FDA recalls some ER metformin for NDMA impurity

Regulatory NewsRegulatory News | 29 May 2020 |  By 

Some extended-release formulations of the diabetes drug metformin contained levels of a nitrosamine impurity falling above the US Food and Drug Administration’s (FDA’s) acceptable intake limit, according to recent testing conducted by the agency.
Several lots of extended-release (ER) metformin tested above the acceptable limit for N-nicrosodimethalymine (NDMA), set by the FDA at 96 nanograms per day for drugs. The substance is ingested in low levels through normal dietary pathways but can raise the risk of cancer with long-term elevated exposure.
Currently, FDA has notified five pharmaceutical firms that they have detected NDMA in their metformin preparations in quantities over the acceptable intake limit; just one manufacturer, Apotex Corp, is named on the FDA website currently. The FDA has recommended all five voluntarily recall the NDMA-containing metformin formulations.
Other metformin products have not been recalled, and FDA continues to work with metformin manufacturers on testing, and to prevent, or reduce the impact of, any resultant metformin shortages. All metformin manufacturers are being asked to test each batch for NDMA before release to the US market and notify the FDA of any results showing NDMA levels above the acceptable intake limit.
Elevated NDMA levels have been found in some finished-dose ER tablets as noted by the FDA but elevated NDMA levels have not been detected in samples of the metformin active pharmaceutical ingredient.
“The FDA has strict standards for safety, effectiveness and quality, and the agency makes every effort based on science and data to help keep the U.S. drug supply safe,” said Patrizia Cavazzoni, acting director of the FDA’s Center for Drug Evaluation and Research. “As we have been doing since this impurity was first identified, we will communicate as new scientific information becomes available and will take further action, if appropriate,” added Cavazzoni in the agency’s press statement announcing the findings.
A citizen petition from a private laboratory alerted FDA officials to higher levels of NDMA in these ER metformin formulations, and the agency’s own testing confirmed elevated NDMA levels in some – but not all – lots identified by the private laboratory. “In other instances, our laboratory detected NDMA in lots that the private laboratory did not,” said the FDA.
“The agency also found that the levels of NDMA, when present, were generally lower than reported by the private laboratory,” said the FDA. “Given FDA scientists’ deep experience quantifying these impurities in drugs, the agency is confident in the reliability of the FDA’s testing method and results and will continue to take action based on the latest scientific information. The results have also been consistent with the findings of other regulatory agencies’ laboratories around the world.”
Singapore, among other countries, had identified elevated NDMA levels in metformin products distributed there. This prompted the FDA to investigate the US metformin supply in December 2019; regulators from Europe, Canada, and the UK initiated their own metformin investigations. The US investigation found just very low levels of NDMA in some of the metformin samples tested at that time.
(RELATED: Metformin: Regulators Respond After Singapore HSA Recalls Drugs for NDMA Impurities Regulatory Focus 06 December 2019; NDMA in Metformin: FDA Finds Low Levels in Only 2 of 10 Tested Products Regulatory Focus 03 February 2020)
Previous FDA investigations have revealed elevated NDMA levels in angiotensin II receptor blockers (ARBs) and in over-the-counter and prescription ranitidine, which the agency asked manufacturers to withdraw from the market. In the case of ranitidine, testing showed that NDMA levels may increase with time and, when stored at high temperatures, may rise to unacceptable levels. Some ARBS were also recalled.
There are additional manufacturers of the metformin ER formulation that supply a significant portion of the US market, and their products are not being recalled. The FDA is continuing to work closely with manufacturers to ensure appropriate testing. Assessments are underway to determine whether metformin ER recalls will result in shortages and the agency will work closely with manufacturers to prevent or reduce any impact of shortages.


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