Impact of early nausea on varenicline adherence and smoking cessation

Peng, Annie R.; Swardfager, Walter; Benowitz, Neal L.; Ahluwalia, Jasjit S.; Lerman, Caryn; Nollen, Nicole L.; Tyndale, Rachel F.

doi:10.1111/add.14810

Cited by 15 publications

(20 citation statements)

References 43 publications

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“…some participants reported stopping medication because of AEs), or contributed to loss to follow‐up or the higher withdrawal rate seen in the varenicline group. Early nausea during varenicline treatment may reduce adherence and be associated with lower likelihood of smoking cessation [ 33 ], so should be anticipated and managed in people taking cytisine or varenicline. The lower incidence of nausea in the cytisine group is probably due to cystine's slower potency at 5‐HT 3 receptors [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial

et al. 2021

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Aim To determine whether cytisine was at least as effective as varenicline in supporting smoking abstinence for ≥ 6 months in New Zealand indigenous Māori or whānau (extended‐family) of Māori, given the high smoking prevalence in this population. Design Pragmatic, open‐label, randomized, community‐based non‐inferiority trial. Setting Bay of Plenty, Tokoroa and Lakes District Health Board regions of New Zealand. Participants Adult daily smokers who identified as Māori or whānau of Māori, were motivated to quit in the next 2 weeks, were aged ≥ 18 years and were eligible for subsidized varenicline. Recruitment used multi‐media advertising. Interventions A total of 679 people were randomly assigned (1 : 1) to receive a prescription for 12 weeks of cytisine or varenicline, plus low‐intensity cessation behavioural support from the prescribing doctor and community stop‐smoking services or a research assistant. Day 5 of treatment was the designated quit date. Measurements The primary outcome was carbon monoxide‐verified continuous abstinence at 6 months, analysed as intention‐to‐treat (with multiple imputation for missing data). Secondary outcomes measured at 1, 3, 6 and 12 months post‐quit date included: self‐reported continuous abstinence, 7‐day point prevalence abstinence, cigarettes per day, time to (re)lapse, adverse events, treatment adherence/compliance and acceptability, nicotine withdrawal/urge to smoke and health‐care utilization/health‐related quality of life. Findings Verified continuous abstinence rates at 6 months post‐quit date were 12.1% (41 of 337) for cytisine versus 7.9% (27 of 342) for varenicline [risk difference 4.29%, 95% confidence interval (CI) = –0.22 to 8.79; relative risk 1.55; 95% CI = 0.97–2.46]. Sensitivity analyses confirmed that the findings were robust. Self‐reported adverse events over 6 months occurred significantly more frequently in the varenicline group (cytisine: 313 events in 111 participants; varenicline: 509 events in 138 participants, incidence rate ratio 0.56, 95% CI = 0.49–0.65, P < 0.001) compared with the cytisine group. Common adverse events were headache, nausea and difficulty sleeping. Conclusion A randomized controlled trial found that cytisine was at least as effective as varenicline at supporting smoking abstinence in New Zealand indigenous Māori or whānau (extended‐family) of Māori, with significantly fewer adverse events.

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Section: Discussionmentioning

confidence: 99%

Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial

et al. 2021

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“…A recent analysis of nausea rates in 2 smoking cessation clinical trials conducted at multiple sites in the U.S. and Canada found that early nausea was indirectly associated with lower cessation rates at multiple timepoints as a result of reduced varenicline adherence (ORs ranging from 0.92–0.94; 95% CI between 0.83–0.99). 16 A prior analysis of 6 varenicline clinical trials found that nausea was the most common AE, occurring in 28.1% of participants. 17 In contrast, in the ORCA-1 study described here, fewer than 10% of participants reported nausea as an AE ( Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…Participants were randomized in a 2:2:1 ratio to receive cytisinicline 1.5 mg, cytisinicline 3 mg, or placebo (Supplemental Figure 1). After randomization, each participant was required to attend 11 clinic visits [ Day 2,3,6,12,16,20 during treatment, at End of Treatment (EOT: Day 27 ± 2), and then weekly post-treatment at Week 5,6,7,8]. All participants received approximately 10 minutes of smoking cessation counseling at each clinic visit provided by experienced counselors.…”

Section: Methodsmentioning

confidence: 99%

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial)

Nides

Rigotti

Benowitz

et al. 2021

Nicotine &Amp; Tobacco Research

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Introduction Cytisinicline (known as cytisine), a nicotinic acetylcholine receptor partial agonist, is a smoking cessation aid currently marketed in Central and Eastern Europe using a 1.5mg/tablet 25-day downward titration schedule. No prior studies have evaluated other doses or administration schedules. This study evaluated effects of a higher dosage and simplified dosing schedule on drug efficacy and tolerability. Methods ORCA-1 was a double-blind, randomized, placebo-controlled clinical trial that provided cytisinicline or placebo tablets plus behavioral support for 25 days. Adult smokers (> 10 cigarettes daily) committed to quitting smoking were randomized to compare 2 cytisinicline doses (1.5 mg and 3 mg) versus placebo, and 2 administration schedules [downward titration versus 3 times daily (TID)]. Primary outcome was reduction in expected cigarettes smoked at end of treatment; secondary outcomes were biochemically confirmed 7-day abstinence at Week 4 and continuous abstinence from Weeks 5 to 8. Results Among 254 participants, those in cytisinicline arms (regardless of dose or schedule) had greater reductions in cigarettes smoked versus placebo, with differences observed in 3 cytisinicline arms statistically significant versus placebo. All cytisinicline arms had statistically significantly higher abstinence rates at Week 4 versus placebo. Both cytisinicline arms using TID schedules had statistically significantly higher continuous abstinence rates from Weeks 5 to 8 compared with placebo. Participants in the cytisinicline 3-mg TID arm had the highest abstinence rate. There were no safety concerns with either 1.5mg or 3mg cytisinicline. Conclusion Based on simpler dose scheduling, excellent tolerability, and best continued abstinence rate, cytisinicline 3mg TID was selected for future Phase 3 studies. Implications Although the 1.5mg 25-day titration schedule has been marketed in Central and Eastern Europe for decades, this study explored using a higher dosage and a simplified dosing schedule for impact on cytisinicline efficacy and tolerability. Based on these results, a Phase 3 program was initiated using cytisinicline 3 mg tablets on a TID schedule for potential market approval in the United States.

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“…Even with dose titration, ~28% of smokers receiving varenicline treatment in clinical trial settings report nausea (3), and nausea is a commonly cited reason for discontinuation of treatment (5). We have shown that in vareniclinetreated smokers, nausea is indirectly associated with lower quit rates, in a relationship that is mediated by reduced varenicline adherence (6). A greater understanding of the factors that increase the risk for varenicline-associated nausea will enable improved treatment approaches that increase medication adherence and promote cessation.…”

Section: Introductionmentioning

confidence: 87%

“…a week after the target quit date). Varenicline levels were measured in saliva samples using LC-MS/MS (details available elsewhere (6,18)). The sensitivity analyses were conducted in SNPTEST version 2.5.2 and the "method -expected" option was specified to control for genotype uncertainty.…”

Section: Sensitivity Analysesmentioning

confidence: 99%

A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers

Chenoweth

Lerman

Knight

et al. 2021

Nicotine &Amp; Tobacco Research

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Introduction Varenicline is the most efficacious smoking cessation treatment, however long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood. Methods We conducted a genome-wide association study of nausea incidence at one week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF) ≥ 10% were considered. Results Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (OR=2.61 for A vs. G allele; 95% CI=1.65,4.15; P=2.1e-7; MAF=48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (P=0.56; n=181) or placebo (P=0.59; n=174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n=74) versus males (20.9%; n=115) (P=0.001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (P for sex*genotype interaction=0.36). Future studies in larger samples are required to test the robustness of this finding. Conclusions Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation. Implications Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an importance cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

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Impact of early nausea on varenicline adherence and smoking cessation

Cited by 15 publications

References 43 publications

Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial

Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial)

A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers

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