What is the pharmaceutical contaminant N-nitrosodimethylamine (NDMA) and what risk does it pose to humans?

Introduction

In July 2018, the Food and Drug Administration (FDA) issued an alert that several pharmaceutical products containing valsartan that were manufactured in China were found to contain unacceptable amounts of an unexpected contaminant, N-nitrosodimethylamine (NDMA).1 This alert was later expanded to include other angiotensin II receptor blockers (ARBs) and combination products containing ARBs manufactured in additional countries; the need for additional product recalls was subsequently identified due to findings of contamination of agents with other carcinogenic compounds, including N-nitroso-N-diethylamine (NDEA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA).1,2 In September 2019, just over a year after the first alerts for contamination of ARBs were posted, the FDA began to issue new alerts due to the finding of NDMA in samples of a new drug, ranitidine.3 The alerts describe NDMA as a probable human carcinogen and the contamination of a number of pharmaceutical products with this impurity has spread concern and mistrust related to the international manufacturing of pharmaceutical products among patients, providers, and a number of other organizations.2 The purpose of this FAQ is to describe NDMA and the process by which it is incorporated into pharmaceutical agents, and review information related to its safety in human beings.

N-nitrosodimethylamine

What is NDMA?

Nitrosamines such as NDMA are formed when a secondary or tertiary amine reacts with a nitrite ion under acidic conditions.4 Once absorbed in the body, NDMA is activated by hydroxylation and ultimately forms a carbonium ion, which can alkylate deoxyribonucleic acid (DNA).4,5 Historically, NDMA was commercially used in the production of rocket fuel, antioxidants, softeners for copolymers, and additives for lubricants; however, it is currently only used for research purposes.6,7 In animal studies, exposure to NDMA in high concentrations through water or food has been associated with an increased risk for developing cancer, most commonly in the liver.6,8 Although there are no data for its carcinogenic potential in humans, NDMA is currently classified as a probable human carcinogen based on animal data.

Today, human exposure to this compound can occur through absorption from the environment, dietary consumption, industrial exposure, or through tobacco products.5,9 On average, the estimated daily intake of NDMA in humans is between 6 and 12 ng through drinking water, 0.1 ng per cubic meter of air, and between <0.16 and 134 mcg in food.8 Higher concentrations of NDMA can be found in nitrite-preserved foods, including cured meats, salami, frankfurters, smoked, dried, or salted fish, and malt beverages.4,8 Using methods described in the “ICH Guidance M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” document issued by the United States Department of Health and Human Services, FDA, Center for Drug Evaluation and Research (CDER), and Center for Biologics Evaluation and Research (CBER), the FDA determined that ingestion of ≤ 96 ng of NDMA per day should be reasonably safe in humans, and would lead to an overall lifetime risk of < 1 incident case of cancer per 100,000 people exposed.1

How does NDMA become a contaminant in pharmaceutical products?

As mentioned previously, industrial manufacturing processes can lead to unintentional production of NDMA. This occurs via chemical reactions that produce alkylamines; plants that manufacture amines, pesticides, dyes, or rubber/tires may produce NDMA during the manufacturing process.7 Tanneries, foundries, fish processing facilities, and surfactant industries have also been implicated in the inadvertent production of NDMA.

After the initial reports of NDMA contamination of the ARBs were further investigated, it was found that incorporation of the impurity initially correlated to a change in manufacturing that began in 2012 to limit the amount of waste and increase the amount of drug product produced.10 To do so, the company changed the process to form the tetrazole ring in the valsartan molecule with sodium azide, which is more reactive, rather than the previous compound, tributyltin azide.10,11 Dimethyl formamide was used as a solvent in this reaction, and sodium nitrite was then required to eliminate excess sodium azide. Under acidic conditions, sodium nitrite forms nitrous acid, which can then react with a degradation product of the solvent, dimethylamine, to ultimately create NDMA.

Risk of NDMA exposure in humans via contaminated pharmaceuticals

FDA determination of risk

The FDA has performed a number of laboratory tests to determine the level of NDMA contamination within specific ARB product or ARB combination product lots produced by manufacturers that were found to be implicated.1 They have also published two separate documents that provide methods for drug manufacturers to perform their own testing on pharmaceutical products to determine whether NDMA contamination is present, and, if so, the concentration of NDMA within the tested product.1,3 After testing, reported average concentrations of NDMA per tablet of various ARB products ranged from concentrations that were below the level of detection to concentrations as high as 20 mcg per tablet; these levels were determined based on the highest possible daily dose that a patient might take of a particular product. Laboratory testing results also indicated that the product impurities may have been present in certain lots of the ARB products for as many as 4 years. Based on the values found in their evaluation, the FDA estimated that if 8,000 patients took 320 mg (the highest dose) of NDMA-contaminated valsartan per day, one additional case of cancer would develop over the lifetimes of all 8,000 patients. Of note, specific data on the concentration of NDMA in ranitidine products are not yet available, since laboratory testing is currently ongoing.3

Literature evaluation

A literature search was performed to identify any literature evaluating the potential risk to humans from NDMA exposure via contaminated pharmaceutical agents, and one study was identified.12 This observational registry study evaluated cancer risk over time in a cohort of 5150 Danish patients that were ≥ 40 years of age, did not have a history of cancer, and used valsartan between January 1, 2012 and June 30, 2017. Prevalent and incident users of valsartan during the study period were followed until they migrated, had a cancer outcome, died, or the study period ended. Individual patient exposures to NDMA contamination were mapped, and prescriptions for valsartan that were considered to be “probably” or “possibly” contaminated with NDMA were pooled for the analysis. N-nitrosodimethylamine exposure was further stratified by cumulative dose of valsartan from prescriptions that were filled with NDMA-containing valsartan tablets, and a 1-year lag time was applied to account for patients that had more recent exposures to NDMA who would be less likely to receive a diagnosis of cancer. The primary outcome was a composite of all cancer diagnoses, which were obtained from registry data. To assess this outcome, the authors compared cancer occurrence during follow up in patients exposed to NDMA to cancer occurrence in patients that were not exposed to NDMA. When considering 5150 patients evaluated over a median period of 4.6 years, exposure to valsartan products that were potentially contaminated with NDMA did not appear to increase the risk for development of cancer compared to use of valsartan products that were not contaminated (adjusted hazard ratio, 1.09; 95% confidence interval, 0.85 to 1.41). This remained consistent regardless of the cumulative dose received, and a dose-response relationship was not observed (p=0.70). Although this epidemiologic study did not show a short-term risk of cancer in humans exposed to NDMA via contaminated valsartan, it is unclear what the long-term risk of these exposures might be.

Conclusion

Based on data in animals, NDMA is likely to be a carcinogen in humans. Although direct data for carcinogenicity in humans are lacking, the FDA has determined that the amount of NDMA in certain lots of contaminated pharmaceutical products far exceeds the 96 ng daily dose that they have determined to be reasonably safe. However, it is unclear what the actual risk for development of cancer will be for patients who have taken the affected products, since the concentration of NDMA is highly variable across contaminated products. Data from a single epidemiologic study of patients who took valsartan tablets that were possibly contaminated with NDMA over several years do not show an increased risk for development of cancer; however, at this time the long-term risk to humans is unknown. Providers should keep up-to-date with recommendations from the FDA regarding products with NDMA contamination, as testing of new lots and agents continues to occur.

References

  1. FDA updates and press announcements on angiotensin II receptor blocker (ARB) recalls (valsartan, losartan, and irbesartan) U.S. Food and Drug Administration website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan. Updated October 15, 2019. Accessed October 15, 2019.
  2. Byrd JB, Chertow GM, Bhalla V. Hypertension hot potato- anatomy of the angiotensin-receptor blocker recalls. N Engl J Med. 2019;380(17):1589-1591.
  3. FDA updates and press announcements on NDMA in Zantac (ranitidine). U.S. Food and Drug Administration website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine. Updated October 2, 2019. Accessed October 15, 2019.
  4. Harrison RJ. Chemicals. In. LaDou J, Harrison RJ, eds. CURRENT Diagnosis & Treatment: Occupational & Environmental Medicine. 5th New York, NY: McGraw-Hill; 2013. http://accessmedicine.mhmedical.com/content.aspx?bookid=1186&sectionid=66483018. Accessed October 17, 2019.
  5. Choudhuri S, Chanderbhan RF, Mattia A. Food toxicology: fundamental and regulatory aspects. In. Klaassen CD, ed. Casarett & Doull’s Toxicology: The Basic Science of Poisons. 9th ed. New York, NY: McGraw-Hill Education; 2019. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2462&sectionid=202677794. Accessed October 22, 2019.
  6. N-Nitrosodimethylamine; CASRN 62-75-9. United States Environmental Protection Agency website. https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0045_summary.pdf. January 31, 1987. Accessed October 23, 2019.
  7. Technical fact sheet- N-nitroso-dimethylamine (NDMA). United States Environmental Protection Agency Website. https://www.epa.gov/sites/production/files/2017-10/documents/ndma_fact_sheet_update_9-15-17_508.pdf. November 2017. Accessed October 23, 2019.
  8. N-nitrosodimethylamine. Hazardous Substances Data Bank [database online]. Bethesda, MD: National Library of Medicine (US); 2013. Available at: https://toxnet.nlm.nih.gov/newtoxnet/hsdb.htm. Accessed October 16, 2019.
  9. Kaplan BF, Sulentic CW, Haggerty HG, Holsapple MP, Kaminski NE. Toxic responses of the immune system. In. Klaassen CD, ed. Casarett & Doull’s Toxicology: The Basic Science of Poisons. 9th New York, NY: McGraw-Hill Education; 2019. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2462&sectionid=202673401. Accessed October 22, 2019.
  10. Charoo NA, Ali AA, Buha SK, Rahman Z. Lesson learnt from recall of valsartan and other angiotensin II receptor blocker drugs containing NDMA and NDEA impurities. AAPS PharmSciTech. 2019;20(5):166.
  11. Snodin DJ, Elder DP. Short commentary on NDMA (N-nitrosodimethylamine) contamination of valsartan products. Regul Toxicol Pharmacol. 2019;103:325-329.
  12. Pottegård A, Kirstensen KB, Ernst MT, Johansen NB, Quartarolo P, Hallas J. Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study. BMJ. 2018;362:k3851.

Prepared by:
Jessica Zacher, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

November 2019

The information presented is current as of October 3, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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