NEW YORK (Reuters Health) – Contrary to earlier and now-retracted findings, oral ranitidine appears to have no tangible role in the production of cancer-causing N-nitrosodimethylamine (NDMA) within the body, according to research funded by the U.S. Food and Drug Administration (FDA).
As Dr. David G. Strauss told Reuters Health by email, “This randomized, placebo-controlled study was designed and conducted to further investigate the findings from a prior small clinical study that observed an approximately 400-fold increase in 24-hour urinary excretion of NDMA, a probable human carcinogen.”
Dr. Strauss of the FDA’s Center for Drug Evaluation and Research, in Silver Springs, Maryland, and colleagues studied 18 healthy men and women with a median age of 33 years. The participants were randomized in a crossover fashion to four treatment sequences over four periods during a clinic stay of 10 days. They received ranitidine (300 mg) or placebo along with a diet including or not including cured meats. The primary outcome was 24-hour urinary excretion of NDMA.
“Each participant received a diet with noncured meats, organic vegetables/fruits and distilled water (noncured-meats diet) for 4 days and then cured meats, conventional vegetables/fruits, and tap water (cured-meats diet) for 4 days,” the researchers explain in JAMA. “The second diet was designed based on the literature to have higher nitrite, nitrate, and NDMA levels.”
Whether administered with or without cured meats, ranitidine did not significantly raise 24-hour urinary NDMA excretion (median of the paired differences, -1.1 ng and 0 ng, respectively).
“In addition, ranitidine did not significantly increase NDMA in blood or the precursor to NDMA, which is called DMA, in blood or urine,” said Dr. Strauss. “The lack of a significant increase occurred despite administering a 300 mg dose versus a 150 mg dose and having participants consume a diet designed to be higher in nitrites, which laboratory studies have suggested can potentiate NDMA formation.”
Moreover, “After completion of our trial and submission of the report to JAMA, the prior clinical study was retracted. In addition, the prior laboratory studies, that had suggested ranitidine could convert to NDMA in people’s stomachs, had used excessive nitrite concentrations far beyond physiologic levels. Taken together our findings suggest that ranitidine is not converted to NDMA in people.”
Dr. Strauss noted that although “ranitidine products were withdrawn from the U.S. market in April 2020 because of higher-than-acceptable NDMA amounts being detected in the drug product, the approvals were not withdrawn. As previously stated by FDA, the agency may consider allowing ranitidine product back on the market if a specific product is stable and NDMA amounts do not increase to unsafe levels over time during storage.”
The FDA issued its request for immediate withdrawal of “all prescription and over-the-counter (OTC) ranitidine drugs” on April 1, 2020. (https://bit.ly/36iYt0D)
Dr. C. Michael White of the University of Connecticut School of Pharmacy, in Storrs, coauthor of an accompanying editorial, told Reuters Health by email, “This is the best study conducted to date in this area and shows that ranitidine is unlikely to form the cancer-causing chemical NDMA inside the human body under normal conditions.”
“However,” Dr. White pointed out, “long-term users may still have been exposed to too much NDMA because ranitidine pills degrade to form NDMA as it sits on the store shelves or in medicine cabinets.”
SOURCE: https://bit.ly/3hjWVcX JAMA, online June 28, 2021.
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