Ranitidine, which blocks histamine-induced acid secretion in the stomach, was approved in 1983. It became widely used over the ensuing decades as a prescription and over-the-counter product. In 2019, the FDA received a citizen petition indicating that high levels of N-nitrosodimethylamine (NDMA), a probable human carcinogen, were detected in specific ranitidine products. The petitioner also proposed that ranitidine could convert to NDMA in humans. In response, the FDA immediately alerted the public, and CDER scientists worked quickly to mobilize specialized FDA laboratory and clinical research capabilities.
CDER’s initial research focused on assessing the amount of NDMA in ranitidine drug products. CDER researchers found that the procedures previously used to quantify NDMA were not appropriate for assessing its presence in ranitidine, owing to the use of high temperatures that could convert ranitidine to NDMA during that analysis. CDER researchers therefore developed and validated low-temperature analytical methods and found that the amounts of NDMA contained in ranitidine products were 3,000-fold lower than those reported in the citizen petition; however, these lower amounts of NDMA were still above the FDA-acceptable level, corresponding to a daily intake limit of 96 ng NMDA per day, in many of the ranitidine lots tested. CDER scientists further observed that the amounts of NDMA in ranitidine samples could increase over time, prompting the FDA to request the market withdrawal of ranitidine products. The agency noted, however, that if ranitidine products could be manufactured to control NDMA amounts, they could be allowed back on the market—but additional information would first be needed to understand whether NDMA could form in vivo from ranitidine in humans.
Assessing the Potential for Ranitidine to Convert to NDMA in Humans
The citizen petition referenced in vitro studies suggesting ranitidine could convert to NDMA in simulated gastric fluid (with high levels of supplemental nitrite) and a prior clinical studyExternal Link Disclaimer with 10 participants. The referenced clinical study reported an approximate 400-fold increase in NDMA excreted in urine over 24-hours after oral ranitidine 150 mg. However, there were multiple limitations to the referenced study, including the lack of placebo-controlled randomization; the lack of information concerning environmental or dietary exposure of study participants to NDMA or the reactants that may contribute to NDMA production; and a lack of detail about biological sample handling and validation of analytical methods.
To better address the possibility of NDMA production from ranitidine in humans, CDER scientists conducted a more rigorous, randomized, double-blinded, placebo-controlled clinical trial, published in JAMA: Journal of the American Medical AssociationExternal Link Disclaimer. The study included 18 participants who each received ranitidine (300 mg) and placebo on two different diets, the second of which was designed to contain higher amounts of nitrites, nitrates, and NDMA from foods such as cured meats. The study used rigorous procedures for handling urine and blood samples and validated low-temperature analytical methods for measuring NDMA. The CDER researchers found no evidence of elevated NDMA content in the urine of participants over the 24 hours after they took ranitidine, regardless of diet. CDER’s clinical trial further found that ranitidine did not increase NDMA in blood plasma and did not increase dimethylamine (DMA) (proposed in the citizen petition to be the precursor to NDMA generated from ranitidine) in plasma or urine.
In addition, CDER researchers conducted an in vitro study, also published by the JAMA networkExternal Link Disclaimer, on the potential for ranitidine to convert to NDMA in simulat...
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