Updates on NMDA Contaminations in Medications

First it was multiple angiotensin receptor blockers (ARBs), then ranitidine, and now perhaps metformin?

N-nitrosodimethylamine (NDMA) is classified as a probable human carcinogen based on animal laboratory tests. NDMA is a by-product of several industrial processes, and is primarily used in laboratory research to induce tumors in experimental animals. At high doses, NDMA is hepatotoxic to rats.¹

The acceptable human daily intake of NDMA, according to the FDA, is 96 nanograms or 0.32 parts per million. NDMA can be found in medications from the drug’s manufacturing process, the medication’s chemical structure, or storage or packaging conditions.²

NDMA contamination in medications has caused concern among consumers, and health care professionals after WHO recalled 1159 lots of ARBs including valsartan, losartan, and irbesartan.³

A recent article published in Circulation indicates that the valsartan recall may have increased emergency department (ED) visits for hypertension in Canada, due to patients self-discontinuing the medication. The study used a segmented regression analysis comparing recalled valsartan users and the impact of non-valsartan medication use, identifying valsartan users by various means.⁴ More population health impact studies need to be done to determine a causal relationship between patients self-discontinuing recalled medications and adverse health outcomes.

The next wide recall associated with NDMA contamination was ranitidine, available by prescription or over the counter. The FDA released its first statement on ranitidine contamination on September 13, 2019 and has since recalled 229 lots of the drug.⁵ The FDA is advising patients who take ranitidine and wish to stop to talk to their care professionals about treatment options.⁶

One manufacturer found NDMA in the same medication class as ranitidine. On January 8, 2020, Mylan Pharmaceuticals issued a voluntary nationwide recall of 3 lots of Nizatidine Capsules, USP due to trace amounts of NDMA contained in the active pharmaceutical ingredient (API) nizatidine. The API is manufactured by Solara Active Pharma Sciences Limited.⁷

Metformin, the first-line agent for type 2 diabetes, is now under the microscope. According to a recent FDA statement, low levels of NDMA were reported in metformin in other countries. The FDA is currently investigating whether metformin in the United States contains NMDA above the daily intake limit of 96 nanograms.⁸

In the past year and a half, probable carcinogen NMDA has been found at levels above the acceptable daily limit in multiple medications. The FDA is continuing to investigate how NDMA contaminated each of these medications. Pharmacists and other health care professionals can stay updated by regularly checking the FDA Drug Recall website and news sources.

Krystal Scinto is a 2020 PharmD Candidate at the University of Connecticut in Storrs.

REFERENCES

• PubChem, U.S. National Library of Medicine. Compound summary: N-nitrosodimethylamine. https://pubchem.ncbi.nlm.nih.gov/compound/6124. Published September 16, 2004. Updated January 4, 2020. Accessed January 7, 2020.
• U.S. Food and Drug Administration. Questions and Answers: NDMA impurities in ranitidine (commonly known as Zantac.) https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-ranitidine-commonly-known-zantac. Published November 1, 2019. Accessed January 7, 2020.
• U.S. Food and Drug Administration. Search List of Recalled Angiotensin II Receptor Blockers (ARBs) including Valsartan, Losartan and Irbesartan. https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and. Published September 23, 2019. Accessed January 7, 2020.
• Jackevicius C, et al. Population impact of generic valsartan recall. Circulation. https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.119.044494. Published November 11, 2019. Accessed January 7, 2020.
• U.S. Food and Drug Administration. Search List of Recalled Ranitidine. https://www.fda.gov/drugs/drug-safety-and-availability/drug-recalls. Published December 31, 2019. Accessed January 7, 2020.
• U.S. Food and Drug Administration. FDA Updates and Press Announcements on NDMA in Zantac (ranitidine). https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine. Published December 14, 2019. Accessed January 7, 2020.
• U.S. Food and Drug Administration. Mylan Initiates Voluntary Nationwide Recall of Three Lots of Nizatidine Capsules, USP, Due to the Detection of Trace Amounts of NDMA (N-Nitrosodimethylamine) Impurity Found in the Active Pharmaceutical Ingredient Manufactured by Solara Active Pharma Sciences Limited. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/mylan-initiates-voluntary-nationwide-recall-three-lots-nizatidine-capsules-usp-due-detection-trace#recall-announcement. Published January 8, 2020. Accessed January 9, 2020.
• U.S. Food and Drug Administration. Statement from Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research, on impurities found in diabetes drugs outside the U.S. https://www.fda.gov/news-events/press-announcements/statement-janet-woodcock-md-director-fdas-center-drug-evaluation-and-research-impurities-found. Published December 5, 2019. Accessed January 7, 2020.