in order to provide patients and healthcare professionals with clear and accurate answers,” said Patrizia Cavazzoni, MD, acting director of the FDA’s Center for Drug Evaluation and Research. “As we have been doing since this impurity was first identified, we will communicate as new scientific information becomes available and will take further action, if appropriate.”

NDMA was one of several nitrosamine impurities implicated in the massive recall of angiotensin II receptor blockers (ARBs), as well as the commonly used H2 antagonists, ranitidine and nizatidine. In April 2020, the FDA required the removal of all ranitidine products from the market after it was discovered that NDMA levels could increase over time under normal storage conditions and that higher levels were associated with older products (the length of time since the product was manufactured). In addition, NDMA was found to increase significantly in ranitidine samples stored at higher temperatures. 

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According to the Agency, patients who take a drug that contains nitrosamine impurities at or below acceptable daily intake levels are not expected to be at an increased risk of cancer, even if the drug is ingested daily for 70 years. However, the risk may be increased in individuals who are exposed to these genotoxic substances above acceptable levels and for long periods of time.

For more information visit fda.gov.