Chantix Recall & Cancer Risk

February 2006: The U.S. Food and Drug Administration (FDA) granted Varenicline a "priority review" designation. This designation shortened the standard ten-month review period to six months. The expedited review was based on Varenicline's proven effectiveness in clinical trials and the absence of apparent safety concerns identified at that time.¹

May 2006: Pfizer receives FDA approval for the use of Chantix (varenicline) 0.5 mg and 1 mg Tablets as an aid to smoking cessation treatment.^2,3

April 2016: Pfizer published the results of a large-scale clinical trial known as the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES). This study assessed the safety profile of varenicline, specifically focusing on neuropsychiatric side effects. The EAGLES trial demonstrated that varenicline use did not lead to a significant increase in such adverse events compared to either nicotine replacement therapy or a placebo.⁴

December 2016: The FDA removed the strongest safety warning ("black box warning") from varenicline (Chantix) labeling. This decision followed a comprehensive review, including the April 2016 EAGLES study, which showed that the benefits of varenicline in smoking cessation outweighed the risks. However, the FDA emphasized continued caution regarding potential neuropsychiatric side effects (depression, suicidal behavior), particularly for individuals with a history of mental illness or current treatment of mental health disorders.⁵

September 2020: Continuing concerns about nitrosamine impurities in medications (e.g., metformin, a diabetes medication, and ranitidine, a heartburn medication) prompted the FDA to set an acceptable daily intake limit (AI) for varenicline nitrosamine impurities at 37 nanograms.⁶ This limit factored in the estimated increased cancer risk of 1 in 100,000 individuals taking a drug at that AI or higher for 70 years.

June 2021: Pfizer paused distribution of Chantix worldwide.⁷

July 2021: Pfizer initiated a voluntary recall of twelve lots of Chantix tablets (various strengths) at the consumer level due to elevated levels of N-nitroso-varenicline, a nitrosamine impurity, exceeding Pfizer's internal safety limit.⁸ The FDA subsequently alerted healthcare professionals and patients about the recall, highlighting the nine originally reported lots recalled by Pfizer.⁹

August 2021: FDA testing revealed N-nitroso-varenicline levels exceeding 150-470 nanograms per tablet in certain tested Chantix lots. Pfizer, in response, initiated a voluntary consumer-level recall of an additional four Chantix lots due to these elevated nitrosamine levels exceeding their established safety threshold.¹⁰

September 2021: Pfizer significantly expanded its voluntary consumer-level recall of Chantix (varenicline) tablets. This included all remaining lots of both 0.5mg and 1mg strengths. The reason for the expanded recall was the presence of N-nitroso-varenicline at levels meeting or exceeding the FDA's interim acceptable intake limit.¹¹

Varenicline is a medication used to help people quit smoking. Its mechanism of action and discovery are described below:

• Nicotine Addiction: Nicotine's addictive properties are linked to its interaction with specific brain cell receptors (called nicotinic acetylcholine receptors, or nAChRs), particularly the α4β2 subtype.^12,13 A cell receptor is like a lock on the surface of a cell that only certain keys, like natural chemical messengers or drugs, can bind to, triggering a change inside the cell.
• Dopamine and Reward: Nicotine activation of these receptors leads to release of dopamine, a neurotransmitter associated with reward, making smoking pleasurable.^14,15
• Withdrawal and Cravings: During smoking cessation, low dopamine levels trigger cravings and withdrawal symptoms.^16,17
• Varenicline's Role: Varenicline acts as a partial agonist at the α4β2 nAChRs. This means it partially activates the receptor, potentially mimicking some of nicotine's effects (like dopamine release) in a weaker way.
• Theoretical Benefit: This partial activation might help counteract the low dopamine state during withdrawal, reducing cravings and withdrawal symptoms, thereby aiding smoking cessation.
• Development of Varenicline: Inspired by the use of Cytisine, a plant-based partial agonist, researchers modified its structure to create varenicline, with improved potency and efficacy for smoking cessation.^{18,19,20,21,22}
• Varenicline Competitive Binding: Varenicline competes with nicotine for binding sites on the α4β2 nAChRs. This potentially prevents nicotine from fully activating the receptors and triggering the rewarding effects of smoking.²²
• Market Presence: Varenicline is marketed as Chantix (US) and Champix (EU) and has been prescribed frequently (over 1.8 million prescriptions).^22,23

Identified nitrosamine impurities with carcinogenic (cancer-causing) potential include:

• NDMA (N-Nitrosodimethylamine)
• NDEA (N-Nitrodiethylamine)
• NMBA (N-Nitrosomethylethylamine)
• N-nitroso-varenicline

Sources of Exposure

Sources of nitrosamine impurities include: ^6,24,25,26

• NDMA: water treatment (chlorination/chloramination), cured meats, fish, beer, tobacco products, tobacco smoke (levels vary)
• NDEA: found as an impurity in a class of blood pressure drugs known as Angiotensin II Receptor Blockers (ARBs), which act by relaxing blood vessels.
• N-nitroso-varenicline: an impurity specific to Chantix

Carcinogenicity Classifications

Nitrosamines can be grouped by cancer risk, as follows:

• NDMA and NDEA: These nitrosamines have been classified as probable human carcinogens by international agencies like the International Agency for Research on Cancer (IARC).²⁷
• NMBA: Animal studies in rats show tumor induction in the gastrointestinal tract and bladder at high doses.^28,29
• N-nitroso-varenicline: Carcinogenicity data is not yet available.

Human Studies on NDMA

Human studies demonstrating increased cancer risk posed by nitrosamine include the following:

• European Prospective Investigation into Cancer and Nutrition (EPIC) Study: The EPIC study evaluated over 23,363 people aged 40-79. Researchers discovered that higher dietary intake of NDMA was associated with an elevated risk of colorectal cancer, after adjusting for other relevant factors.³⁰
• Canadian Case-Control Study: This study linked increased dietary NDMA intake to a higher risk of colorectal cancer.³¹

Liver Cancer and Association with NDMA and NDEA

Research suggests NDMA and NDEA may increase risk of liver cancer, as follows:

• Human Study in Germany: Researchers found that NDMA-contaminated valsartan was associated with a slightly increased risk (1.16-fold) of liver cancer.³²
• Experimental Studies in Animals: NDEA used at high doses in mice induces liver tumors, potentially through DNA damage.^33,34

Regulatory Limits and Recalls

FDA regulatory limits on nitrosamine contaminants led to the following recalls:

• Recalls of Valsartan and Other ARB Medications: Impurities exceeding the FDA's interim acceptable intake limit (0.08 ppm) of NDEA led to recalls of the blood pressure medication, valsartan, and other ARB medications.^26,35,36
• Zantac (Ranitidine) Recall: Valisure detected concerning NDMA levels exceeding 300,000 nanograms (ng) per tablet when analyzing Zantac (ranitidine) at high temperatures, likely due to inherent instability of the ranitidine molecule.³⁷ Opportunities for high-temperature exposure exist throughout the supply chain. This is significantly higher than the FDA's current acceptable daily intake limit of 96 ng for NDMA.³⁸ These findings led to a recall of all ranitidine products in 2020.
• Metformin Recall: Batches of metformin were voluntarily recalled by Viona Pharmaceuticals Inc. in 2022 due to the detection of NDMA impurity.³⁹

FDA Findings and Safety Limits

The FDA set safety limits on N-nitroso-varenicline found in Chantix, as follows:⁶

• Testing: In August 2021, the FDA identified elevated levels of N-nitroso-varenicline (a nitrosamine impurity) in certain Chantix batches, ranging from 150-470 ng per tablet.
• Daily Intake Limit: The FDA established a daily intake limit of 37 ng (18.5 ppm) of N-nitroso-varenicline, which was considered safe based on lifetime exposure modeling.

Higher Limits and Risk: Agency scientists determined that higher intake levels, up to 185 ng/day (92.5 ppm), pose a slightly increased cancer risk compared to the 37 ng/day limit.

N-Nitroso-Varenicline and Carcinogenicity

The cancer risk of N-nitroso-varenicline can be summarized as follows:

• Proposed Mechanism: The potential carcinogenicity of N-nitroso-varenicline is linked to its metabolic activation. It's believed that cytochrome P450 enzymes convert N-nitroso-varenicline into alkyl diazonium ions, which can directly damage DNA through alkylation (adding unwanted chemical groups).⁴⁰
• Selective Tumor Induction: The varying distribution of these activating enzymes in different tissues may explain why nitrosamines like N-nitroso-varenicline might selectively cause tumors in specific organs.⁴⁰

Alternative Mechanism: Nitrosamines may also disrupt cellular DNA repair processes, leading to mutations and potentially increasing cancer risk.^41,42

Strength of available evidence: MODERATE

• While nitrosamines are closely correlated with cancer development and a proposed mechanism of action for carcinogenic properties of N-nitroso-varenicline exists, further research is needed to confirm that Chantix use increases risk of cancer.