The Food and Drug Administration is contacting five drug companies that make extended-release versions of metformin, the popular diabetes medication, after the agency found pills contaminated with a chemical known to cause cancer.The news, first reported by Bloomberg, illustrates the persistent problem NDMA, or N-Nitrosodimethylamine, has created for U.S. regulators over the past two years. The chemical has been discovered in several heart medications, leading to widespread recalls and concerns about the FDA’s ability to ensure quality manufacturing at the foreign plants where these drugs are typically made.The FDA is recommending the five firms, one of which is Canada’s Apotex, voluntarily recall the contaminated pills. An agency spokesperson said FDA tests have not shown elevated levels of NDMA in immediate-release versions of metformin. The agency is advising patients not to stop taking their prescription medications without first talking to their healthcare provider.

The FDA in December said it was aware that other countries had reported low levels of NDMA in some metformin drugs. While it claimed these levels were “within the range that is naturally occurring in some foods and in water,” the agency still decided to investigate the amount of NDMA found in U.S. metformin products.

By early February, the FDA had posted lab tests showing NDMA levels in the low- to not-detectable range for certain metformin products. The results prompted the agency to conclude in a Feb. 3 statement that, to date, “no sample of metformin that FDA has tested exceeds the acceptable daily intake for NDMA.”

That’s no longer the case, however, as the agency now finds itself reaching out to the metformin manufacturers whose products tested above the acceptable level.

On Thursday, the FDA posted a notice from Apotex indicating the company is recalling all lots of its metformin hydrochloride extended-release tablets. The generic drugmaker stopped selling the product in the U.S. in February 2019, and said only limited supplies of the product remained on the market.

Notices from the other four companies referenced by the FDA have not yet been posted.

The recall action adds to the list of NDMA-related recalls that have taken place over the last couple years. In July 2018, Chinese company Zhejiang Huahai Pharmaceuticals agreed to stop distributing its active ingredient used to make valsartan, a generic blood pressure medicine, because of NDMA contamination. In turn, generics drugmakers Teva Pharmaceuticals USA, Prinston Pharmaceutical and Major Pharmaceuticals all voluntarily pulled their valsartan drugs from the market.

Valsartan hasn’t been the only drug affected. Companies have also recalled the related heart medications losartan and irbesartan due to contamination from chemicals from the same family as NDMA. Some believe these contaminants come from undesired chemical reactions in the drugs’ manufacturing process.

More recently, British drug giant GlaxoSmithKline voluntarily recalled its over-the-counter heartburn treatment Zantac from the market because of NDMA contamination, as did Novartis’ with its generic prescription version.

A recall of metformin could impact many patients, given that the drug serves as a foundational first-line treatment for patients with Type 2 diabetes. According to Bloomberg, data compiled by the company’s Intelligence arm shows that about 21 million prescriptions were written last year in the U.S. for extended-release metformin. That figure would represent around a quarter of overall metformin prescriptions.

The FDA noted, however, that there are additional companies beyond the five manufacturers it contacted that supply a “significant portion” of the U.S. market. Their metformin products are not being recalled, the agency said.

On Wednesday, online pharmacy Valisure disclosed results from an independent evaluation of crowdsourced samples of metformin. After acquiring 38 batches of the drug from 22 companies, Valisure said it found 16 —​ or 42% —​ of the batches contained NDMA that exceeded the FDA’s daily acceptable intake limit.