Analysis: Potentially high NDMA levels after ranitidine ingestion

Regulatory NewsRegulatory News | 02 February 2021 |  By 

A new analysis showed elevated levels of the contaminant N-nitrosodimethylamine (NDMA) after the ingestion of ranitidine capsules across a range of physiologic conditions, with levels exceeding federal guidelines by several orders of magnitude in some conditions.
The study, conducted under conditions that simulate the human gastric environment, bolsters the U.S. Food and Drug Administration’s request in April 2020 for all ranitidine manufacturers to pull their products from the market.
The agency’s regulatory move, which keeps ranitidine products off the market unless a manufacturer can demonstrate that the product does not generate excess NDMA, came after it was discovered that NDMA levels increased over time and when the product was stored at higher temperatures (RELATED: “FDA seeks withdrawal of heartburn drugs due to new carcinogen concerns,” Regulatory Focus 01 April 2020). NDMA is considered a probable human carcinogen.
In the current analysis, researchers sought to characterize the conditions under which ranitidine could produce NDMA by using liquid chromatography-high resolution mass spectrometry (LC-HRMS) to detect NDMA in simulated gastric fluid. They tested varying pH and nitrite concentrations and with different commercially available doses of the heartburn drug ranitidine (Zantac). The findings were published in a research letter in JAMA Network Open.
The analysis showed NDMA formation from ranitidine in simulated gastric fluid across a range of physiologic conditions; NDMA levels often exceeded the FDA’s acceptable daily intake limit of 96 ng.
Keeping pH constant at 2.5 and increasing the nitrite concentration, 150 mg of ranitidine produced increasing amounts of NDMA after 2 hours. At 1 mmol/L of sodium nitrite, 947 ng of NDMA was detected, while at 50 mmol/L of sodium nitrite, 320,000 ng of NDMA was detected.
NDMA was also elevated (reaching 198,000 ng) for 150 mg or 300 mg tablets of ranitidine when sodium nitrite was constant at 50 mmol/L and the pH was lowered further to 1.2.
Under “optimally reactive physiologic conditions,” with a pH of 2.5 and 50 mmol/L of sodium nitrite, NDMA increased to 612,000 ng from a 300 mg ranitidine tablet.
“The results of this study suggest that ranitidine may be a significant source of NDMA under a range of physiologically relevant conditions,” study author Lior Z. Braunstein, MD, of Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Namely, under simulated gastric conditions, NDMA yield from a standard tablet of ranitidine was seen to increase with both increasing nitrite and decreasing pH to levels up to 3 orders of magnitude beyond established limits.”
Braunstein and colleagues noted that the study had limitations and the conditions simulated may exceed the “usual gastric milieu.”
The results point to the need to investigate other drugs with dimethylamine groups to determine if they create NDMA when stored at higher temperatures or after ingestion, C. Michael White, PharmD, wrote in an accompanying invited commentary.
“If more than 10,000 ng of NDMA can be created by standard ranitidine doses, it is possible that some of these other finished pharmaceutical products could generate doses in excess of 96 ng,” wrote White, of the University of Connecticut School of Pharmacy. “If NDMA is found in dangerous amounts after hot temperature storage or after ingestion, these drugs should likewise be avoided in lieu of other similarly effective alternatives.”
The FDA did not offer a response to the findings of the new analysis. Charles Kohler, a spokesman in the FDA’s Center for Drug Evaluation and Research, said the agency generally does not comment on specific studies, “but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
The analysis was funded through a grant from the National Cancer Institute.
JAMA Network Open


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