Effect of Oral Ranitidine on Urinary Excretion of N-Nitrosodimethylamine (NDMA): A Randomized Clinical Trial

Abstract

Importance: In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption.

Objective: To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo.

Design, setting, and participants: Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020.

Interventions: Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA.

Main outcome and measure: Twenty-four-hour urinary excretion of NDMA.

Results: Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported.

Conclusions and relevance: In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population.

Trial registration: ClinicalTrials.gov Identifier: NCT04397445.

Figure 1.. Flow of Participants in Study, Interventions, and Overall Study Design

^aThe most common reason for participant exclusion was a history of Helicobacter pylori infection or ulcer disease or a positive H pylori breath test result (n = 12). Additional reasons for exclusion: abnormal medical history findings, clinical laboratory results, vital sign measurements, 12-lead electrocardiogram results, or physical examination findings at screening (n = 5); having signs or symptoms consistent with COVID-19 (n = 3); nicotine use within 6 weeks of screening (n = 1); history of clinically significant disorder, condition, or disease (n = 1); or clinically significant laboratory results (n = 1). ^bA sample size of 14 participants was determined to have greater than 90% power to detect an increase in 24-hour urinary excretion of N-nitrosodimethylamine (NDMA). Eighteen participants were randomized in a single cohort to account for potential dropouts without needing to enroll an additional cohort. This was done so all participants would be served identical meals with the same sourcing of fresh foods to avoid potential variability in nitrite, nitrate, or NDMA content. Because there was a delay between screening and determining final eligibility for the study (eg, receiving all laboratory tests), 10 additional people met all inclusion criteria and were eligible to be alternates (eg, if someone had to cancel or did not show up at check-in) or replacements (eg, if there had been fewer than 14 completers and a second cohort was enrolled). ^cRandomization was conducted in block sizes of 4. The remaining 2 participants were randomly placed in 2 of the 4 treatment sequences.

Figure 2.. Twenty-Four–Hour Urinary Excretion and Maximum Plasma Concentration of NDMA and DMA by Treatment

Individual participant (n = 17) observed data and box-and-whisker plot summaries. The line through each box represents the median. The lower and upper borders of the box represent the 25th and 75th percentile, respectively. The whisker extends from the box border to the last observation within 1.5 times the interquartile range. Twenty-four–hour urinary excretion and maximum plasma concentration of ranitidine by treatment are shown in eFigure 7 in Supplement 2. DMA indicates dimethylamine; NDMA, N-nitrosodimethylamine. ^aTwo participants had 24-hour urinary excretion of NDMA in 1 or more periods that are outside the scale of the graph in panel A. Participant 12 had a cumulative NDMA excretion of 512 ng with the ranitidine/noncured-meats diet, 649 ng with the ranitidine/cured-meats diet, and 746 ng with the placebo/cured-meats diet (see post hoc assessments section of the Results and eTable 6 in Supplement 2 for additional information on this participant). Participant 03 had a cumulative NDMA excretion of 271 ng with the placebo/cured-meats diet.

Figure 3.. Effect of Ranitidine and Diet on Cumulative Excretion of NDMA in Urine Over 24 Hours

Paired differences in cumulative excretion of N-nitrosodimethylamine (NDMA) in urine over 24 hours. At each listed time point on the x-axis since study drug administration (ie, 0 [pre-dose], 3, 6, 9, 12, 15, and 24 hours), the y-axis shows the median (point) and interquartile range (lines) of the paired differences in cumulative NDMA excretion between the 2 specific treatment groups up until that time point. Note that the median and interquartile range of the paired differences is calculated by first determining the difference between 2 treatments for each individual participant and then determining the median and interquartile range of those values. Ranitidine or placebo was administered at 0 hours. Meals were administered at 0, 4, 7.5, and 11.5 hours. Individual participant profiles for each treatment group are shown in eFigure 1 in Supplement 2.