番茄社区

This past May, 番茄社区 covered the FDA's announcement that certain extended-release metformin products were contaminated with excess N-nitrosodimethylamine (NDMA), a potential carcinogen, and should be pulled from store shelves. In this follow-up feature, we review some of the developments since that initial recall.

The saga actually began in December 2019, when it was aware of certain metformin products overseas that were contaminated with low levels of NDMA.

Just a few months later, in February 2020, the FDA said initial lab analyses of certain domestic metformin products did in fact show traces of NDMA in some samples. At that time, however, the agency wasn't recommending any measures be taken.

Fast forward to May 28: additional laboratory testing conducted by the agency found that the levels of NDMA in several lots of extended-release formulations of the type 2 diabetes drug were considered "higher-than-acceptable," thus prompting the FDA to recommend that manufacturing companies .

While everyone is exposed to some levels of NDMA -- a genotoxic substance and known carcinogen most typically found in contaminated water or cured and grilled foods -- the FDA now limits the acceptable daily intake to 96 ng.

This particular cap is a somewhat recent development and was set after the 2018 NDMA-related recalls of certain lots of drugs containing valsartan, an angiotensin receptor blocker (ARB). It was chosen specifically because a would approximate a 1:100,000 cancer risk after 70 years of exposure.

This first round of May recalls involved five manufacturing firms, in which the FDA recommended a voluntary recall of their contaminated lots of extended-release metformin. It included all lots of extended-release metformin from Apotex and Amneal, 14 lots from Teva (labeled as Actavis), one lot from Marksans Pharma (labeled as Time-Cap Labs; XP9004), and one lot from Lupin (G901203).

These initial recalls did not include any immediate-release metformin products.

"Now that we have identified some metformin products that do not meet our standards, we're taking action," said Patrizia Cavazzoni, MD, acting director of the FDA's Center for Drug Evaluation and Research, in a statement during the first round of recalls.

Over the next few weeks, the regarding the recalls, which included the following remarks from Matt Petersen, vice president of medical information and professional engagement for the ADA: "Patients should continue to take their metformin until their pharmacist supplies a different manufacturer's product or their doctor prescribes a different treatment. Medications should not be stopped unless directed to do so by their doctor."

Following this statement, the FDA penned in early July, which was published in the American Association of Pharmaceutical Scientists journal, explaining the reasoning behind reported testing discrepancies between the agency's NDMA findings and those of a private laboratory.

This paper was prompted by a private testing laboratory that had submitted a Citizen Petition to the FDA with findings that 16 of 38 metformin products tested above the limit of 96 ng/day of NDMA. However, the FDA responded by stating it tested the same set of 38 samples and only found eight products that tested above the allowable intake of 96 ng/day and also found across-the-board lower values than the private lab reported. In the FDA's "cautionary tale" response, the agency said the cause of the discrepancy was due to N,N-dimethylformamide (DMF) conflating levels in mass spectrometry measurements.

But not long thereafter in a mid-July alert to healthcare professionals and patients, the FDA expanded the list of recalls due to possibly high levels of NDMA. This second round of voluntary recalls included Granules Pharmaceuticals (12 lots), Lupin Pharmaceuticals (now all lots), AvKARE (repackager for Amneal; all lots), PD-Rx Pharmaceuticals (repackager for Amneal; 31 lots and repackager for Marksans; 26 lots), the Harvard Drug Group (repackager for Apotex; one lot), and Preferred Pharmaceuticals (repackager for Marksans; four lots).

Subsequently, in late August, Bayshore Pharmaceuticals added its name to the ever-growing list, recalling two of its extended-release metformin lots -- one lot of 750-mg tablets and one lot of 500-mg tablets.

After a quiet September, the next addition to the list of recalled metformin products came in early October. At this time, Marksans Pharma (labeled as Time-Cap Labs) voluntarily recalled additional lots to its July recall, now adding 76 additional unexpired lots of extended-release metformin tablets to its recall (500 mg and 750 mg).

At the same time, Sun Pharmaceutical Industries voluntarily recalled one lot of (brand name Riomet ER; 500 mg/5 mL). This particular liquid metformin product was relatively new to the U.S. market, having only come to shelves in late February 2020.

And in the latest development to the burgeoning list, Nostrum Laboratories' voluntarily recalled four lots of extended-release metformin in early November. This included two lots of 500-mg tablets, as well as two lots of 750-mg tablets.

But with every new round of recalls, the FDA reiterated that testing has not shown any abnormal NDMA contamination in immediate-release metformin products, also pointing out that immediate-release formulas are the most commonly prescribed type of metformin.

Providers with concerned patients can advise them to discuss which manufacturer their metformin is coming from with their pharmacist, although no pharmacies should be distributing any tampered medication. But if providers have any lingering concerns, they can temporarily switch patients to an immediate-release metformin product instead, as none of these formulations have been recalled (yet).

The FDA maintains a complete list (as of Nov. 4, 2020) of the 254 recalled metformin products, .

Comment