Update [7/13/2020] FDA is alerting patients and health care professionals to several voluntary recalls of extended release (ER) metformin by the companies listed below. The companies are recalling metformin due to the possibility the medicines could contain nitrosodimethylamine (NDMA) above the acceptable intake limit.
- Granules Pharmaceuticals – 12 lots
- Lupin Pharmaceuticals – All lots (expansion of previous recall)
- Avkare (repackager for Amneal) – All lots
- PD-Rx Pharmaceuticals (repackager for Amneal) – 31 lots
- PD-Rx Pharmaceuticals (repackager for Marksans) – 26 lots
- The Harvard Drug Group (repackager for Apotex) – One lot (T-02134)
- Preferred Pharmaceuticals (repackager for Marksans) – Four lots (J0119M, K1419L, K2719J, A0220H)
FDA published a recalled metformin list including details about metformin products that have been recalled. Patients taking recalled ER 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. 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).
Update [7/2/2020] Today, the AAPS Journal, an official journal of the American Association of Pharmaceutical Scientists, published FDA’s manuscript entitled, “A Cautionary Tale: Quantitative LC-HRMS Analytical Procedures for the Analysis of N-Nitrosodimethylamine in Metformin.”
This paper assesses the cause for the discrepancy between the NDMA values FDA found in its testing of metformin drug products and the values a private laboratory reported.
The private laboratory reported levels of NDMA above the acceptable intake limit in 16 of the 38 metformin products they tested. FDA immediately acted to analyze the same 38 samples. Overall, FDA observed that in orthogonal tests, the levels of NDMA, when present, were generally lower than reported by the private laboratory.
The paper provides additional details of FDA’s investigation and the importance of selection and validation of testing methods.
In summary, the agency found the private laboratory method to be inappropriate for quantifying NDMA in metformin drug products due to presumptive overestimation of NDMA caused by the presence of a substance that interfered with the testing results.
Update [6/11/2020] FDA is alerting patients and health care professionals to five companies’ voluntary recalls of certain extended release (ER) metformin drugs. The agency recently announced it was in contact with five companies to recommend they voluntarily recall ER metformin because the agency’s testing showed N-Nitrosodimethylamine (NDMA) above the acceptable intake limit in certain lots.
- Apotex – All lots
- Amneal – All lots
- Marksans (labeled as Time-Cap) – One lot (XP9004)
- Lupin – One lot (G901203)
- Teva (labeled as Actavis) – 14 lots
There are additional companies that manufacturer ER metformin and supply a significant portion of the U.S. market, whose products are not being recalled at this time.
Patients taking recalled ER 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. 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).
FDA updated its laboratory test results showing the levels of NDMA the agency has found in samples of metformin to date. FDA has also posted a second liquid chromatography-electrospray ionization-high resolution mass spectrometry (LC- ESI-HRMS) testing method to provide an option for regulators and industry to detect eight different nitrosamine impurities in metformin drug substances and drug products.
The agency is also asking all companies manufacturing ER metformin to evaluate the risk of their product containing NDMA above the acceptable intake limit 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 companies must inform the agency and should not release the batch to the U.S. market.
[2/3/2020] The U.S. Food and Drug Administration posted laboratory results showing N- Nitrosodimethylamine (NDMA) levels in some metformin products approved in the U.S. FDA has determined that the levels of NDMA in metformin products tested range from not detectable to low levels. To date, no sample of metformin that FDA has tested exceeds the acceptable daily intake for NDMA. FDA has not recommended metformin recalls in the U.S.
Metformin is a prescription drug used to control high blood sugar in patients with type 2 diabetes. Patients should continue taking metformin to keep their diabetes under control. It could be dangerous for patients with this serious condition to stop taking their metformin without first talking to their health care professionals.
FDA plans to post the methods used in laboratory testing of metformin in the near future. FDA is also collaborating with international regulators to share testing results for metformin, along with testing results for other drugs.
FDA will continue to monitor NDMA in metformin, along with other drugs products, and will provide timely updates of new developments, including product recalls. For more information about NDMA, visit FDA’s nitrosamines webpage.
FDA encourages health care professionals and patients to report adverse reactions or quality problems with any human drugs to the agency’s MedWatch Adverse Event Reporting program:
- Complete and submit the report online at www.fda.gov/medwatch/report.htm; or
- Download and complete the form, then submit it via fax at 1-800-FDA-0178