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Nicotine & Tobacco Research : Official... Jan 2016Postmarketing analyses and case reports have associated varenicline use with suicidal behaviors. This article reviews postmarketing analyses, case reports, clinical...
OBJECTIVE
Postmarketing analyses and case reports have associated varenicline use with suicidal behaviors. This article reviews postmarketing analyses, case reports, clinical trials, uncontrolled observational studies, controlled observational studies, and studies in smokers with psychiatric problems that have tested this association.
METHOD
The author searched the literature for relevant reports via computer and other searches to undertake a qualitative, systematic review.
RESULTS
Two pooled analyses of 10 and 17 placebo-controlled trials failed to find more suicidal outcomes in the varenicline condition. Seven large uncontrolled observational studies reported low rates of suicide outcomes in varenicline users (<0.1%), and 1 study reported a higher rate (6%). Five large controlled observational studies did not find more suicide outcomes in varenicline users than in those using prescribed bupropion or over-the-counter nicotine medications. Small placebo-controlled trials and observational studies of smokers with current psychiatric problems did not find varenicline was associated with suicidal outcomes.
CONCLUSIONS
Among the more valid study designs (pooled analyses of placebo controlled trials or large controlled observational studies), there is consistent evidence that varenicline either does not cause increased suicide outcomes, or if it does, the effect is very small. Warnings to consumers and clinicians should reflect, not just the results of postmarketing studies, but the results of the more valid research designs.
Topics: Drug Labeling; Female; Humans; Nicotinic Agonists; Smoking Cessation; Suicide; Tobacco Use Cessation Devices; United States; United States Food and Drug Administration; Varenicline
PubMed: 25572451
DOI: 10.1093/ntr/ntu275 -
The Spine Journal : Official Journal of... Feb 2020Smoking is detrimental to obtaining a solid spinal fusion mass with previous studies demonstrating its association with pseudoarthrosis in patients undergoing spinal...
BACKGROUND CONTEXT
Smoking is detrimental to obtaining a solid spinal fusion mass with previous studies demonstrating its association with pseudoarthrosis in patients undergoing spinal fusion. Varenicline is a pharmacologic adjunct used in smoking cessation which acts as a partial agonist of the same nicotinic receptors activated during tobacco use. However, no clinical or basic science studies to date have characterized if varenicline has negative effects on spinal fusion and bone healing by itself.
PURPOSE
Our study's aim was to elucidate whether varenicline affects the frequency or quality of posterolateral spinal fusion in a rodent model at an endpoint of 12 weeks.
STUDY DESIGN
Randomized control trial.
PATIENT SAMPLE
Fourteen male Lewis rats randomly separated into two experimental groups.
OUTCOME MEASURES
Manual palpation of fusion segment, radiography, μCT imaging, and four-point bend.
METHODS
Fourteen male Lewis rats were randomly separated into two experimental groups undergoing L4-L5 posterior spinal fusion procedure followed by daily subcutaneous injections of human dose varenicline or saline (control) for 12 weeks postsurgery. Spine samples were explanted, and fusion was determined via manual palpation of segments by two independent observers. High-resolution radiographs were obtained to evaluate bridging fusion mass. μCT imaging was performed to characterize fusion mass and consolidation. Lumbar spinal fusion units were tested in four-point bending to evaluate stiffness and peak load. Study funding sources include $5000 OREF Grant. There were no applicable financial relationships or conflicts of interest.
RESULTS
At 3 months postsurgery, 12 out of 14 rats demonstrated lumbar spine fusion (86% fused) with no difference in fusion frequency between the varenicline and control groups as detected by manual palpation. High-resolution radiography revealed six out of seven rats (86%) having complete fusion in both groups. μCT showed no significant difference in bone mineral density or bone fraction volume between groups in the region of interest. Biomechanical testing demonstrated no significant different in the average stiffness or peak loads at the fusion site of the varenicline and control groups.
CONCLUSION
Based on the results of our rat study, there is no indication that varenicline itself has a detrimental effect on the frequency and quality of spinal fusion.
Topics: Animals; Bone Regeneration; Lumbar Vertebrae; Male; Postoperative Complications; Random Allocation; Rats; Rats, Inbred Lew; Smoking Cessation Agents; Spinal Fusion; Varenicline
PubMed: 31377475
DOI: 10.1016/j.spinee.2019.07.015 -
Addiction (Abingdon, England) Jan 2020Varenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND AND AIMS
Varenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible effect of nausea on smoking cessation outcomes mediated by adherence.
DESIGN
Mediation path analysis.
SETTING
Multiple sites within Canada and the United States.
PARTICIPANTS
Treatment-seeking smokers receiving varenicline from two smoking cessation clinical trials: Quit2Live (NCT01836276; n = 449) and Pharmacogenetics of Nicotine Addiction Treatment (PNAT) (NCT01314001; n = 421).
MEASUREMENTS
Nausea severity was collected through self-report and adherence was biologically assessed using varenicline concentrations (Quit2Live, plasma sample at week 4; PNAT, saliva sample at week 2). In Quit2Live, the end-points were cotinine-verified abstinence at weeks 4, 12 and 26. In PNAT, the end-points were carbon monoxide-verified abstinence at weeks 2, 12 and 26.
FINDINGS
Early nausea was not directly associated with abstinence [odds ratio (OR) ranging from 0.73-1.28; P ≥ 0.26]. However early nausea was indirectly associated with lower cessation rates at multiple timepoints (ORs ranging from 0.92-0.94; 95% CI between 0.83-0.99) in a relationship mediated by reduced varenicline adherence (assessed by plasma varenicline concentrations) in the primary trial (Quit2Live). This relationship between nausea, adherence and cessation was similar in direction but weaker in effect size (ORs ranging from 0.98-0.99; 95% CI between 0.90-1.03) in a secondary trial (PNAT), where adherence was assessed using salivary varenicline concentrations.
CONCLUSIONS
These data suggest that early nausea during varenicline treatment may be indirectly associated with lower likelihood of smoking cessation through reducing varenicline adherence. Differences in robustness between the trials may be due to the different biological matrices (plasma vs. saliva) and/or timing used to assess varenicline adherence. The results of the first study suggest that improved management of early nausea during varenicline treatment may positively impact smoking cessation success through increasing varenicline adherence.
Topics: Adult; Canada; Female; Humans; Male; Mediation Analysis; Medication Adherence; Middle Aged; Nausea; Smoking Cessation; Smoking Cessation Agents; United States; Varenicline
PubMed: 31502736
DOI: 10.1111/add.14810 -
International Journal of Clinical... Feb 2020Varenicline is an effective drug for smoking cessation. The aim of the present study was to compare the pharmacokinetics and safety profiles of two different varenicline...
BACKGROUND AND OBJECTIVE
Varenicline is an effective drug for smoking cessation. The aim of the present study was to compare the pharmacokinetics and safety profiles of two different varenicline formulations (varenicline tartrate (reference) and varenicline oxalate (test)), each containing 1 mg varenicline base in humans.
MATERIALS AND METHODS
A randomized, open-label, two-sequence, two-period, single-dose crossover study with a 2-week washout period was conducted with 30 healthy male participants. Blood samples for the pharmacokinetic analysis of varenicline were collected up to 96 hours following the administration of each drug. Pharmacokinetic parameters were also calculated, including the peak plasma concentration (C), area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUC) as well as AUC from time zero to infinity (AUC). ANOVA for pharmacokinetic equivalence was assessed using log-transformed C and AUC values, and the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were assessed as well. The safety profiles were also assessed.
RESULTS
27 participants completed the study. No significant differences were found for any pharmacokinetic parameters of varenicline between the two formulations. The observed average values of C, AUC, and AUC were 4.46 ng/mL, 97.68 ng×h/mL, and 101.60 ng×h/mL for reference and 4.54 ng/mL, 97.10 ng×h/mL, and 100.97 ng×h/mL for test, respectively. The GMRs and 90% CIs for C, AUC, and AUC were 1.0106 (0.9626 - 1.0610), 0.9904 (0.9540 - 1.0282), and 0.9885 (0.9517 - 1.0268), respectively. No clinically relevant changes were observed in the physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were found.
CONCLUSION
The results of the present study reveal that varenicline oxalate and varenicline tartrate have similar pharmacokinetic characteristics as varenicline, and that these two formulations exhibit pharmacokinetic equivalence to meet the regulatory criteria. Both varenicline formulations were generally well tolerated.
Topics: Area Under Curve; Biological Availability; Cross-Over Studies; Humans; Male; Oxalates; Tablets; Therapeutic Equivalency; Varenicline
PubMed: 31699211
DOI: 10.5414/CP203574 -
International Review of Neurobiology 2015Despite availability of smoking cessation aids with proven efficacy and tolerability in those with schizophrenia, addiction to tobacco-derived nicotine remains highly... (Review)
Review
Despite availability of smoking cessation aids with proven efficacy and tolerability in those with schizophrenia, addiction to tobacco-derived nicotine remains highly prevalent among those with schizophrenia spectrum disorders. While smokers with serious mental illness have been excluded from most large nicotine-dependence treatment studies, and these treatments are woefully underutilized for smokers with psychiatric illness, a growing evidence base is available to guide cessation treatment for smokers with schizophrenia. The aim of this review is to present the evidence on safety and efficacy of smoking cessation interventions for those with schizophrenia spectrum illness. Smokers with schizophrenia spectrum disorders should receive varenicline or bupropion with or without nicotine replacement therapy in combination with behavioral treatment. Clinical practice guidelines now recommend duration of treatment be 12 weeks, but evidence indicates that maintenance pharmacotherapy for 1 year improves sustained abstinence rates. Controlled trials have found no evidence that in patients with serious mental illness, the use of pharmacotherapeutic cessation aids worsens psychiatric symptoms or increases the rate of psychiatric adverse events. Converging evidence indicates that a majority of smokers with serious mental illness want to quit smoking and that available pharmacotherapeutic cessation aids combined with behavioral support are both effective for, and well tolerated by, these smokers.
Topics: Antipsychotic Agents; Behavior Therapy; Bupropion; Humans; Schizophrenia; Smoking Cessation; Tobacco Use Disorder; Varenicline
PubMed: 26472528
DOI: 10.1016/bs.irn.2015.08.001 -
Addiction (Abingdon, England) Sep 2023Treatment of depression-related psychological factors related to smoking behavior may improve rates of cessation among adults with major depressive disorder (MDD). This... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of combination behavioral activation for smoking cessation and varenicline for treating tobacco dependence among individuals with current or past major depressive disorder: A 2 × 2 factorial, randomized, placebo-controlled trial.
BACKGROUND AND AIMS
Treatment of depression-related psychological factors related to smoking behavior may improve rates of cessation among adults with major depressive disorder (MDD). This study measured the efficacy and safety of 12 weeks of behavioral activation for smoking cessation (BASC), varenicline and their combination.
DESIGN, SETTING, PARTICIPANTS
This study used a randomized, placebo-controlled, 2 × 2 factorial design comparing BASC versus standard behavioral treatment (ST) and varenicline versus placebo, taking place in research clinics at two urban universities in the United States. Participants comprised 300 hundred adult smokers with current or past MDD.
INTERVENTIONS
BASC integrated behavioral activation therapy and ST to increase engagement in rewarding activities by reducing avoidance, withdrawal and inactivity associated with depression. ST was based on the 2008 PHS Clinical Practice Guideline. Both treatments consisted of eight 45-min sessions delivered between weeks 1 and 12. Varenicline and placebo were administered for 12 weeks between weeks 2 and 14.
MEASUREMENTS
Primary outcomes were bioverified intent-to-treat (ITT) 7-day point-prevalence abstinence at 27 weeks and adverse events (AEs).
FINDINGS
No significant interaction was detected between behavioral treatment and pharmacotherapy at 27 weeks (χ = 0.19, P = 0.67). BASC and ST did not differ (χ = 0.43, P = 0.51). Significant differences in ITT abstinence rates (χ = 4.84, P = 0.03) emerged among pharmacotherapy arms (16.2% for varenicline, 7.5% for placebo), with results favoring varenicline over placebo (rate ratio = 2.16, 95% confidence interval = 1.08, 4.30). All significant differences in AE rates after start of medication were higher for placebo than varenicline.
CONCLUSION
A randomized trial in smokers with major depressive disorder found that varenicline improved smoking abstinence versus placebo at 27 weeks without elevating rates of adverse events. Behavioral activation for smoking cessation did not outperform standard behavioral treatment, with or without adjunctive varenicline therapy.
Topics: Adult; Humans; Varenicline; Tobacco Use Disorder; Smoking Cessation; Depressive Disorder, Major; Nicotinic Agonists; Benzazepines; Treatment Outcome; Quinoxalines
PubMed: 37069490
DOI: 10.1111/add.16209 -
Addiction Biology Sep 2020Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small...
Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small effect sizes, and improved treatments are needed. Smoking and AUD share heritability and are pharmacologically associated, since drug-induced dopamine (DA) output in nucleus accumbens (nAc) involves nicotinic acetylcholine receptors (nAChRs) in both cases. Smoking therapy agents, such as the partial nAChR agonist varenicline or the DA/noradrenaline transporter inhibitor bupropion, could potentially also be used for AUD. To investigate this hypothesis, the effects of varenicline, bupropion, or a combination of the two on nAc DA levels, ethanol intake, and the alcohol deprivation effect (ADE) were examined. In vivo microdialysis showed that varenicline (1.5 mg/kg) and bupropion (2.5, 5, or 10 mg/kg) elevated nAc DA levels and that the combination produced additive effects. Five days treatment with varenicline, bupropion, or the combination did not suppress ethanol consumption, as compared with vehicle-treated control. However, combined administration of varenicline and bupropion completely blocked the ADE when readministering ethanol following 14 days of abstinence. Since ADE is considered highly predictive for the clinical outcome in man, our data suggest that the combination of varenicline and bupropion could be a promising treatment for AUD.
Topics: Alcohol-Related Disorders; Animals; Bupropion; Disease Models, Animal; Dopamine; Drug Therapy, Combination; Male; Nucleus Accumbens; Rats; Rats, Wistar; Smoking Cessation Agents; Varenicline
PubMed: 31293045
DOI: 10.1111/adb.12807 -
Journal of Managed Care & Specialty... Aug 2022Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical method that derives indirect comparisons between treatments when... (Review)
Review
Matching-adjusted indirect comparison of phase 3 clinical trial outcomes: OC-01 (varenicline solution) nasal spray and cyclosporine a 0.05% ophthalmic emulsion for the treatment of dry eye disease.
Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical method that derives indirect comparisons between treatments when head-to-head studies have not been performed. To compare the efficacy of OC-01 varenicline nasal spray (OC-01 VNS) 0.03 mg to cyclosporine A (CsA) 0.05% ophthalmic emulsion on tear production in patients with dry eye disease based on data from the respective phase 3 clinical trials using the MAIC technique. Individual patient data were drawn from the phase 3 registry trial of OC-01 VNS; aggregate data were drawn from 2 phase 3 trials of CsA in the publicly available New Drug Application for CsA 0.05% ophthalmic emulsion (RESTASIS). Using unanchored MAIC methods, the individual patient data were weighted based on 4 clinically relevant baseline variables (age, race, sex, and baseline Schirmer test score [STS]) to produce a weighted OC-01 VNS dataset matched to the key demographics of the CsA dataset. Least-squares mean change from baseline in STS for OC-01 VNS was calculated using the identical analysis of variance model used to calculate the same value for CsA in the RESTASIS New Drug Application, which were then compared. Proportions of subjects with improvement of 10 mm or more from baseline in STS were compared in the weighted OC-01 VNS and CsA dataset. Time points available for comparisons were CsA trials at 3 and 6 months and OC-01 data at 2 and 4 weeks. Data from 511 subjects in the OC-01 VNS phase 3 trial and 585 in the CsA phase 3 trials were analyzed. The least-squares mean STS change from baseline for OC-01 VNS at 2 and 4 weeks was significantly higher than that for CsA at 3 and 6 months ( < 0.0001 for all comparisons). Mean STS improvements were approximately 6-7 mm for OC-01 VNS and approximately 1 mm for CsA. The proportion of subjects with improvement of 10 mm or more from baseline in STS was significantly higher for OC-01 VNS (50.2%) than CsA (11.7 and 17.1% in the 2 CsA studies; < 0.0001 for both comparisons). This MAIC analysis demonstrates OC-01 VNS produces significantly greater improvement in mean STS and results in significantly greater numbers of patients with substantial improvement in STS (percentage ≥ 10 mm) compared with CsA. Together, absent more robust data from head-to-head trials, findings may suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with CsA for the treatment of dry eye disease within conditions of the analysis methodology. Dr Visco was a consultant for Novartis, Allergan, and Oyster Point, Inc. Ms Hendrix and Drs Macsai and Gibson are employees and shareholders for Oyster Point Pharma, Inc. Drs Sun and Tam participated in clinical research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc sponsored the Phase 3 OC-01 (varenicine solution) clinical study from which analysis data are obtained.
Topics: Cyclosporine; Dry Eye Syndromes; Emulsions; Humans; Immunosuppressive Agents; Nasal Sprays; Ophthalmic Solutions; Tears; Treatment Outcome; Varenicline
PubMed: 35687793
DOI: 10.18553/jmcp.2022.22005 -
Journal of Clinical PsychopharmacologyPeople who smoke cigarettes and drink alcohol heavily are less likely to quit smoking compared with those who do not drink heavily. The current study examined the... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE/BACKGROUND
People who smoke cigarettes and drink alcohol heavily are less likely to quit smoking compared with those who do not drink heavily. The current study examined the effects of a 12-week treatment phase of combination varenicline and nicotine patch compared with placebo and nicotine patch on smoking cessation (primary outcome) and alcohol consumption (secondary outcome) in heavy drinking smokers at 26-week follow-up.
METHODS/PROCEDURES
Participants were daily smokers who met heavy drinking criteria. They were randomly assigned to receive either varenicline and nicotine patch (n = 61) or placebo and nicotine patch (n = 61) for 12 weeks. At week 26, self-reports of point prevalence cigarette abstinence were biochemically confirmed, and past-month alcohol drinking days and heavy drinking days were assessed.
FINDINGS/RESULTS
At week 26, smoking quit rates did not differ by treatment group (25% varenicline and 26% placebo). Relative to week 12 outcomes, week 26 quit rates significantly dropped off in the varenicline group but not in the placebo group. Alcohol drinking reductions for the whole sample that were previously observed from baseline to week 12 were sustained at week 26, although they did not differ between treatment groups.
IMPLICATIONS/CONCLUSIONS
In heavy drinking smokers, smoking cessation success was evident in a quarter of the total sample at 3 months postmedication discontinuation. At this time, quit rates were the same between those who received varenicline and nicotine patch and those who received nicotine patch alone. Future research is warranted to examine what may aid in longer-term smoking quit rates in heavy drinking smokers.
Topics: Humans; Varenicline; Smoking Cessation; Male; Female; Tobacco Use Cessation Devices; Adult; Middle Aged; Follow-Up Studies; Smoking Cessation Agents; Alcohol Drinking; Drug Therapy, Combination; Treatment Outcome; Nicotinic Agonists; Double-Blind Method
PubMed: 38752924
DOI: 10.1097/JCP.0000000000001864 -
Epilepsy & Behavior : E&B Aug 2019Varenicline is an effective smoking cessation agent; however, its use is limited because of black box warnings issued by regulatory agencies in the U.S. and Australia....
OBJECTIVE
Varenicline is an effective smoking cessation agent; however, its use is limited because of black box warnings issued by regulatory agencies in the U.S. and Australia. The U.S. Food and Drug Administration updated the label for varenicline in 2015 to warn about the risk of varenicline-induced seizures. The objective of this study was to examine the risk of seizure associated with varenicline use.
METHODS
A nested case-control study was performed using IMS LifeLink PharMetrics Plus administrative claims data (2009-2015). The outcome was presumptive seizures. All smokers making an attempt to quit smoking and having no recent seizure events were included in the nest. Cases and controls were matched (1:4) on age (±5 years), sex, index date (±30 days), event date, and duration of enrollment. An exposure period of 90 days preceding the event date was used. Chi-square tests were used to compare the characteristics of cases and controls. Conditional logistic regression was conducted to determine if an association between presumptive seizures and varenicline use exists.
RESULTS
Our final sample was comprised of 1342 cases and 5368 controls. The adjusted analysis showed that odds of a seizure for patients with a varenicline prescription were 1.09 (confidence interval [CI] = 0.88-1.36) times those of patients with no varenicline exposure.
CONCLUSIONS
This study did not find a significant association between varenicline and increased risk of presumptive seizures. These findings raise questions regarding the necessity for a warning label for increased risk of seizures associated with varenicline.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cigarette Smoking; Female; Humans; Logistic Models; Male; Middle Aged; Risk Factors; Seizures; Smoking Cessation; Smoking Cessation Agents; Varenicline; Young Adult
PubMed: 31252274
DOI: 10.1016/j.yebeh.2019.05.031