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Original Investigation
June 28, 2021

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

Author Affiliations
  • 1Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 2Booz Allen Hamilton, McLean, Virginia
  • 3Spaulding Clinical Research, West Bend, Wisconsin
  • 4Division of Inflammation and Immune Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 5Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 6Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St Louis, Missouri
  • 7Division of Gastroenterology, Office of Immunology and Inflammation, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
JAMA. 2021;326(3):240-249. doi:10.1001/jama.2021.9199
Key Points

Question  What is the 24-hour urinary excretion of N-nitrosodimethylamine (NDMA), a probable human carcinogen, after oral ranitidine (300 mg) compared with placebo?

Findings  In this crossover, randomized clinical trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when administered with a noncured-meats diet or a cured-meats diet (median of the paired differences, 0 [interquartile range, −6.9 to 0] ng and −1.1 [interquartile range, −9.1 to 11.5] ng, respectively).

Meaning  The findings do not support that ranitidine is converted to NDMA in a general, healthy population.

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

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