Update: Oral Prescription Drugs Recalled Due to Nitrosamine Contamination

The organic compounds known as nitrosamines are found in very low amounts in water and foods, including meat (especially cured and grilled meats), dairy products and vegetables.[1] Animal studies have shown that these products can cause genetic mutations.[2] 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.[3]

Since 2018, various nitrosamines have been discovered in certain oral prescription drugs. This contamination can occur during the manufacturing, packaging or storage of these drugs, or as part of their natural degradation.[4]

The Food and Drug Administration (FDA) recommends that drug manufacturers measure nitrosamine levels in their drugs and, when found, take action to reduce or remove these contaminants.[5] However, the FDA continues to permit nitrosamine-contaminated drugs to be on the market if their content of various nitrosamines does not exceed certain acceptable intake levels (ranging from 27 to 96 nanograms per daily dosage, depending on the specific type of these compounds).[6] These levels approximate an increased cancer risk of one additional case in 100,000 individuals, based on a conservative assessment of daily exposure to a given nitrosamine over 70 years. Therefore, the FDA has permitted certain drugmakers to state that there is no immediate or short-term danger from using medications that are tainted with nitrosamines.

The following section highlights the specific oral prescription drugs that are being recalled from the nationwide U.S. market as of June 2023 because they contain more than the acceptable daily intake limits of nitrosamines and what to do if you are taking any of them.[7] All of these recalls were voluntarily initiated by the respective drugmakers in consultation with the FDA. This article updates our article on this topic in the March 2022 issue of Worst Pills, Best Pills News.[8]

Nitrosamine-contaminated drugs recalled as of June 2023

Certain generic versions of extended-release metformin, a diabetes drug

Since 2020, several generic versions of extended-release metformin have been recalled due to nitrosamine contamination.[9] At present, Nostrum Laboratories LLC is recalling its 500- and 750-milligram (mg) tablets of this drug.[10] Additionally, Viona Pharmaceuticals Inc. is recalling its 750-mg tables of this drug formulation.[11]

Importantly, generic extended-release metformin formulations from other companies are not being recalled due to nitrosamine contamination. Moreover, 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 prescribed type of metformin) have not been recalled due to nitrosamine contamination.

A hypertension drug and its combination products

Since early 2022, Pfizer Inc. has issued voluntary recalls of certain batches of its brand-name quinapril (ACCUPRIL)[12] tablets as well as its ACCURETIC tablets, which are a combination of quinapril with the diuretic (water pill) hydrochlorothiazide.[13]

In late 2022, Lupin Pharmaceuticals Inc. also began recalling certain batches of its generic quinapril tablets.[14] Similarly, Aurobindo Pharma has been recalling batches of its generic quinapril-and-hydrochlorothiazide combination tablets.[15] Notably, generic formulations of quinapril and its combination products are not being recalled.

Oral blood thinner

As of March 2023, Ascend Laboratories LLC has been recalling generic capsules of dabigatran — a drug that is used to lower the risk of stroke and blood clots — due to nitrosamine contamination.[16] Notably, brand-name (PRADAXA) and generic formulations of this drug from other companies are not being recalled.

Muscle-relaxant drug

Since March 2022, Sandoz Inc. has been recalling certain batches of generic extended-release orphenadrine tablets due to nitrosamine contamination.[17] The company recommends that patients should stop taking the recalled tablets immediately. This drug is only available in generic formulations. At present, formulations of the drug from other companies are not being recalled. Notably, Public Citizen’s Health Research Group has designated this drug as Do Not Use.

Smoking-cessation drug

In July 2021, Pfizer Inc. started recalling certain batches of its brand-name varenicline (CHANTIX) tablets because of nitrosamine contamination.[18]

In September 2021, the company removed all Chantix tablets from the U.S. market.[19] Pfizer is still recalling this drug through at least the end of 2023. Notably, generic varenicline products are not being recalled.

Diabetes medication that has not been recalled

In August 2022, the FDA announced that it was aware of nitrosamine contamination in certain samples of sitagliptin (JANUVIA), an oral drug that is used to treat type 2 diabetes.[20] So far, the agency has allowed the temporary distribution of formulations of this drug that contain a certain level of nitrosamines. Importantly, we have designated sitagliptin — and other gliptin and incretin mimetic drugs — as Do Not Use.[21] Before discontinuing sitagliptin, we recommend that patients speak with their doctors regarding a safer alternative drug.

What You Can Do

If you are taking any of the oral drugs discussed in this article, there is no reason to panic. Recalled batches of orphenadrine are the only drugs that should be discontinued immediately. Users of other drugs — especially drugs used to treat high blood pressure or diabetes or to prevent stroke or blood clots — should continue to take their medications until they talk to their doctors regarding an alternative treatment.[22] The risks of inadequate treatment due to stopping these drugs far outweigh the risks of short-term exposure to nitrosamine impurities.

To find out whether the specific batches of drugs you are taking have been recalled due to nitrosamine contamination or any other reason, you can search the FDA recalls webpage (www.fda.gov/safety/recalls-market-withdrawals-safety-alerts) by drug name.

You also can call your pharmacist or the FDA’s Division of Drug Information at 855-543-DRUG or email druginfo@fda.hhs.gov. If you contact the FDA, you will need the following information: active ingredient(s), national drug code and lot number, and manufacturer name. This information can usually be found on the drug container.

If your drug has been recalled, your pharmacist may be able to provide you with the same drug from a batch that has not been recalled, if applicable. Also, patients taking recalled medications can contact the drug company for possible reimbursement.

Report adverse effects or quality problems experienced with the use of any prescription drug to the FDA’s MedWatch adverse-event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] 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 June 14, 2023.

[2] 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 June 14, 2023.

[3] 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 June 14, 2023.

[4] 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 June 22, 2023.

[5] 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 June 14, 2023.

[6] Ibid.

[7] Food and Drug Administration. Recalls, market withdrawals, & safety alerts. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts. Accessed June 14, 2023.

[8] Certain commonly used oral drugs tainted with cancer-causing nitrosamine impurities. Worst Pills, Best Pills News. March 2022. https://www.worstpills.org/newsletters/view/1452. Accessed June 14, 2023.

[9] 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 June 14, 2023.

[10] Food and Drug Administration. Nostrum Laboratories, Inc. expands voluntary nationwide recall of metformin HCl extended release tablets, USP 750 mg, due to n-nitrosodimethylamine (NDMA) content above the acceptable daily intake (ADI) Limit. January 25, 2021. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/nostrum-laboratories-inc-expands-voluntary-nationwide-recall-metformin-hcl-extended-release-tablets-0. Accessed June 14, 2023.

[11] Food and Drug Administration. Viona Pharmaceuticals Inc., issues voluntary nationwide recall of metformin HCl extended-release tablets, USP 750 mg, due to the detection of n-nitrosodimethylamine (NDMA) impurity. June 11, 2021. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/viona-pharmaceuticals-inc-issues-voluntary-nationwide-recall-metformin-hcl-extended-release-tablets. Accessed June 13, 2023.

[12] Food and Drug Administration. Pfizer Voluntary nationwide recall of lots of ACCUPRIL (quinapril HCl) due to n-nitroso-quinapril content. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/pfizer-voluntary-nationwide-recall-lots-accuprilr-quinapril-hcl-due-n-nitroso-quinapril-content. April 22, 2022. Accessed June 14, 2023.

[13] Food and Drug Administration. Sandoz, Inc. Pfizer voluntary nationwide recall of lots of Accuretic (quinapril HCl/hydrochlorothiazide), quinapril and hydrochlorothiazide tablets, and quinapril HCl/hydrochlorothiazide tablets due to n-nitroso-quinapril content. March 22, 2022. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/pfizer-voluntary-nationwide-recall-lots-accuretic-quinapril-hclhydrochlorothiazide-quinapril-and. Accessed June 14, 2023.

[14] Food and Drug Administration. Lupin Pharmaceuticals, Inc. issues voluntary nationwide recall of four lots of quinapril tablets due to potential presence of n-nitroso-quinapril impurity. December 21, 2022. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/lupin-pharmaceuticals-inc-issues-voluntary-nationwide-recall-four-lots-quinapril-tablets-due. Accessed June 14, 2023.

[15] Food and Drug Administration. Aurobindo Pharma USA, Inc. Initiates voluntary nationwide recall of two (2) lots of quinapril and hydrochlorothiazide tablets USP 20mg/12.5mg, due to the detection of n-nitroso quinapril impurity. October 24, 2022. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/aurobindo-pharma-usa-inc-initiates-voluntary-nationwide-recall-two-2-lots-quinapril-and. Accessed June 14, 2023.

[16] Food and Drug Administration. Ascend Laboratories LLC. issues voluntary nationwide recall of dabigatran etexilate capsules, USP 75 mg and 150 mg, due to the detection of n-nitroso-dabigatran (NDAB) Impurity. March 22, 2023. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/ascend-laboratories-llc-issues-voluntary-nationwide-recall-dabigatran-etexilate-capsules-usp-75-mg. Accessed June 14, 2023.

[17] Food and Drug Administration. Sandoz, Inc. issues nationwide recall of 13 lots of orphenadrine citrate 100 mg extended release tablets due to presence of a nitrosamine impurity. March 21, 2022. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/sandoz-inc-issues-nationwide-recall-13-lots-orphenadrine-citrate-100-mg-extended-release-tablets-due. Accessed June 14, 2023.

[18] Food and Drug Administration. Pfizer issues a voluntary nationwide recall for twelve lots of CHANTIX (varenicline) tablets due to n-nitroso varenicline content. July 19, 2021. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/pfizer-issues-voluntary-nationwide-recall-twelve-lots-chantixr-varenicline-tablets-due-n-nitroso. Accessed June 14, 2023.

[19] Food and Drug Administration. Pfizer expands voluntary nationwide recall to include all lots of CHANTIX (varenicline) tablets due to n-nitroso varenicline content. September 16, 2021. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/pfizer-expands-voluntary-nationwide-recall-include-all-lots-chantixr-varenicline-tablets-due-n. Accessed June 14, 2023.

[20] Food and Drug Administration. FDA works to avoid shortage of sitagliptin following detection of nitrosamine impurity. August 9, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-works-avoid-shortage-sitagliptin-following-detection-nitrosamine-impurity. Accessed June 14, 2023.

[21] “Do Not Use” type 2 diabetes gliptin drugs also raise risk of gallbladder inflammation. Worst Pills, Best Pills News. March 2023. https://www.worstpills.org/newsletters/view/1521. Accessed June 13, 2023.

[22] 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 June 13, 2023.