FDA Investigates Nitrosamine Impurities in Diabetes Drug Metformin

By Emily Forster -

December 12, 2019

Janet Woodcock, Director of the Center for Drug Evaluation and Research of the US Food and Drug Administration provided an update on the FDA’s investigation of nitrosamine impurities in metformin, a diabetes drug. This is the third active pharmaceutical ingredient (API) in which the FDA has been investigating nitrosamine impurities, including N-nitrosodimethylamine (NDMA).

The FDA and the European Medicines Agency have investigated nitrosamine impurities “sartan”-containing APIs, used in anti-hypertensive and cardiovascular drugs, such as valsartan candesartan, irbesartan, losartan, and olmesartan, and later 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.

“The FDA is aware that some metformin diabetes medicines in other countries were reported to have low levels of NDMA,” said Woodcock in a December 5, 2019 agency statement. “Based on the information we have available, the levels of NDMA seen outside the US are within the range that is naturally occurring in some foods and in water. While we are aware that some regulatory agencies outside the US may be recalling some metformin drugs, there are no metformin recalls affecting the US market at this time.”

The FDA says it is investigating whether metformin in the US market contains NDMA, and whether it is above the acceptable daily intake limit of 96 nanograms. The agency said it will also work with companies to test samples of metformin sold in the US and will recommend recalls as appropriate if high levels of NDMA are found.

The FDA provided its update on its investigation into nitrosamine impurities in metformin following the recall of certain products by regulatory agencies outside the US. Singapore’s Health Sciences Authority (HSA) has recalled three out of 46 locally marketed metformin medicines after determining they contained NDMA above the internationally acceptable level.

The recalled metformin medicines are Glucient XR Tablet 500 mg, batch 2881382, supplied by Glorious Dexa Singapore; Meijumet Prolonged Release Tablet 750 mg, all batches, supplied by Pharmazen Medicals Pte Ltd; Meijumet Prolonged Release Tablet 1,000 mg, all batches, supplied by Pharmazen Medicals Pte Ltd. The other 43 metformin medicines in Singapore are not affected.

The HSA says the risk to patients who have been taking the three affected metformin medicines is very low. This is because the potential risk of nitrosamines is associated with long-term use and the three affected medicines have only been supplied locally for a shorter period of time since 2018. Nitrosamines are commonly found in low levels in processed food (pickled vegetables, salted fish, processed meat products such as bacon and sausages) and in air pollution.

The HSA says it is working with the companies supplying these medicines and international regulatory agencies to verify the causes of the contamination and to identify the necessary measures to address the issue.

Source: Singapore’s Health Sciences Authority, US Food and Drug Administration