The US Food and Drug Administration (FDA) has called on manufacturers selling the extended-release formulation of metformin on the US market to check supplies and voluntarily recall the type 2 diabetes drug.

Some batches of the extended release formulation have been found to be contaminated with unacceptable levels of the “probable carcinogen” N-Nitrosodimetjylamine (NDMA), the federal health watchdog said.

According to the World Health Organization (WHO), animal tests have shown that in high doses NDMA can cause liver, lung and kidney problems as well as gastric or colorectal cancer.

Acceptable intake limit for NDMA in medications is 96 ng a day, and the FDA said it does not expect the substance to cause harm at levels below this cutoff.  The agency said it is working with drugmakers to determine whether the recall of the extended release formulation would cause shortages of metformin in the US.

US firms selling metformin on the US market have been identified in US press reports as Apotex, Amneal, Lupin, Marksans and Teva subsidiary Actavis. As of Jun. 3, Apotex and Amneal had announced a recall of some of their drugs.

The FDA has conducted investigations into metformin drugs since late 2010, when its examination of when multiple batches of the diabetes drug made outside the country were found to contain low levels of the substance. In late 2019, it acknowledged its lab testing had found low, but acceptable levels of NDMA in sample lots sold in the US market. At that time it did not recommend a recall.

In March this year, online pharmacy and independent testing laboratory Valisure set the wheels in motion for a recall, announcing it had turned up NDMA contamination at unacceptable levels in 42% of the batches it checked. In a Public Citizen petition, it asked for an immediate recall of the contaminated products.

In 38 batches of metformin from 22 companies tested, Valisure – which played a role in effecting the US recall of the generic antacid ranitidine and similar products in April  – said 11 metformin batches from 22 companies showed NDMA contamination exceeding the FDA’s acceptable daily level. Several batches contained levels 10 times above 96 ng, with amounts varying from batch to batch.

CDO says FDA foreign plant inspections lagging

Testifying before the US Senate’s Finance Committee this week, Valisure CEO David Light suggested that the FDA's ability to keep up with inspections was lagging. The Covid-19 pandemic, he said, “has exposed significant flaws in the agency’s ability to adequately inspect drugs produced by foreign manufacturers and might cause quality concerns in the US for years to come.”

Light pointed to the FDA’s Covid-related freeze on inspections of foreign plants, announced in March, as a potentially serious problem. Warning that the combination of a strained global supply chain and structural issues could damage consumer confidence, he proposed independent laboratory testing of all imported drugs as a prerequisite for US distribution.

Contamination of metformin products has also been a problem outside the US. Last month, South Korea's public health agency suspended the registrations of 31 diabetic drugs containing metformin, due to contamination with NDMA.