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

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 primari...

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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
Citations: Items that this one cites
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Summary: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
ISSN:0098-7484
1538-3598
DOI:10.1001/jama.2021.9199