Pharmacovigilance Study on Adverse Events of Nicotine Replacement Therapy, Bupropion, and Varenicline in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the most prevalent respiratory disorders, with smoking being a major risk factor. Smoking cessation is therefore crucial in the management of COPD. This study aimed to comprehensively evaluate the safety profiles of common cessation therapies, including nicotine replacement therapy, bupropion, and varenicline.

Patients and methods: Using the FDA Adverse Event Reporting System (FAERS) database from Q1 2004 to Q2 2024, we analyzed adverse events (AEs) associated with bupropion, nicotine, and varenicline in COPD patients. Disproportionality analysis, case-by-case evaluation, and co-medication analysis were performed to identify positive safety signals.

Results: Eighty-eight positive safety signals were identified, primarily involving psychiatric, nervous system, and gastrointestinal disorders. Notable AEs included depression, nausea, anxiety, abnormal dreams, and insomnia. Critically, eight PTs indicated serious AEs associated with psychiatric disorders that were not present in the labeling but required Important Medical Event (IME) surveillance. Experiencing severe neuropsychiatric symptoms (eg, suicidal thoughts and suicide attempts) was the major reason for limiting the use of these drugs, especially varenicline, for which the FDA issued a black box warning in 2009. Nicotine combined with varenicline showed higher risks for skin reactions and gastrointestinal issues. Most AEs occurred within the first 30 days of therapy, with some persisting beyond a year.

Conclusion: This study highlights significant psychiatric, neurological, and gastrointestinal AEs associated with smoking cessation therapies in patients with COPD. Clinicians are advised to be particularly cautious of these risks, especially when using combination therapies or treating patients with a predisposition to psychiatric disorders.

Keywords: FAERS database; bupropion; chronic obstructive pulmonary disease; nicotine; varenicline.

Graphical abstract

Figure 1

Flowchart depicting the study process.

Figure 2

Comprehensive analysis of target drugs’ data. (A) Frequency of target drugs’ AEs in the FAERS database (2004Q1 - 2024Q2). (B) AE ratio for target drugs versus the total AE reports (2004Q1 - 2024Q2). (C) Number of target drugs’ cases in the FAERS database (2004Q1 - 2024Q2). (D) The frequency of AEs occurred in different time periods (2004Q1 - 2024Q2).

Figure 3

Classification of the AEs related to bupropion, nicotine and varenicline.

Figure 4

The reporting odds ratios of the top 20 AEs related to target drugs. (A) The reporting odds ratios of the top 20 AEs related to bupropion, nicotine and varenicline. (B) The reporting odds ratios of the top 20 AEs related to bupropion. (C) The reporting odds ratios of the 19 AEs related to nicotine. (D) The reporting odds ratios of the top 20 AEs related to varenicline.

Figure 5

Time-to-onset analysis of the top 20 AEs reported for target drugs. Reported time-to-onset analysis and duration of treatment of the top 20 AEs with (A) bupropion, nicotine and varenicline, (B) bupropion (Only five), (C) nicotine (Only nine), (D) varenicline.

Figure 6

The heatmap of the AEs related to target drugs in combination. (A) PTs of nicotine combined with varenicline. (B) PTs of bupropion combined with varenicline. (C) PTs of bupropion combined with nicotine.