The US Food and Drug Administration (FDA) reports its laboratory testing has shown levels of the nitrosamine impurity, N-nitrosodimethylamine (NDMA), a potential carcinogen, above the agency’s acceptable intake limit in several lots of the extended-release (ER) formulation of metformin, a drug to treat Type 2 diabetes.

The agency is in contact with five firms to recommend they voluntarily recall their products. The FDA says there are additional manufacturers of metformin ER products that supply a significant portion of the US market and their products are not being recalled. The agency is asking all manufacturers of metformin with ER formulations to evaluate the risk of excessive NDMA in their products and to test each batch before it is released into the US market. The FDA is advising companies that if testing shows NDMA above the acceptable intake limit, the manufacturer should inform the agency and should not release the batch to the US market.

The FDA says it is continuing to work with manufacturers to ensure appropriate testing and that assessments are underway to determine whether metformin ER recalls will result in shortages. The agency says it will work with manufacturers to prevent or reduce the impact of any shortages.

The FDA’s investigation into nitrosamine impurities in metformin is part of ongoing investigations and company recalls due to nitrosamine impurities in other active pharmaceutical ingredients (APIs). In 2018, the FDA and the European Medicines Agency initiated investigations of nitrosamine impurities in certain “sartan”-containing APIs, used in anti-hypertensive and cardiovascular drugs, such as valsartan, candesartan, irbesartan, losartan, and olmesartan. They later broadened those investigations into prescription and over-the-counter forms of ranitidine, a H2 (histamine-2) blocker used to decrease the amount of acid created by the stomach.

In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency began testing to determine whether the metformin in the US supply was at risk as part of its ongoing investigation into nitrosamine impurities across medication types. By February 2020, the agency had identified very low levels of NDMA in some samples, but at that time, no FDA-tested sample of metformin exceeded the acceptable intake limit for NDMA. The FDA’s acceptable intake limit for NDMA in drug formulations is 96 nanograms per day.

Recently, the FDA says it became aware of reports of higher levels of NDMA in certain ER formulations of metformin via a citizen petition filed by a private laboratory. FDA laboratories tested the same metformin lots that the private laboratory found to contain NDMA above the acceptable intake limit. The agency confirmed unacceptable NDMA levels in some, but not all, of those lots. In other instances, the agency’s laboratory detected NDMA in lots that the private laboratory did not. The FDA says it also found that the levels of NDMA, when present, were generally lower than reported by the private laboratory. The FDA says its results have also been consistent with the findings of other regulatory agencies’ laboratories.

The FDA says that agency testing has not shown NDMA in immediate-release metformin products, which is the most commonly prescribed type of metformin. The FDA says it is working with manufacturers of the recalled tablets to identify the source of the NDMA impurity. At this time (as reported on May 28, 2020), the elevated levels of NDMA have been found in some finished-dose tablets of the ER formulation, but NDMA has not been detected in samples of the metformin API.

NDMA is a common contaminant found in water and foods, including cured and grilled meats, dairy products, and vegetables. The FDA says it and the international scientific community do not expect NDMA to cause harm when ingested at low levels.

Source: US Food and Drug Administration