The American Journal of Drug and Alcohol Abuse Encompassing All Addictive Disorders ISSN: 0095-2990 (Print) 1097-9891 (Online) Journal homepage: http://www.tandfonline.com/loi/iada20 Combination bupropion SR and varenicline for smoking cessation: a systematic review Tiffany Vogeler, Claire McClain & Kirk E. Evoy To cite this article: Tiffany Vogeler, Claire McClain & Kirk E. Evoy (2016) Combination bupropion SR and varenicline for smoking cessation: a systematic review, The American Journal of Drug and Alcohol Abuse, 42:2, 129-139, DOI: 10.3109/00952990.2015.1117480 To link to this article: http://dx.doi.org/10.3109/00952990.2015.1117480 Published online: 25 Jan 2016. Submit your article to this journal Article views: 836 View related articles View Crossmark data Citing articles: 2 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iada20 Download by: [UCSF Library] Date: 12 July 2017, At: 17:24 AM J DRUG ALCOHOL ABUSE 2016, VOL. 42, NO. 2, 129–139 http://dx.doi.org/10.3109/00952990.2015.1117480 REVIEW Combination bupropion SR and varenicline for smoking cessation: a systematic review Tiffany Vogeler, PharmDa, Claire McClain, PharmDb, and Kirk E. Evoy, PharmD, BCACP, TTS c aPalm Beach Atlantic University, West Palm Beach, FL, USA; bTexas Children’s Hospital, Houston, TX, USA; cCollege of Pharmacy, University of Texas at Austin, San Antonio, TX, USA ABSTRACT ARTICLE HISTORY Background: Tobacco is the leading cause of preventable death in the world. Current cessation Received 3 September 2015 medications include nicotine replacement therapy (NRT), varenicline, and bupropion, while com- Revised 13 October 2015 bination therapy primarily entails NRT with either varenicline or bupropion. However, recent Accepted 3 November 2015 studies have examined varenicline and bupropion in combination. Objectives: A systematic review KEYWORDS assessing the efficacy and safety of combination varenicline and bupropion was conducted. Bupropion; varenicline; Methods: PubMed and Clinicaltrials.gov were searched using terms: “varenicline combination”, combination; smoking “bupropion combination”, “bupropion AND varenicline”, and “bupropion AND varenicline combi- cessation; review nation smoking cessation”, yielding four studies including 1193 total patients. Results: Combination therapy yielded greater efficacy than varenicline monotherapy in two randomized controlled trials and one retrospective outcomes study. One single-arm Phase II trial provided additional efficacy and safety data. Of the prospective trials, one displayed a greater 4-week smoking abstinence for weeks 8–11 with combination (39.8%) versus monotherapy (25.9%) (OR = 1.89; 95% CI = 1.07–3.35). The other demonstrated greater prolonged abstinence (continuous abstinence from week 2) at 12 weeks (OR = 1.49; 95% CI = 1.05–2.12) and 26 weeks (OR = 1.52; 95% CI = 1.04–2.22), though results were not significant at 52 weeks in this study. The retro- spective study displayed higher success rates (continuous abstinence rates at 52 weeks) with combination varenicline and bupropion (55.0%; compared to varenicline monotherapy (32.1%), p < 0.001). Subgroup analyses suggest that this combination may be more beneficial in males and ’ patients with higher baseline nicotine dependence. Conclusion: To the authors knowledge, this is the first review conducted to compile current literature on this novel pharmacotherapy combina- tion for smoking cessation. Combination bupropion SR and varenicline displayed greater efficacy in smoking cessation than varenicline monotherapy, though further safety analysis is warranted to rule out additive psychiatric adverse effects. Introduction cessation (5,6). Varenicline acts as a partial agonist at the Tobacco continues to be the leading cause of preven- α4β2 nicotinic receptor. Its efficacy in smoking cessation table death in the United States and in the world, as its is thought to be due to its high affinity and selective use is a major contributor in four out of the five leading binding to these receptors, simultaneously preventing causes of death: heart disease, cancer, chronic lower nicotine from binding (5). Bupropion SR inhibits neuro- respiratory disease, and cerebrovascular diseases (1). nal reuptake of dopamine and norepinephrine in the Smoking cessation confers tremendous immediate and reward center of the brain, which may stimulate rewards long-term health benefits (2). Current pharmacologic similar to those achieved when smoking, thus reducing treatments available to aid in smoking cessation the craving for nicotine (6). Bupropion SR is also believed include: nicotine replacement therapy (NRT), vareni- to function as a noncompetitive nicotine antagonist at the cline and bupropion sustained release (SR) (3). α4β2 receptors (7). Due to these mechanisms, varenicline Unfortunately, with current pharmacotherapy, success and bupropion SR may produce additive or synergistic rates remain low, with less than 25% of smokers effects. However, as both drugs act on the central nervous remaining abstinent one year after treatment (4). system and each feature black box warnings for suicidal Varenicline (Chantix®) and bupropion SR (Zyban®) are ideation, concern of additive side-effects could limit their non-nicotine pharmacologic treatment options approved use in combination. Recently, several clinical trials have by the Food and Drug Administration (FDA) for smoking been conducted to assess the safety and efficacy of CONTACT Kirk E. Evoy, PharmD, BCACP, TTS [email protected] College of Pharmacy, University of Texas at Austin, 5600 Babcock Rd., Apt. 5207, San Antonio, TX 78240, USA. © 2016 Taylor & Francis 130 T. VOGELER ET AL. combination varenicline and bupropion SR for smoking point-prevalence or prolonged abstinence up to a spe- cessation. This narrative review provides the evidence cified time-point. However time-points at which 7-day from each study individually, specifically focusing on point-prevalence and prolonged abstinence were efficacy in terms of point-prevalence and prolonged assessed varied between studies. Abstinence was deter- smoking abstinence as well as safety and tolerability of mined based on patient self-reporting and confirmed bupropion and varenicline in combination. Additionally, through measured exhaled CO levels in all studies, but efficacy in specific subpopulations and strengths and lim- method of self-reporting and acceptable CO levels var- itations of the identified trials are discussed. This systema- ied slightly. The fourth study assessed complete absti- tic review is the first to evaluate the total body of evidence nence rates at 52 weeks (CAR 52 weeks), measured by available relating to the use of this combination for smok- CO concentrations (10). Table 1 describes the primary ing cessation. endpoints of each trial. Two of the studies (8,9) featured a uniform defini- Methods tion of adherence (pill counts and self-reported missed doses during each visit), while a third (4) assessed Search strategy adherence, but based on daily diary entry of missed doses. The fourth study (10) did not report adherence PubMed and ClinicalTrials.gov were searched up to 5 assessment. August 2015 with the following terms specified a priori: “varenicline combination”, “bupropion combination”, “bupropion AND varenicline”, and “bupropion AND Description of included studies varenicline combination smoking cessation”. Human Two phase III trials, both published in 2014, were studies featuring a treatment arm in which patients included, one comparing combination varenicline and received both bupropion and varenicline concurrently bupropion SR versus varenicline plus placebo for 12 were included without language restrictions. Abstracts weeks in nicotine patch non-responders via an adaptive of studies identified were screened for eligibility, initi- treatment paradigm (4) and the other assessing combi- ally by two reviewers, with 100% agreement. A third nation varenicline and bupropion SR versus varenicline reviewer assessed the included studies post-agreement plus placebo for 12 weeks with subsequent follow-up by the initial reviewers. Details of the trials (timeframe, through week 52 (9). Additionally, one phase II clinical inclusion criteria, demographics, sample size, study trial, published in 2009, assessing the efficacy and safety design, outcomes, trial length and follow-up, recruit- of combination varenicline and bupropion SR, was ment methods, adverse effects, overall results and sub- included (8). The fourth study featured retrospective group analyses) were extracted and imported into a outcome research, assessing 52-week abstinence in spreadsheet (Table 1). Any discrepancies identified patients treated with varenicline monotherapy versus between the studies were discussed and reviewers patients with either bupropion, a serotonin reuptake reached a consensus before proceeding. inhibitor (SSRI), or both added to varenicline (10). Results Summary of evidence Search results Ebbert et al. conducted a phase II, open-label, one-arm The literature search yielded 1295 results. Those that trial to obtain preliminary data on the potential effec- were not conducted in humans (245) were excluded. Of tiveness and safety of combination therapy with vareni- the remaining 1050 results, only four published studies cline and bupropion SR for the treatment of tobacco included a combined varenicline and bupropion SR dependence (8). Patients were included if they met the arm.