Effect of Oral Ranitidine on Urinary Excretion ofN-Nitrosodimethylamine (NDMA)

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 RELEVANCEIn 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.

New science, drug regulation, and emergent public health issues: The work of FDA’s division of applied regulatory science

“…Division of Applied Regulatory Science developed and published a mechanistic COVID-19 disease model that can be used to guide candidate drug selection and dosing strategies Division of applied regulatory science (DARS) designed a rigorous clinical study that carefully controlled for factors known to influence N-nitrosodimethylamine (NDMA) measurements including diet. The study found no evidence of increased NDMA content in participants' urine who were administered ranitidine (12).…”

“…Office of Pharmaceutical Quality, designed a rigorous clinical study that carefully controlled for factors known to influence NDMA exposure and measurements including diet (12). DARS developed and validated a sensitive analytical method that was used to measure NDMA in study participants' urine and blood.…”

“…Additionally, the petitioner postulated that ranitidine could convert to NDMA in people. In response, DARS, working with FDA’s Office of New Drugs and Office of Pharmaceutical Quality, designed a rigorous clinical study that carefully controlled for factors known to influence NDMA exposure and measurements including diet ( 12 ). DARS developed and validated a sensitive analytical method that was used to measure NDMA in study participants’ urine and blood.…”

Orthogonal Chemical Reporter Strategy Enables Sensitive and Specific SERS Detection of Hydrazine Derivatives

“…Over the past few years, NDMA has been recognized as a toxic agent widely found in multiple pharmaceuticals and fermented foods . NDMA is a strong carcinogen with a low acceptable daily limit of the US Food and Drug Administration (0.096 μg or 0.32 ppm per day) and potentially exposes millions of people to a risk of cancer . Therefore, there is a great need for a method for rapidly and sensitively detecting and quantifying NDMA.…”

“…56 NDMA is a strong carcinogen with a low acceptable daily limit of the US Food and Drug Administration (0.096 μg or 0.32 ppm per day) and potentially exposes millions of people to a risk of cancer. 57 Therefore, there is a great need for a method for rapidly and sensitively detecting and quantifying NDMA. Although chromatography/tandem mass spectrometry is a sensitive and reliable technique for ppb-level quantification, the operation process is particularly not suitable for highthroughput screening.…”