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Nitrosamine impurities in the H2 inhibitor ranitidine (Zantac) do not appear to be converted to N-nitrosodimethylamine (NDMA), a probable human carcinogen, in a healthy population, according to a randomized phase I trial of 18 participants.

The study found no statistically significant difference in 24-hour urinary excretion of NDMA with oral 300-mg ranitidine compared with placebo, reported David Strauss, MD, PhD, of the FDA's Center for Drug Evaluation and Research, and colleagues.

"The lack of a significant increase occurred even when participants were served a diet designed to be higher in nitrites, which in vitro studies have suggested can potentiate NDMA formation. Furthermore, exploratory analyses did not reveal any significant difference between ranitidine and placebo for NDMA in plasma or DMA [dimethylamine] in urine or plasma," they wrote in .

Strauss and team noted that the study followed a 2019 citizen petition to the FDA stating that specific lots of ranitidine contained NDMA and could convert to NDMA in humans, which led to the drug's subsequent withdrawal from market.

This study was designed to investigate the findings from a 2016 study () that linked use of ranitidine with approximately 400-fold and 2.5-fold increases in 24-hour urinary excretion of NDMA and DMA, respectively, the group explained.

"The most important part of the study ... may be that the investigators devised and validated a process [using and analytic techniques] 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. By not using these ... techniques on their urine samples, it is likely that [the 2016] study on urinary NDMA did not detect NDMA produced in the body," noted C. Michael White, PharmD, and Adrian Hernandez, MD, PhD, of the University of Connecticut School of Pharmacy in Storrs, in an .

For the study, 18 healthy volunteers (median age 33) were randomized to a diet lower or higher in nitrates/nitrites, as reflected by non-cured meats or cured meats. The group was split evenly between men and women; 39% were white, 61% were African American, and 17% were Hispanic or Latino.

The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (interquartile range [IQR] 0-29.7) and 10.5 ng (IQR 0-17.8), respectively, with a non-cured meats diet, and 11.9 ng (IQR 5.6-48.6) and 23.4 ng (IQR 8.6-36.7), respectively, with a cured meats diet.

The researchers found no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a non-cured meats diet (median of the paired differences 0 ng, P=0.54) or a cured meats diet (median of the paired differences -1.1 ng, P=0.71).

White and Hernandez noted some limitations to the study, including that ranitidine was administered with breakfast rather than dinner, as recommended in the drug labeling, which meant that investigators might have missed a saliva source of nitrites. In addition, the effects observed in healthy participants may not be reproduced in those with disorders that affect gastric pH and flora, such as chronic reflux disease or ulcers.

Strauss and team also acknowledged that the use of healthy volunteers was a limitation, as was the fact that the exact dietary amounts of nitrite, nitrate, and NDMA were not known.

In a separate in vitro study of NDMA formation after the addition of one ranitidine tablet (150 mg) to 50 mL and 250 mL of simulated gastric fluids with a range of nitrite concentrations, it was found that NDMA was not detected until the nitrite level reached 5,000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These results were published online in by David Keire, PhD, also of the FDA's Center for Drug Evaluation and Research, and colleagues.

"The vast differences in NDMA production between 50 mL vs 250 mL of 5,000 μmol/L sodium nitrite in the study ... clearly shows that the amount rather than the concentration of nitrite in contact with ranitidine is the driver of NDMA production," the editorialists wrote, adding that the study referenced 27 other studies supporting "that nitrite concentrations in a physiologic stomach environment would be unlikely to exceed 100 μmol/L."

Given the potential 2-L stomach volume of an obese person, "it cannot be excluded that ranitidine use with a large acidic and nitrite-rich meal could drive appreciable NDMA production," they noted. "Importantly, at higher nitrite concentrations, [Keire and team] found much greater production of NDMA at lower pH levels, suggesting that little conversion of ranitidine to NDMA would occur in the intestines or the bloodstream."

However, "despite the reassuring data from these 2 FDA studies, patients and clinicians should not expect the return of ranitidine to the market anytime soon," White and Hernandez cautioned.