Certain Commonly Used Oral Drugs Tainted With Cancer-Causing Nitrosamine Impurities

Nitrosamines are organic compounds that are known byproducts in many chemical manufacturing processes.[1] They also are found in very low amounts in water and foods, including meat (especially cured and grilled meats), dairy products and vegetables.[2]

Animal studies have shown that nitrosamines can cause genetic mutations.[3] Therefore, the World Health Organization has classified many of these substances as “probably or possibly carcinogenic to humans” if a person is exposed to high levels of them over a prolonged period of time.[4]

Since 2018, some nitrosamines have been discovered in certain drugs for diabetes, hypertension, heartburn, smoking cessation and tuberculosis. These products can form during the manufacturing, packaging or storage of some drugs or due to the natural degradation of others.[5]

Although the Food and Drug Administration (FDA) has determined that nitrosamines should not exist in any drug,[6] it temporarily has permitted affected drugs to remain on the market if their content of various nitrosamines does not exceed a certain level (ranging from 27 to 96 nanograms [ng] per daily dosage).[7]

The agency also recommended that drug manufacturers measure nitrosamine levels in their drugs and take action to reduce or remove these contaminants.

Learn which drugs have been recalled due to this contamination and what you can do if you are taking any of them.

Three heart and high-blood-pressure drugs

Batches (lots) of multiple generic versions of the angiotensin II receptor blocker (ARB) drug valsartan and certain combination drug products containing valsartan were the first drugs implicated in nitrosamine contamination.[8] This led to recalls of these affected products. FDA scientists estimated that if 8,000 individuals took the highest dose of tainted valsartan products on a daily basis for four years, there may be one additional cancer case in those individuals.

Subsequently, specific batches of generic versions of two additional ARBs — irbesartan and losartan — and some of their combinations with other drugs have been recalled due to nitrosamine contamination.

Importantly, none of the brand-name versions any ARB drug — valsartan products marketed under the brand names DIOVAN, DIOVAN HCT, ENTRESTO, EXFORGE and EXFORGE HCT; irbesartan products marketed under the brand names AVALIDE and AVAPRO; and losartan products marketed under the brand names COZAAR and HYZAAR — has been found to contain high levels of nitrosamines.[9]

Two stomach-acid–suppressant drugs

The histamine-2 (H2) blocker ranitidine (including its brand-name over-the-counter formulation ZANTAC), which is used to treat acid reflux, heartburn and ulcers in the stomach and intestines, and other conditions, has been found to contain unacceptably high levels of nitrosamine impurities.[10] Therefore, in April 2020, the FDA requested removal of all forms of this drug from the market.

Recently, Zantac has been relaunched with a new active ingredient (the H2 blocker famotidine), which has not been found to be contaminated with nitrosamines, according to FDA testing.[11]

A few batches of generic nizatidine, another H2 blocker, have been recalled due to nitrosamine impurities.

One diabetes drug

Since 2020, several generic versions of extended-release metformin have been recalled due to nitrosamine contamination.[12]

Importantly, brand-name versions of extended-release metformin — FORTAMET and GLUMETZA — as well as combination drug products containing metformin and immediate-release forms of metformin (the most commonly prescribed type of metformin) have not been found to contain elevated levels of nitrosamines.

Two antibiotics

In August 2020, the FDA found that generic versions of rifampin as well as generic and brand-name versions of rifapentine (PRIFTIN) contain higher than the acceptable levels of nitrosamines.[13] As of press time, however, the agency decided to keep certain forms of these drugs with high nitrosamine levels on the market because they are essential, life-saving antibiotics used to treat tuberculosis and certain other infections.

One smoking-cessation drug

In July 2021, Pfizer started recalling some batches of its brand-name varenicline (CHANTIX) because of nitrosamine contamination.[14] Two months later, the company decided to remove all Chantix products from the market.

To maintain an adequate supply of varenicline, the FDA permitted certain varenicline generics with a predetermined higher nitrosamine level to remain on the market. It also has temporarily allowed the importation of Canadian-approved APO-VARENICLINE tablets made by Apotex.

What You Can Do

If any of your current drugs contain any of the drugs discussed in this article, do not panic or stop taking it. Instead, continue to take it, particularly in the case of ARBs or extended-release metformin, because the risks of inadequate treatment due to stopping these drugs far outweigh the risks of short-term exposure to nitrosamine impurities.[15]

To find out whether the specific batches from which your drugs came have been recalled, call your pharmacist or the FDA’s Division of Drug Information at 855-543-DRUG or email druginfo@fda.hhs.gov.[16] If you contact the FDA, you will need the following information, which usually can be found on your drug container: active ingredient(s), national drug code and lot number, and manufacturer name.

You also can search the FDA recalls webpage (www.fda.gov/safety/recalls-market-withdrawals-safety-alerts) by drug name to find out if your drug has been recalled. Make a note to check these resources in the future because other batches may be recalled.

If your drug has been recalled, your pharmacist may be able to provide you the same drug from a batch that has not been recalled. Also, you can discuss other treatment options with your doctor.
 

References

[1] Erskine D, Wood D. What is the significance of nitrosamine contamination in medicines? Drug Ther Bull. 2021;59(3):39-42.

[2] Food and Drug Administration. Information about nitrosamine impurities in medications. November 18, 2021 https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications#updates. Accessed January 4, 2022.

[3] Food and Drug Administration. Control of nitrosamine impurities in human drugs. Guidance for industry. Revision 1. February 2021. https://www.fda.gov/media/141720/download. Accessed January 4, 2022.

[4] World Health Organization. International Agency for Research on Cancer monographs on the identification of carcinogenic hazards to human. https://monographs.iarc.who.int/list-of-classifications. Accessed January 4, 2022.

[5] Food and Drug Administration. Information about nitrosamine impurities in medications. November 18, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications#updates . Accessed January 4, 2022.

[6] Food and Drug Administration. FDA updates and press announcements on angiotensin II receptor blocker (ARB) recalls (valsartan, losartan, and irbesartan). November 13, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan. Accessed January 4, 2022.

[7] Food and Drug Administration. Control of nitrosamine impurities in human drugs. Guidance for industry. Revision 1. February 2021. https://www.fda.gov/media/141720/download. Accessed January 4, 2022.

[8] Food and Drug Administration. FDA updates and press announcements on angiotensin II receptor blocker (ARB) recalls (valsartan, losartan, and irbesartan). November 7, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan. Accessed January 4, 2022.

[9] Food and Drug Administration. Search list of recalled angiotensin II receptor blockers (ARBs) including valsartan, losartan and irbesartan. October 20, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and. Accessed January 4, 2022.

[10] 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 January 4, 2022.

[11] Food and Drug Administration. Questions and Answers: NDMA impurities in ranitidine (commonly known as Zantac). April 1, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-ranitidine-commonly-known-zantac. Accessed January 4, 2022.

[12] Food and Drug Administration. FDA updates and press announcements on NDMA in metformin. January 6, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin. Accessed January 4, 2022.

[13] Food and Drug Administration. FDA updates and press announcements on nitrosamines in rifampin and rifapentine. January 28, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamines-rifampin-and-rifapentine. Accessed January 4, 2022.

[14] Food and Drug Administration. FDA updates and press announcements on nitrosamine in varenicline (Chantix). September 17, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix. Accessed January 4, 2022.

[15] Food and Drug Administration. Information about nitrosamine impurities in medications. November 18, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications#updates. Accessed January 4, 2022.

[16] 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 January 4, 2022.