FDA Sets a Temporary Impurity Limit as Varenicline Recalls Threaten a Shortage (2021)

Table of Contents

1. What the FDA Did in July 2021
2. What N-Nitroso-Varenicline Is
3. The Two Limits: 37 and 185 Nanograms a Day
4. How the Recall Grew, July to September 2021
5. What FDA Laboratory Testing Found
6. What the FDA Told Patients and Health Care Professionals
7. Background: Nitrosamines in Medicines
8. What the Action Does Not Do
9. Dates and Legal Status as of October 18, 2026
10. How It Fits Earlier and Later FDA Actions
11. Primary Documents
12. Key Research Papers
13. Connections
14. Featured Videos

1. What the FDA Did in July 2021

The action is recorded on a single FDA web page, “FDA Updates and Press Announcements on Nitrosamine in Varenicline,” in the agency’s Drug Alerts and Statements series. The page is a running log: each entry is dated, and the 2021 entries are dated July 2, July 16, July 19, August 18, August 23 and September 17. It is not a Federal Register document, so the 2021 steps carry no Federal Register citation and no public docket (the numbered public file where an agency collects comments on a proposal).

Two steps of a different kind are recorded there:

• July 2, 2021 — a recall alert. The FDA alerted patients and health care professionals that the brand-name manufacturer was voluntarily recalling nine lots of varenicline “to the warehouse level” because they might contain N-nitroso-varenicline above the FDA’s acceptable intake limit. The recall was the company’s; the FDA’s part was to announce it and to say what it had asked for (section 4).
• July 16, 2021 — the FDA’s own action. “To ensure patient access to varenicline,” the FDA said it would not object to certain manufacturers temporarily distributing varenicline tablets that contained the impurity above the acceptable intake limit of 37 nanograms per day but below an interim limit of 185 nanograms per day, “until the impurity can be eliminated or reduced to acceptable levels.” It also said it was temporarily exercising “regulatory flexibility and discretion” so that a generic varenicline approved in Canada could be distributed in the United States up to that interim limit, which, in the FDA’s words, “will help maintain adequate varenicline supply in the U.S. for the near term.”

The FDA described this as a temporary exercise of “regulatory flexibility and discretion”; no rule was changed. The July 16 entry adds that the agency “continues to evaluate data and may update the interim acceptable limit in the future.”

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2. What N-Nitroso-Varenicline Is

The July 2 entry explains the impurity in these terms: “N-Nitroso-varenicline belongs to the nitrosamine class of compounds, some of which are classified as probable or possible human carcinogens (substances that could cause cancer), based on laboratory tests such as rodent carcinogenicity studies.”

The FDA also stated what was not known. “Although there are no data available to directly evaluate the carcinogenic potential of N-nitroso-varenicline,” the entry says, “information available on closely related nitrosamine compounds was used to calculate lifetime exposure limits for N-nitroso-varenicline.” In other words, the limits were worked out from related chemicals, not from studies of this compound itself.

On the size of the risk, the same entry states that N-nitroso-varenicline “may be associated with a potential increased cancer risk in humans, but there is no immediate risk to patients taking this medication. An increased cancer risk would be associated with long-term use.”

The analytical method the FDA published for detecting the impurity describes it as a varenicline NDSRI, a “nitrosamine drug substance-related impurity”: a nitrosamine that is chemically related to the medicine’s own active ingredient, rather than one that comes from an outside source. The food side of the subject is covered on the site’s Nitrates and Nitrites page.

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3. The Two Limits: 37 and 185 Nanograms a Day

An acceptable intake limit is the daily amount of an impurity that the FDA treats as acceptable in a medicine. A nanogram (ng) is one billionth of a gram. Two numbers run through the 2021 documents:

• 37 ng per day — the acceptable intake limit. The FDA’s laboratory-results page states that “consuming up to the acceptable intake limit, 37 nanograms, of N-nitroso-varenicline per day is considered reasonably safe for humans, based on lifetime exposure,” and that a person taking a drug that contains the impurity at or below this limit “every day for 70 years is not expected to have an increased risk of cancer.” The same page also expresses the limit as 18.5 parts per million (ppm).
• 185 ng per day — the interim limit of July 2021. According to the July 16 entry, “Agency scientists evaluated the risk of exposure to N-nitroso-varenicline at interim acceptable intake levels up to 185 ng per day and determined that it presents minimal additional cancer risk when compared to a lifetime of exposure to N-nitroso-varenicline at the 37 ng per day level.” The laboratory-results page gives the interim figure as 92.5 ppm.

The interim figure is five times the acceptable intake limit. It was not a new permanent standard: the FDA tied it to the period “until the impurity can be eliminated or reduced to acceptable levels,” and it ended in May 2022 (section 9).

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4. How the Recall Grew, July to September 2021

A drug recall can reach different points in the supply chain. In the July 2 entry, the FDA explained that the brand-name manufacturer was “recalling the varenicline lots currently stored in warehouses,” and that the “FDA recommended” the company “revise its recall to the consumer level in order to take into account the product currently on the market, but the company has not yet done so.” The same entry says the company was also holding back release of varenicline to the U.S. market until it could confirm impurity levels below what it considered acceptable.

The FDA’s update page records the recall growing in four steps:

1. July 2, 2021: nine lots, to the warehouse level. The lots listed had expiration dates from September 2021 to May 2023.
2. July 19, 2021: the recall expanded to 12 lots, now to the consumer level, “due to the presence of N-nitroso-varenicline above the company’s acceptable limit for this impurity.”
3. August 18, 2021: four more lots were added, for 16 in total, to the consumer level.
4. September 17, 2021: the recall was expanded “to include all lots” of the brand-name varenicline 0.5 mg and 1 mg tablets, “due to the presence of unacceptable N-nitroso-varenicline levels.”

Each step was a voluntary company recall. With the September 17 entry, the FDA repeated its July interim-limit position and gave its reason in these words: “To lessen the impact to patients from a drug shortage due to this ongoing recall, FDA will not object to certain manufacturers distributing varenicline tablets containing N-nitroso-varenicline above FDA’s acceptable intake limit of 37 ng per day but below the interim acceptable intake limit of 185 ng per day.” Already on July 2, the FDA had written that it was “actively considering options to help mitigate a shortage of varenicline in the U.S. including working to identify an alternate supplier.” The July 16 entry points readers to the FDA’s drug shortages listing for varenicline tablets; that listing was not read for this page.

The FDA page lists the recalled lot numbers and expiration dates in tables in its July 2 and July 19 entries.

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5. What FDA Laboratory Testing Found

On August 23, 2021 the FDA posted “Laboratory analysis of varenicline products,” a table of N-nitroso-varenicline levels its own laboratories measured in varenicline products then available for the U.S. market. The page states that the FDA “has identified levels of N-nitroso-varenicline above FDA’s acceptable intake limit in some samples of varenicline finished drugs,” that testing was still ongoing, and that the agency had posted the analytical method it used.

The table reports levels per tablet. Without naming the makers, the results were:

• Brand-name 1 mg tablets (six lots tested): 150 to 470 ng of N-nitroso-varenicline per tablet (155–474 ppm).
• Another U.S. manufacturer’s 1 mg tablet (two lots tested): 3 ng per tablet (3 ppm). The page notes that this product was approved by the FDA on August 11, 2021.
• The Canadian-approved generic distributed under the FDA’s temporary flexibility: 27 to 44 ng per tablet in the 1 mg strength (27–44 ppm) and 14 to 21 ng per tablet in the 0.5 mg strength (27–42 ppm), each from three lots.

These are amounts per tablet, while the limits in section 3 are amounts per day; how many tablets make up a daily dose is not stated on the FDA page, so no per-day total is given here. The FDA also published its testing method so that, in its words, regulators and industry have “an option” for detecting nitrosamine impurities in varenicline drug substances and drug products; the FDA notes that the method has to be validated by anyone whose results support a required quality assessment or a regulatory submission.

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6. What the FDA Told Patients and Health Care Professionals

The FDA repeated one sentence in its July 2, July 16, July 19, August 18 and September 17 entries: “The health benefits of stopping smoking outweigh the cancer risk from the nitrosamine impurity in varenicline.”

For patients, the FDA’s July 2 entry advised continuing the current medicine until a doctor or pharmacist provides a replacement or a different treatment option, and contacting a health care professional with questions. The later entries repeat that the FDA “reminds patients taking recalled varenicline to continue taking their current medicine until their pharmacist provides a replacement or their doctor prescribes a different medication that treats the same condition.”

For health care professionals, the July 2 entry states: “FDA has determined the recalled varenicline poses an unnecessary risk to patients. Therefore, FDA recommends health care professionals consider other available treatment options for the patient’s medical condition.” It also asked them to quarantine samples of the recalled drug rather than hand them to patients, and it asked patients and professionals to report adverse reactions with varenicline to MedWatch, the FDA’s safety-reporting program.

These are the FDA’s statements, reported as such. Decisions about any medicine, including a stop-smoking medicine, belong with a clinician.

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7. Background: Nitrosamines in Medicines

The varenicline recall was one of several nitrosamine findings in medicines. The FDA’s page “Information about Nitrosamine Impurities in Medications” gathers them and gives the agency’s general explanation:

• Everyday exposure. “Nitrosamines are common in water and foods, including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of nitrosamines.”
• Limits and recalls. The FDA, together with regulators in other countries, has set “internationally-recognized acceptable daily intake limits for nitrosamines.” When a drug contains more than these limits, the FDA recommends that it be recalled by the manufacturer as appropriate.
• Where they come from. The FDA says the source “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged,” and that nitrosamines can also form as foods and drugs are processed in the body.
• Why more were being found. The varenicline update page states: “Improved technology enables us to detect even trace amounts of impurities in drug products and may be the reason why more products have been recently found to have detectable levels of nitrosamines.”

The July 2 entry also points to the FDA’s September 2020 guidance for industry, “Control of N-Nitrosamine Impurities in Human Drugs,” which, in the FDA’s description, “recommends steps manufacturers of active pharmaceutical ingredients (APIs) and drug products should take to detect and prevent objectionable levels of nitrosamine impurities in pharmaceutical products.” A guidance document sets out the FDA’s current thinking on a subject; it does not itself create legal requirements.

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8. What the Action Does Not Do

• It was not a ban on varenicline. The FDA did not withdraw the drug’s approval or find it unsafe to take; throughout 2021 it told patients to keep taking their current medicine until a replacement or a different treatment was provided (section 6).
• The recalls were not FDA orders. Each recall step was a voluntary company recall. The FDA recommended that the first one be widened to the consumer level; the FDA’s own action was the interim limit and the enforcement flexibility.
• It did not raise the permanent limit. The 37 ng per day acceptable intake limit stayed in place. The 185 ng per day figure was a temporary level the FDA said it would not object to while the impurity was being reduced.
• It did not rest on studies of this exact compound. The FDA stated that no data were available to directly evaluate N-nitroso-varenicline’s cancer-causing potential; the limits were calculated from closely related nitrosamines.
• It did not claim an immediate danger. The FDA stated there was “no immediate risk” to patients and that any increased cancer risk would be associated with long-term use.
• It was not a rule. No regulation was proposed or changed, and nothing was published in the Federal Register in 2021 for this action.

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9. Dates and Legal Status as of October 18, 2026

• July 2, 2021: the FDA announces the voluntary warehouse-level recall of nine brand-name lots and its recommendation that the recall go to the consumer level.
• July 16, 2021: the FDA says it will not object to distribution of varenicline with N-nitroso-varenicline below an interim limit of 185 ng per day, and allows temporary distribution of a Canadian-approved generic.
• July 19, 2021: the recall expands to 12 lots, to the consumer level.
• August 11, 2021: another U.S. manufacturer’s varenicline tablet is approved, according to the FDA’s laboratory-results page.
• August 18, 2021: the recall expands to 16 lots.
• August 23, 2021: the FDA posts its laboratory test results and testing method.
• September 17, 2021: the recall expands to all lots of the brand-name 0.5 mg and 1 mg tablets; the FDA restates the interim limit.
• May 5, 2022: the FDA says it is “now confident in manufacturers’ ability to supply patients with varenicline containing the N-nitroso-varenicline impurity at or below the agency’s acceptable intake limit of 37 ng per day,” and that “Any newly manufactured varenicline for the U.S. market should have levels of the N-nitroso-varenicline impurity at or below that limit.”
• February 27, 2023: a Federal Register notice (88 FR 12384; Docket No. FDA-2022-P-1013) announces the FDA’s determination that the brand-name varenicline tartrate 0.5 mg and 1 mg tablets have “not been withdrawn from sale for reasons of safety or effectiveness to the extent that the drug can be manufactured or formulated in a manner that satisfies any applicable acceptable intake limit for nitrosamine impurities.” The notice explains that this means the FDA will not begin procedures to withdraw approval of the generic-drug applications (abbreviated new drug applications, or ANDAs) that refer to the product, and can continue approving such applications that meet the legal requirements.

Status as of October 18, 2026: ended. The 2021 interim limit and enforcement flexibility ended with the FDA’s May 5, 2022 update; the 37 ng per day acceptable intake limit applies to newly manufactured varenicline for the U.S. market. A check of the Federal Register for FDA documents mentioning varenicline from 2021 through October 18, 2026 found the February 2023 determination above and no document that reinstates the interim limit. The full text of the 2023 notice could not be read for this page, so only its summary is reported here.

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10. How It Fits Earlier and Later FDA Actions

The FDA’s nitrosamine information page lists varenicline alongside other medicines for which the agency kept similar update pages: losartan, valsartan and other angiotensin II receptor blockers (ARBs), metformin, ranitidine, and rifampin and rifapentine. The dates of those actions are not given on that page and are not reported here.

After 2021, the same FDA page records two further guidance documents on nitrosamines in drugs:

• August 4, 2023: “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs),” issued for immediate implementation, which the FDA describes as “a recommended framework for a risk-based safety assessment of NDSRIs that could be present in approved and marketed drug products.”
• September 4, 2024: a revised guidance, “Control of Nitrosamine Impurities in Human Drugs,” also for immediate implementation, which the FDA says “explains the agency’s updated thinking” on how manufacturers can detect and prevent unacceptable levels of nitrosamine impurities, including NDSRIs, and gives a timeline for putting the recommendations in place.

Among the site’s other 2021 FDA pages, the hand sanitizer safety actions also concern contaminated or substandard drug products, and the menthol cigarette commitment, the flavored e-cigarette marketing denials and the first e-cigarette marketing authorization are the year’s tobacco actions. Other 2021 drug-safety actions are reported on the JAK inhibitor boxed warnings, propylhexedrine inhaler and statin pregnancy warning pages. No 2022–2026 page on the site covers varenicline.

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11. Primary Documents

1. U.S. Food and Drug Administration. FDA Updates and Press Announcements on Nitrosamine in Varenicline. Drug Alerts and Statements, entries dated July 2, July 16, July 19, August 18, August 23 and September 17, 2021 and May 5, 2022; content current as of May 5, 2022. No Federal Register docket — fda.gov varenicline nitrosamine updates page
2. U.S. Food and Drug Administration. Laboratory analysis of varenicline products. Drug Safety and Availability, content current as of August 23, 2021 — fda.gov varenicline laboratory results
3. U.S. Food and Drug Administration. Information about Nitrosamine Impurities in Medications. Drug Safety and Availability, content current as of September 4, 2024 — fda.gov nitrosamine impurities page
4. Food and Drug Administration, HHS (2023). Determination that the brand-name varenicline tartrate tablets, 0.5 milligram and 1 milligram, have not been withdrawn from sale for reasons of safety or effectiveness. Notice. Federal Register 88 FR 12384, February 27, 2023. Docket No. FDA-2022-P-1013 — FR Doc. 2023-03947
5. Public docket FDA-2022-P-1013 — regulations.gov FDA-2022-P-1013

The company recall announcements posted on fda.gov, the FDA drug shortages listing and the 2020, 2023 and 2024 guidance documents themselves were not read for this page; every fact about them above comes from the FDA pages listed. The title of the 2023 notice is given here with the brand name replaced by a description.

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Key Research Papers

1. Livingstone-Banks J, Fanshawe TR, Thomas KH, Theodoulou A, Hajizadeh A, Hartman L, Lindson N (2023). Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews 5(5):CD006103 — PubMed PMID: 37142273
2. Anthenelli RM, Benowitz NL, West R, St Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE (2016). Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 387(10037):2507-2520 — PubMed PMID: 27116918
3. Jackson SE, Brown J, Tattan-Birch H, Shahab L (2024). Impact of the disruption in supply of varenicline since 2021 on smoking cessation in England: A population study. Addiction 119(7):1203-1210 — PubMed PMID: 38688323
4. Lepert A, Bourneau-Martin D, Lebrun-Vignes B, Gentil A, Brunel P, Berlin I, Briet M (2025). Clinical consequences of varenicline shortage: A study on the French national pharmacovigilance database. Therapie 80(6):639-646 — PubMed PMID: 40140298
5. Seo JE, Xu HS, Revollo JR, Miranda-Colon JA, Atrakchi AH, McGovern TJ, Davis Bruno KL, Keire DA, Heflich RH, Guo X (2026). Mutagenicity of N-nitroso-fluoxetine and N-nitroso-varenicline in human HepaRG cell models. Mutagenesis 41(4):175-188 — PubMed PMID: 41725400
6. Hassan MA, Sibhat G, Reddy IK, Khan MA, Rahman Z (2026). Stability Assessment of FDA Approved Varenicline Tartrate Products for Critical Quality Attributes - N-Nitroso Varenicline, Solid Form, and Dissolution. AAPS PharmSciTech 27(3):174 — PubMed PMID: 41957248
7. Li X, Le Y, Guo X, King ST, Dorsam RT, Atrakchi AH, McGovern TJ, Davis-Bruno KL, Keire DA, Heflich RH, Mei N (2024). Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells. Regulatory Toxicology and Pharmacology 154:105730 — PubMed PMID: 39433234
8. Sedlo I, Kolonić T, Tomić S (2021). Presence of nitrosamine impurities in medicinal products. Arhiv za Higijenu Rada i Toksikologiju 72(1):1-5 — PubMed PMID: 33787187

The first two papers are a systematic review and a large randomised trial of varenicline as a stop-smoking medicine. The third and fourth study what happened in England and France after varenicline supplies were disrupted. The fifth and seventh are laboratory studies of how nitrosamine drug substance-related impurities, including N-nitroso-varenicline, behave in human cell models. The sixth studies N-nitroso-varenicline and other quality measures in approved varenicline tablets, and the eighth is a review of nitrosamine impurities in medicines.

PubMed Topic Searches

1. PubMed: N-nitroso-varenicline
2. PubMed: nitrosamine drug substance-related impurities
3. PubMed: varenicline shortage
4. PubMed: varenicline and smoking cessation

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Connections

• FDA Actions of 2021
• FDA and Regulation
• Addiction and Substance Use Disorders
• COPD
• Lung Cancer
• Nitrates and Nitrites
• Secondhand Smoke
• Nicotine
• Hand Sanitizer Safety Actions (2021)
• Menthol Cigarette Ban Commitment (2021)
• Flavored E-Cigarette Marketing Denials (2021)
• First E-Cigarette Marketing Authorization (2021)
• JAK Inhibitor Boxed Warnings (2021)
• Statins Pregnancy Warning Removed (2021)

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