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

• Published in: JAMA : the journal of the American Medical Association 2021-07, Vol.326 (3), p.240-249
• Main Authors: Florian, Jeffry, Matta, Murali K, DePalma, Ryan, Gershuny, Victoria, Patel, Vikram, Hsiao, Cheng-Hui, Zusterzeel, Robbert, Rouse, Rodney, Prentice, Kristin, Nalepinski, Colleen Gosa, Kim, Insook, Yi, Sojeong, Zhao, Liang, Yoon, Miyoung, Selaya, Susan, Keire, David, Korvick, Joyce, Strauss, David G
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Adverse events; African Americans; Bacteria; Carcinogens; Clinical trials; Cross-Over Studies; Denitrifying bacteria; Diet; Dimethylnitrosamine - urine; Double-Blind Method; Double-blind studies; Drugs; Ethnicity; Excretion; Female; Histamine H2 Antagonists - administration & dosage; Histamine H2 Antagonists - pharmacokinetics; Humans; Male; Management; Minority & ethnic groups; N-Nitrosodimethylamine; Nitrates; Nitrites; Online First; Oral administration; Original Investigation; Petition; Pharmacology; Placebos; Placebos - pharmacokinetics; Ranitidine; Ranitidine - administration & dosage; Ranitidine - pharmacokinetics; Regulatory agencies; Statistical analysis
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2021.9199

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 REGIST