FDA Requests Recall of Tainted Metformin

The US Food and Drug Administration (FDA) has asked 5 US drug manufacturers to voluntarily recall several lots of extended-release (ER) metformin after agency laboratory testing found unacceptable levels ofnitrosamine impurity N-Nitrosodimethylamine, or NDMA.

Company recalls, the agency noted in a press release, will be posted on FDA's website.

There are manufacturers of ER metformin in addition to these 5 that supply a significant portion of the US market, and their products are not being recalled. FDA and manufacturers are working closely to ensure appropriate testing is carried out. There also are assessments in progress, the FDA said, to determine whether recalls of the drug will result in metformin ER shortages. The agency will work closely with industry to prevent or mitigate any impact of shortages.

Metformin is widely used as a first-line treatment to control hyperglycemia in patients diagnosed with type 2 diabetes.

In the news release, acting director of the FDA’s Center for Drug Evaluation and Research Patrizia Cavazzoni, MD, said that FDAhas been examining the situation over several months in order to provide patients and prescribers with "clear and accurate answers. Now that we have identified some metformin products that do not meet our standards, we’re taking action," she stated.

"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.”

Late in 2019, the FDA announced it had been made aware of NMDA in some metformin products in other countries and began testing to determine whether product in the US supply was at risk. Having identified very low levels in some metformin samples by February 2020, FDA nonetheless determined those levels did not exceed acceptable levels of intake for NDMA.

NDMA is naturally present in small amounts in food and water, such as cured and grilled meats, dairy products and vegetables, and the acceptable intake limit is 96 nanograms per day. The agency previously said that amounts above that limit may increase the risk for cancer.

Based on its collaboration with manufacturers of the recalled tablets to identify the source of contamination, FDA states that elevated levels of NDMA have been found in some finished-dose tablets of the ER formulation but have not been detected in samples of the metformin active pharmaceutical ingredient.

NDMA in the drug supply

Investigation of nitrosamines in the US drug supply began with the antihypertensive medications angiotensin II receptor blockersand later expanded to include heartburn medicines, ranitidine and nizatidine, as well as diabetes medication, metformin and other medicines. In April 2020, the agency requested manufacturers withdraw all prescription and over-the-counter ranitidine drug products from the market because of test results showing that NDMA in some ranitidine products increases over time and, when stored at higher than room temperatures, may result in consumer exposure to unacceptable levels of this impurity.

There are multiple reasons for the presence of NDMA in drugs. The FDA has previously found that the source of NDMA can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed.