Nitrosamine Impurities in Medications

Since 2018, the Food and Drug Administration (FDA), prompted by private pharmacies, has found that certain common medications used to treat high blood pressure, heart failure, diabetes and heartburn contain unacceptable levels of nitrosamine impurities (contaminants).[1],[2]

Nitrosamines are organic compounds that are associated with liver damage in animals and are considered probable human carcinogens that have been linked to gastrointestinal tract, kidney, liver and lung cancer in humans.[3]

The FDA has published testing methods that can be used by drug manufacturers to detect nitrosamine impurities.[4] It also has requested the recall of tainted medication batches and asked drug manufacturers to test all new batches of these medications before making them available to consumers.

To alleviate fears about this issue, learn about the risks of nitrosamines, which medications have been affected so far and what to do if you or any of your loved ones are taking or considering taking any of these medications.

About nitrosamines

Nitrosamines are known environmental chemical contaminants that include three main substances: N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA).[5]

We all are exposed to nitrosamines in our everyday lives because these chemicals exist in low amounts in water and certain foods (such as cured and grilled meat, dairy products and vegetables).

Nitrosamines also can be present in variable amounts in certain medications because of the manufacturing process or the conditions in which medications are stored or packaged.[6] In some cases, contamination occurs when nitrosamines are formed as a byproduct of the chemical reactions used to produce certain medications.[7]

The FDA and international drug regulators have set acceptable daily intake limits for nitrosamines (for example, the limit for NDMA is 96 nanograms per day based on lifetime exposure).[8],[9] If a medication contains a nitrosamine in higher levels than the acceptable daily limits, the FDA recommends that medication be recalled by the manufacturer because its long-term use is likely to increase the risk of cancer.

The FDA claims that taking a medication that contains nitrosamines at or below the acceptable daily intake limits every day for 70 years is not expected to increase the risk of cancer.

Medications affected by nitrosamine impurities

High levels of nitrosamines were first discovered in multiple generic versions of the high blood pressure medication valsartan (DIOVAN, DIOVAN HCT, ENTRESTO, EXFORGE, EXFORGE HCT), which belongs to the angiotensin II receptor blocker (ARB) class.[10] Some generic versions of two other ARBs, irbesartan (AVALIDE, AVAPRO) and losartan (COZAAR, HYZAAR), also have been found to contain high levels of nitrosamines. Importantly, none of the brand name versions of each of these three ARBs have been found to have high levels of nitrosamines. Moreover, as of April 4, 2019, the FDA had identified 43 generic medications in this class, including many combination products, that did not contain any known nitrosamine impurities.[11]

In 2019, multiple versions of the stomach-acid suppressant histamine-2 (H2) blocker ranitidine, including the brand name product ZANTAC, which is used to treat heartburn and ulcers in the stomach and intestines, gastroesophageal reflux disease and other conditions, were found to contain high amounts of nitrosamines.[12] Months after several ranitidine manufacturers had halted their worldwide distribution of the drug,[13] the FDA finally requested its removal from the U.S. market on April 1 after the agency determined that the nitrosamine impurities in some ranitidine products increase over time and when stored at high temperatures.[14] Other experts believe that the problem is inherent to ranitidine itself because the drug can easily convert to nitrosamines.

Another histamine-2 blocker, nizatidine (AXID AR), that is chemically similar to ranitidine has been found to be prone to nitrosamine formation during manufacturing.[15] In 2020, the FDA alerted patients and health care professionals that Amneal Pharmaceuticals and Mylan had recalled their generic nizatidine products due to nitrosamine contamination and asked other manufacturers to test their products containing this drug.[16]

Most recently, the FDA requested that multiple manufacturers of generic extended-release forms of the diabetes drug metformin (GLUMETZA, RIOMET ER) recall these products because of high nitrosamine content.[17] These manufacturers include Apotex, Amneal Pharmaceuticals, AvKARE, Granules Pharmaceuticals, Lupin Pharmaceuticals, PD-Rx Pharmaceuticals and Teva Pharmaceuticals, among others. Importantly, none of the brand name versions of extended-release metformin have been found to have high levels of nitrosamines. Fortunately, FDA testing of immediate-release forms of metformin (the most commonly prescribed type of metformin) also has not shown elevated levels of nitrosamines, and these forms are safe to use.[18]

What You Can Do

If you are taking one of the prescription medications discussed in this article, do not panic or stop that medication right away. Instead, continue to take it, particularly in the case of ARBs for high blood pressure or heart disease and extended-release metformin for diabetes, because the risks of inadequate treatment for these health conditions far outweigh any possible risks of short-term exposure to the high levels of nitrosamines found in contaminated medications.

To find out if the specific batch your medication came from has been recalled due to nitrosamine contamination, call your pharmacist or the FDA’s Division of Drug Information at 855-543-DRUG or email druginfo@fda.hhs.gov. You also can find information about the medications that have been recalled due to potential nitrosamine impurities by visiting the FDA recalls webpage (http://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts). Make a note to check these resources in the future because other drugs may be recalled.

If you find out that your medication has been recalled, your pharmacist may be able to provide you the same medication from a batch that has not been recalled. Also, your doctor can prescribe you an alternative treatment option, as appropriate.

If you are using over-the-counter ranitidine that you obtained before the drug was withdrawn from the market on April 1 or a recalled nizatidine, consider using another approved over-the-counter stomach-acid suppressant, such as an antacid (including aluminum hydroxide and magnesium trisilicate [GAVISCON]) or another H2 blocker (such as cimetidine [TAGAMET HB] or famotidine [PEPCID]).

Talk to your doctor if have taken a recalled product and are concerned about your health.

Report all serious adverse events associated with medication use to the FDA’s MedWatch adverse event reporting program by visiting https://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] Food and Drug Administration. What to know and do about possible nitrosamines in your medication. June 2, 2020. https://www.fda.gov/consumers/consumer-updates/what-know-and-do-about-possible-nitrosamines-your-medication. Accessed August 31, 2020.

[2] Adamson RH, Chabner BA. The finding of N-nitrosodimethylamine in common medicines. Oncologist. 2020;25(6):460-462.

[3] White CM. Understanding and preventing (N-nitrosodimethylamine) NDMA contamination of medications. Ann Pharmacother. 2020;54(6):611-614.

[4] Food and Drug Administration. Information about nitrosamine impurities in medications. February 3, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications. Accessed August 31, 2020.

[5] Food and Drug Administration. What to know and do about possible nitrosamines in your medication. June 2, 2020. https://www.fda.gov/consumers/consumer-updates/what-know-and-do-about-possible-nitrosamines-your-medication. Accessed August 31, 2020.

[6] Food and Drug Administration. Information about nitrosamine impurities in medications. February 3, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications. Accessed August 31, 2020.

[7] White CM. Understanding and preventing (N-Nitrosodimethylamine) NDMA contamination of medications. Ann Pharmacother. 2020;54(6):611-614.

[8] Food and Drug Administration. FDA updates and press announcements on NDMA in Zantac (ranitidine). April 16, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine. Accessed August 31, 2020.

[9] Food and Drug Administration. Information about nitrosamine impurities in medications. February 3, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications. Accessed August 31, 2020.

[10] Food and Drug Administration. Statement from the commissioner. FDA statement on the agency’s list of known nitrosamine-free valsartan and ARB class medicines, as part of agency’s ongoing efforts to resolve ongoing safety issue. April 4, 2019. https://www.fda.gov/news-events/press-announcements/fda-statement-agencys-list-known-nitrosamine-free-valsartan-and-arb-class-medicines-part-agencys. Accessed August 31, 2020.

[11] Food and Drug Administration. FDA's assessment of currently marketed ARB drug products. April 4, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fdas-assessment-currently-marketed-arb-drug-products. Accessed August 31, 2020.

[12] Food and Drug Administration. Statement alerting patients and health care professionals of NDMA found in samples of ranitidine. September 13, 2019. https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine. Accessed August 31, 2020.

[13] Outrage of the month: FDA foot-dragging on tainted heartburn drug endangers public health. Health Letter. February 2020. https://www.citizen.org/article/outrage-of-the-month-fda-foot-dragging-on-tainted-heartburn-drug-endangers-public-health/. Accessed August 31, 2020.

[14] Food and Drug Administration. FDA news release: FDA requests removal of all ranitidine products (Zantac) from the market. April 1, 2019. https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market. Accessed August 31, 2020.

[15] White CM. Understanding and preventing (N-nitrosodimethylamine) NDMA contamination of medications. Ann Pharmacother. 2020;54(6):611-614.

[16] Food and Drug Administration. FDA updates and press announcements on NDMA in Zantac (ranitidine). April 16, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine. Accessed August 31, 2020.

[17] Food and Drug Administration. FDA updates and press announcements on NDMA in metformin. August 21, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin. Accessed September 1, 2020.

[18] Food and Drug Administration. Questions and answers: NDMA impurities in metformin products Important information about the NDMA impurity in metformin products. May 28, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-metformin-products. Accessed September 1, 2020.