N-nitrosodimethylamine (NDMA) contamination of ranitidine products: A review of recent findings.
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ABSTRACT:
SUBMITTER: Aldawsari FS
PROVIDER: S-EPMC9261846 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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N-nitrosodimethylamine (NDMA) contamination of ranitidine products: A review of recent findings.
Aldawsari Fahad S FS Alshehry Yahya M YM Alghamdi Thamer S TS
Journal of food and drug analysis 20210315 1
Ranitidine is a medication that has been used to alleviate heartburn and other disorders for over 40 years. Following reports of N-nitrosodimethylamine (NDMA) contamination in ranitidine products, there have been many recalls and registration suspensions. Here, we revise the literature information confirming ranitidine association with NDMA. Then, we highlight the documented mechanisms for NDMA release from ranitidine. In addition, the stability issue for this medicine is discussed. After that, ...[more]
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Project description:ImportanceA publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies.ObjectiveTo characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels.Design, setting, and participantsOne 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method.Main outcomes and measuresNDMA detected in simulated gastric fluid 2 hours after adding ranitidine.ResultsAt a supraphysiologic nitrite concentration (ie, 10 000 μmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L).Conclusions and relevanceIn this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.
| S-EPMC8239951 | biostudies-literature
Project description:ImportanceIn 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.ObjectiveTo evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo.Design, setting, and participantsRandomized, 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.InterventionsParticipants 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 measureTwenty-four-hour urinary excretion of NDMA.ResultsAmong 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.Trial registrationClinicalTrials.gov Identifier: NCT04397445.
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Project description:ObjectiveTo perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products.DesignNationwide cohort study.SettingDanish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses.Participants5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant's exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag.Main outcome measuresAssociation between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analyses, the risk of individual cancers was determined.ResultsThe final cohort comprised 5150 people followed for a median of 4.6 years. In total, 3625 cohort participants contributed 7344 person years classified as unexposed to NDMA, and 3450 participants contributed 11 920 person years classified as ever exposed to NDMA. With 104 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P=0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null.ConclusionsThe results do not imply a markedly increased short term overall risk of cancer in users of valsartan contaminated with NDMA. However, uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk.
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Project description: Not available
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Project description:N-Nitrosodimethylamine (NDMA) detected above the acceptable level in ranitidine products has been a great global concern. To examine the risk of cancer among people treated with ranitidine, we conducted a cohort study using the National Health Insurance Service-National Sample Cohort data (2002-2015) of South Korea. Patients were aged 40 or above as of January 2004 and began receiving ranitidine or other histamine-2 receptor antagonist (H2RA), active comparator, without a history of H2RAs prescription during the prior 2-years. The lag time was designated up to 6 years. The outcomes were an overall incident cancer risk and the risk of major single cancers during the follow-up. The association between ranitidine use and cancer risk was examined by Cox regression model. After exclusion and propensity score matching, 25,360 patients were available for analysis. The use of ranitidine was not associated with the overall cancer risk and major individual cancers [overall cancer: incidence rate per 1000 person-years, 2.9 vs 3.0 among the ranitidine users and other H2RAs users, respectively; adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for all cancers, 0.98 (0.81-1.20)]. The higher cumulative exposure to ranitidine did not increase the cancer risk. Given the insufficient follow-up period, these findings should be interpreted carefully.
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Project description:The use of herbal medicinal products (HMPs) has grown significantly across low-and-middle-income countries (LMICs). Consequently, the safety of these products due to contamination is a significant public health concern. This systematic review aimed to determine the prevalence, types, and levels of contaminants in HMPs from LMICs. A search was performed in seven online databases, i.e., Africa journal online (AJOL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Directory of Open Access Journals (DOAJ), Health Inter-Network Access to Research Initiative (HINARI), World Health Organization Global Index Medicus (WHO GIM), Scopus, and PubMed using appropriate search queries and reported as per the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines. Ninety-one peer-reviewed articles published from 1982 to 2021 from 28 different countries across four continents were included in the study. Although metals, microbial, mycotoxins, pesticides, and residual solvents were the reported contaminants in the 91 articles, metals (56.0%, 51/91), microbial (27.5%, 25/91), and mycotoxins (18.7%, 17/91) were the most predominant. About 16.4% (1236/7518) of the samples had their contaminant levels above the regulatory limits. Samples tested for microbial contaminants had the highest proportion (46.4%, 482/1039) of contaminants exceeding the regulatory limit, followed by mycotoxins (25.8%, 109/423) and metals (14.3%, 591/4128). The proportion of samples that had their average non-essential metal contaminant levels above the regulatory limit was (57.6%, 377/655), 18.3% (88/480), 10.7% (24/225), and 11.3% (29/257) for Pb, Cd, Hg, and As, respectively. The commonest bacteria species found were Escherichia coli (52.3%, 10/19) and Salmonella species (42.1%, 8/19). This review reported that almost 90% of Candida albicans and more than 80% of moulds exceeded the required regulatory limits. HMP consumption poses profound health implications to consumers and patients. Therefore, designing and/or implementing policies that effectively regulate HMPs to minimize the health hazards related to their consumption while improving the quality of life of persons living in LMICs are urgently needed. Highlights • A systematic review of contaminants in HMPs using PRISMA guidelines was conducted.• The study included 91 articles from 1982 to 2021 in 28 countries across 4 continents.• Metals, microbial, and mycotoxins were the most predominant contaminants identified.• Almost 16% of the samples had their contaminant levels above the regulatory limits.• The highest proportion of contaminants exceeding the regulatory limit was microbial.
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