FDA studies: No post-ingestion NDMA from ranitidine

Regulatory NewsRegulatory News | 30 June 2021 |  By 

An editorial that accompanied two recent studies examining the potential for nitrosamine formation from the antacid ranitidine welcomed reassuring news provided by the US Food and Drug Administration- (FDA-) led investigations.
The two FDA-led studies taken together “should serve to alleviate much of the previous concern about [N-nitrosodimethylamine] production of dimethylamine drugs in the human body,” according to C. Michael White of the School of Pharmacy at the University of Connecticut and Adrian Hernandez of Hartford (CT) Hospital and Lima, Peru’s Universidad San Ignacio de Loyola, writing in the 28 June online edition of JAMA.
In April 2020, FDA requested that all ranitidine be pulled from the market because of the risk of contamination with the potential carcinogen N-nitrosodimethylamine (NDMA).
Since then, “FDA meticulously evaluated sources of NDMA and other nitrosamine contamination during the manufacturing process and established new procedures that manufacturers can take to prevent this issue from occurring in the future,” explained White and Hernandez. (RELATED: N-Nitrosamine impurities: FDA issues detection, prevention guidance, Regulatory Focus 01 September 2020)
The authors commented on a pair of new FDA-led studies. The first, led by Jeffry Florian of FDA’s Office of Clinical Pharmacology at the Center for Drug Evaluation and Research (CDER), was a randomized crossover clinical trial of 18 participants who ingested either 300 mg of ranitidine or placebo and then ingested either a noncured-meats diet or a cured-meats diet.
Ranitidine and certain other dimethylamine drugs can form NDMA because of product degradation over time and with exposure to a common drinking water disinfectant, researchers have found. An older 2016 study also found NDMA in the urine of individuals taking NDMA. Another in vitro study conducted in 2021 found that large amounts of NDMA were created in acidic conditions that simulated the human stomach when ranitidine was introduced in conjunction with sodium nitrite, which is present in some foods and may be created with the metabolism of dietary nitrates, common in cured foods.
Florian and his coauthors, examining 24-hour urine collection samples from participants, found no statistically significant difference in urinary NDMA levels between participants ingesting ranitidine or placebo. The dietary variable of the presence or absence of cured meats did not affect urinary NDMA levels. “The findings do not support that ranitidine is converted to NDMA in a general, healthy population,” wrote Florian and his colleagues.
In comparing the recent FDA study to the 2016 urinary NDMA study, White and Hernandez observed that the earlier study did not use “FDA-developed stabilization and analytic techniques on their urine samples,” making it likely that the NDMA detected was not produced in the body, but rather may have been “subsequently created ex vivo,” according to White and Hernandez. That study was later retracted.
“The most important part of the study by Florian et al may be that the investigators devised and validated a process to ensure that the NDMA quantified in a urine sample represented what was created in the body and not what was subsequently created ex vivo,” wrote the editorialists. This method averts the potential for erroneously identifying urinary NDMA as having been produced in the body, the likely problem in the retracted study.
The second new study discussed by Hernandez and White was also led by an FDA official, Zongming Gao of CDER’s Division of Complex Drug Analysis and Division of Pharmaceutical analysis within the Office of Pharmaceutical Quality.
Gao and colleagues added 150-mg ranitidine to simulated gastric fluid and then varied gastric nitrite concentrations from the upper range of physiologic levels to supraphysiologic levels. The authors varied the acidity of the simulated gastric fluid as well, finding that “NDMA did not form when gastric nitrite concentrations were at the upper range of physiologic or at nitrite concentrations as much as 50-fold greater than the upper range.”
In comparing the recent work by GAO with the older stomach simulation study, White and Hernandez noted that the researchers in the earlier study only used levels of nitrite that have not been empirically observed to occur in the human stomach, though theoretical risks remain.
The editorialists also observed that a small human study with healthy participants and an in vitro study “are far from definitive evidence.” Many variables relating to the human condition – the presence of obesity, whether an individual was fed or fasted at the time of dimethylamine drug ingestion, the acidity of a meal – may alter the risk of NDMA production within the body.
Though the gestalt from the two studies is reassuring, “patients and clinicians should not expect the return of ranitidine to the market anytime soon,” wrote White and Hernandez, observing that alternative medicines exist that do not form NDMA.


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Tags: FDA, NDMA, nitrosamines, US

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