The U.S. Food and Drug Administration is announcing today that agency laboratory testing has revealed levels of the nitrosamine impurity N-Nitrosodimethylamine (NDMA) above the agency’s acceptable intake limit in several lots of the extended-release (ER) formulation of metformin, a prescription drug used to control high blood sugar in patients with type 2 diabetes. The agency is in contact with five firms to recommend they voluntarily recall their products. Company recall notices will be posted on FDA’s website. There are additional manufacturers of the metformin ER formulation that supply a significant portion of the U.S. market, and their products are not being recalled. The FDA is continuing to work closely with manufacturers to ensure appropriate testing. Assessments are underway to determine whether metformin ER recalls will result in shortages and the agency will work closely with manufacturers to prevent or reduce any impact of shortages.
“The FDA has strict standards for safety, effectiveness and quality, and the agency makes every effort based on science and data to help keep the U.S. drug supply safe. 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 health care professionals with clear and accurate answers,” said Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation and Research. “Now that we have identified some metformin products that do not meet our standards, we’re taking action. 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.”
Patients should continue taking metformin tablets even after recalls occur, until they consult with their health care professional who can prescribe a replacement. Patients with type 2 diabetes could face dangerous health risks if they stop taking their prescribed metformin. The FDA recommends that health care professionals continue to prescribe metformin when clinically appropriate; FDA testing has not shown NDMA in immediate release (IR) metformin products (the most commonly prescribed type of metformin). The agency is working with manufacturers of the recalled tablets to identify the source of the NDMA impurity. At this time, the elevated levels of NDMA have been found in some finished-dose tablets of the ER formulation but have not been detected NDMA in samples of the metformin active pharmaceutical ingredient.
The agency is also asking all manufacturers of metformin containing ER products to evaluate the risk of excessive NDMA in their product and to test each batch before it is released into the U.S. market. If testing shows NDMA above the acceptable intake limit, the manufacturer should inform the agency and should not release the batch to the U.S. market.
In late 2019, the FDA announced it had become aware of NDMA in some metformin products in other countries. The agency immediately began testing to determine whether the metformin in the U.S. supply was at risk, as part of the 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 has maintained that it would continue with ongoing testing of metformin and other medications, and if any levels of NDMA or other impurities were identified, swift action would be taken.
Recently, the FDA 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, our laboratory detected NDMA in lots that the private laboratory did not. The agency also found that the levels of NDMA, when present, were generally lower than reported by the private laboratory. Given FDA scientists’ deep experience quantifying these impurities in drugs, the agency is confident in the reliability of the FDA’s testing method and results and will continue to take action based on the latest scientific information. The results have also been consistent with the findings of other regulatory agencies’ laboratories around the world.
NDMA is a common contaminant found in water and foods including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of NDMA. The FDA and the international scientific community do not expect it to cause harm when ingested at low levels. The FDA’s acceptable intake limit for NDMA in drug formulations is 96 nanograms per day. The 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.
The FDA has previously investigated the presence of nitrosamines in the U.S. drug supply. The investigation began with the blood pressure and heart failure medicines called angiotensin II receptor blockers (ARBs) and 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 (OTC) 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.
The FDA is taking a systematic approach to identify medicines with nitrosamines above the acceptable intake limit and remove them from the market. Improved technology enables the detection of even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA. Today, better testing methods exist, and the FDA better understands the specific manufacturing steps that may increase the risk of nitrosamine formation. The FDA works closely with international drug regulatory agencies, who have also been testing drug products for NDMA and are collaborating to investigate the sources of these impurities.