Varenicline expert opinion


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1. 1. Introduction 2. Introduction to the compound 3. Clinical efficacy 4. Safety and regulatory affairs 5. Harm reduction/effects on reward 6. Newer clinical trials 7.…
  • 1. 1. Introduction 2. Introduction to the compound 3. Clinical efficacy 4. Safety and regulatory affairs 5. Harm reduction/effects on reward 6. Newer clinical trials 7. Varenicline use, dosing and duration 8. Comparison of varenicline with nicotine replacement therapy 9. Combination therapy of varenicline with other pharmacotherapies 10. Varenicline use in smokers with medical comorbidity 11. Varenicline use in specific populations 12. Varenicline use for smokeless tobacco 13. Conclusion 14. Expert opinion Review Varenicline for tobacco dependence: panacea or plight? Jill M Williams† , Michael B Steinberg, Marc L Steinberg, Kunal K Gandhi, Rajiv Ulpe & Jonathan Foulds † UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA Introduction: This review examines the postmarketing experience with vare- nicline, including case reports, newer clinical trials and secondary analyses of large clinical datasets. Areas covered: Varenicline has been shown to be an effective treatment in a broad range of tobacco users with medical, behavioral and diverse demo- graphic characteristics. Recent studies finding excellent safety and efficacy in groups of smokers with diseases including chronic obstructive pulmonary disease are particularly encouraging and call for increased use of this medica- tion for smoking cessation. Despite case reports of serious neuropsychiatric symptoms in patients taking varenicline, including changes in behavior and mood, causality has not been established. Recent analyses of large datasets from clinical trials have not demonstrated that varenicline is associated with more depression or suicidality than other treatments for smoking cessation. Expert opinion: Now that additional clinical trials in specific populations and observational studies on treatment-seeking smokers outside of clinical trials have been published, we can be confident that varenicline remains the most efficacious monotherapy for smoking cessation and that its side-effect profile remains good. The risk-to-benefit ratio of receiving varenicline to quit smok- ing must include the increased chances of quitting smoking and avoiding the sizeable risks of smoked-caused disease and death that remain if tobacco addiction is not properly treated. Keywords: pharmacotherapy, smoking, smoking cessation, tobacco, varenicline Expert Opin. Pharmacother. [Early Online] 1. Introduction The FDA approval of varenicline for smoking cessation in 2006 was greatly antici- pated by researchers and clinicians treating tobacco dependence as it was the first new non-nicotine (Box 1) compound approved by the FDA for smoking cessation since 1997. The previous compound (bupropion) had been available in various forms since 1985. The story behind the development of varenicline is interesting; its structure is based on cytisine, a little known plant alkaloid that was used in East- ern Europe as a smoking cessation aid for decades. Cytisine has a molecular struc- ture similar to that of nicotine and acetylcholine and is a nicotinic agonist at a4b2 nicotinic receptors. A review of cytisine indicated that, despite the existence of placebo-controlled trials demonstrating efficacy, the results remained unnoticed to most of the world and were not cited in the English-language literature until after the emergence of varenicline [1]. The first scientific publication of varenicline appeared in 2005 describing the discovery of a new class of selective nicotinic receptor partial agonists [2]. These early reports suggested that a4b2 selective nicotinic receptor partial agonists like vareni- cline would be ideally suited to smoking cessation by blocking the action of nicotine and at the same time providing a low level of dopaminergic activation to limit 10.1517/14656566.2011.587121 © 2011 Informa UK, Ltd. ISSN 1465-6566 1 All rights reserved: reproduction in whole or in part not permitted ExpertOpin.Pharmacother.Downloadedfrominformahealthcare.combyUniversityofMedicine&Dentistryon06/07/11 Forpersonaluseonly.
  • 2. craving and withdrawal symptoms. Varenicline received a ‘priority review’ by the FDA in February 2006, shortening the usual 10-month review period to 6 months because of its demonstrated efficacy in clinical trials and perceived lack of safety issues [3]. Three publications appeared in a July 2006 issue of JAMA under the heading ‘JAMA-Express’, which is a system of rapid review and publication of major articles that have practice-changing implications or substantial public health importance [4]. Carefully designed studies estab- lished its efficacy compared with placebo but also when com- pared with sustained-release bupropion in a head-to-head comparison [5,6]. A third study demonstrated superiority of continuing varenicline (compared with placebo) for an addi- tional 12 weeks after successful cessation during a 12 week open-label period of treatment [7]. In addition to strong effi- cacy data, the side-effect profile seemed to be mild and lim- ited to mainly nausea and sleep disturbance. The drug is eliminated in the body almost exclusively by the kidneys and it is therefore free of nearly all possible interactions with other medications that are metabolized in the hepatic system, making its use relatively straightforward in smokers taking other medications for other conditions. Now, in 2011, the story sounds quite different as compared with the promise in 2006. The FDA has since issued two label- ing updates for varenicline including a black-box warning because of the possibility of serious neuropsychiatric side effects, although data on this are limited to mostly case reports. Use has been decreasing owing to anecdotal reports in the media of serious side effects and consequent bans in certain hospital or employment settings. This review examines the recent story of postmarketing experience with varenicline and reviews all available evidence for current recommendations. 2. Introduction to the compound Varenicline is a selective nicotinic receptor partial agonist that binds specifically and potently at the a4b2 receptor, which is one of the main subtypes of nicotinic receptors implicated in nicotine addiction. As a partial agonist it mimics some of the effects of nicotine, resulting in the release of dopamine in the nucleus accumbens, but it also blocks the effect of the full ago- nist, nicotine [2]. Although there is also binding at other nico- tinic receptor subtypes including a7, affinity for a4b2 is highest [2]. Varenicline is highly absorbed after oral adminis- tration and little is metabolized, making it virtually 100% bioavailable. Varenicline is not significantly protein bound and the compound is excreted primarily unchanged in the urine. Less than 10% is metabolized in the liver and few metabolites are created. The half-life is 17 -- 30 h [8]. The approved dosing regimen in adults is 1 mg twice daily for 12 weeks (renewable for another 12 weeks), starting with a 1-week titration. In Canada the drug is also approved at a dose of 0.5 mg twice daily. 3. Clinical efficacy Several trials have shown that varenicline is efficacious for smoking cessation. Varenicline increases the chances of quit- ting smoking nearly threefold compared with placebo and by 50% compared with sustained-release bupropion [6,9-11]. The primary outcome measure in these studies is 4 weeks of continuous abstinence from weeks 9 -- 12 after quitting. Mul- ticenter, placebo-controlled clinical trials demonstrating effi- cacy of varenicline included more than 5000 men and women smokers (n = 5229) who were motivated to stop smoking; most were caucasian, and they had an average age of 43 years. More than 75% of the smokers reported smoking the first cigarette of the day within the first 30 min of waking up in the morning; the majority smoked at least 11 cigarettes/ day, and, of these, > 40% smoked at least 20 cigarettes/ day [12]. A pooled analysis of varenicline trials found the fol- lowing adverse events to be reported significantly more often than in the placebo groups: nausea (OR = 3.17, 95% CI 2.35 -- 4.29); flatulence (OR = 2.04, 95% CI 1.16 -- 3.57); and constipation (OR = 2.57, 95% CI 1.21 -- 5.45) [10]. Nausea is the most prevalent dose-dependent side effect, more commonly seen in women but generally mild and not leading to drug discontinuation [12]. An additional trial evaluated the effect of 24 weeks of therapy with varenicline to delay or prevent smoking relapse after successful cessation [7]. This is an innovative research design that examines the continued effect of treatment after successful cessation. Following 12 weeks of open-label vareni- cline treatment, those with confirmed abstinence were ran- domized to continue either varenicline 1 mg twice daily or placebo for an additional 12 weeks. Continuous abstinence rates (CAR) were significantly better in the varenicline-treated subjects than in the placebo group at both week 24 and week 52. The time to first lapse was significantly longer in the varenicline-treated group. These published clinical trials establishing efficacy of varenicline have many strengths and strictly adhere to Box 1. Drug summary. Drug name Varenicline Phase Launched Launched indication Smoking cessation Pharmacology description Neuronal nicotinic receptor partial agonist Route of administration Alimentary, po Chemical structure Pivotal trial(s) Randomized, double-blind, placebo-controlled, parallel-assignment Phase III trial (Inter-ACTIV ; 2008-007948-34; ANRS 144) Pharmaprojects - copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. and Citeline ( Varenicline for tobacco dependence 2 Expert Opin. Pharmacother. [Early Online] ExpertOpin.Pharmacother.Downloadedfrominformahealthcare.combyUniversityofMedicine&Dentistryon06/07/11 Forpersonaluseonly.
  • 3. guidelines for testing smoking cessation therapies in clinical trials [13]. All participants received 12 weeks of brief individual smoking cessation counseling along with the study drug. Inclusion and exclusion criteria were similar to those used in trials that had demonstrated the efficacy of bupropion allow- ing for post hoc comparisons. In addition, two studies had identical trial design, allowing for direct comparison [5,6]. Some of the criticisms of these early studies were the lack of racial diversity in the samples and the exclusion of smokers with mental illness comorbidity [14,15]. Randomized trials of varenicline excluded patients not only with serious mental ill- nesses like psychosis and bipolar disorder but also more com- mon conditions including major depression (past year), current or lifetime panic disorder, and drug or alcohol abuse or dependence (past year). It is standard practice in drug development studies to enroll healthy volunteers usually with- out complex comorbid issues to establish drug safety and effi- cacy. This is partly done to protect at-risk individuals from exposure to as yet unproven medicines. However, population studies have indicated that, perhaps increasingly, smokers are overrepresented with comorbid psychiatric or substance use disorders making the definition of a ‘representative smoker’ increasingly complex. A brief review of smoking and mental illness comorbidity is relevant to an understanding of the risks and benefits of tobacco-dependence treatment. Numerous studies have shown increased smoking rates among patients with psychiat- ric illnesses and substance use disorders compared with the general population [16,17]. Clinical samples of individuals try- ing to quit smoking reveal sizeable percentages (~ 50%) with mental health issues [18-20]. There is a strong link between smoking and major depression and the nicotine withdrawal syndrome can include mood symptoms including depression, anxiety and irritability in addition to insomnia. Smoking has also been linked to suicidal thoughts and behavior in many studies, although the mechanism is unclear [21-25]. A 10-year longitudinal study found that current daily smoking, but not past smoking, was a predictor of suicidal thoughts or attempts, independent of previous depression or substance use and adjusting for other suicide predictors including previ- ous suicidality [22]. An analysis of smokers with a history of major depression indicated that smoking abstinence did not lead to increases in depression, anxiety or suicidal ideation; however, failed quit attempts did [26]. More studies of this emerging area are needed because the effect of successful and unsuccessful smoking cessation on depressed mood, anxiety and suicide-risk outcomes is unclear. 4. Safety and regulatory affairs By March of 2009, there was concern that varenicline might cause serious neuropsychiatric adverse events. An analysis of adverse event reports submitted to the FDA between May 2006 and November 2007 found 116 cases of suicidal ideation and 37 cases of suicidal behavior, more than half resulting in death [27]. Half of the patients reporting either sui- cidal ideation or suicidal behavior had a history of psychiatric problems, 26% had no such history, and 24% had an unknown psychiatric history. The FDA’s preliminary assessment revealed that many of the cases reflect new onset of depressed mood, suicidal idea- tion and changes in emotion and behavior within days to weeks of initiating varenicline treatment. The role of vareni- cline in these cases is not clear because smoking cessation, with or without treatment, is associated with nicotine with- drawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness. At least one highly publicized case of erratic behavior leading to the death of a patient using varenicline may have been linked to alcohol consumption [28]. Moore et al. [29] published the results of 78 adverse event reports from the FDA MedWatch database that included pos- sible acts or thoughts of aggression/violence. Of these, the authors concluded 26 cases met their described criteria for probable or possible association and included 10 assaults, 9 cases of homicidal ideation without a physical act of aggres- sion, and 7 cases of other violent or aggressive thoughts. The authors concluded the temporal relationship evidence was strong, with an early and often immediate onset of abnormal dreams and thoughts, and the adverse effects usually resolved with discontinuation of treatment. In 2008, the FDA issued an alert that serious neuropsychi- atric symptoms have occurred in patients taking varenicline. These symptoms include changes in behavior, agitation, depressed mood, suicidal ideation and attempted and com- pleted suicide. While some patients may have experienced these types of symptoms and events as a result of nicotine withdrawal, some patients taking varenicline who experienced serious neuropsychiatric symptoms and events had not yet discontinued smoking. According to their report most cases of neuropsychiatric symptoms developed during varenicline treatment, but in others, symptoms developed following withdrawal of varenicline therapy. We identified 10 case reports of smokers with mental illness (schizophrenia, bipolar disorder, post-traumatic stress disorder, depression, substance use or borderline personality) who experienced worsening of symptoms during treatment with varenicline (see Table 1) [30-40]. All were being treated with pharmacotherapy for their condition in addition to varenicline and there is variability in the time course and presentation of adverse symptoms reported. There are also isolated case reports of medical side effects potentially attrib- utable to varenicline, including renal failure, cutaneous drug eruption and hypoglycemia [41-43]. Far fewer are cases of neuropsychiatric symptoms in individuals with no history of mental illness [33]. There are almost an equal number of published case reports or open-label studies of positive effects from varenicline. Twelve smokers with schizophrenia showed significant improvements in cognitive test scores associated with verbal Williams, Steinberg, Steinberg, Gandhi, Ulpe & Foulds Expert Opin. Pharmacother. [Early Online] 3 ExpertOpin.Pharmacother.Downloadedfrominformahealthcare.combyUniversityofMedicine&Dentistryon06/07/11 Forpersonaluseonly.
  • 4. Table1.Peer-reviewedadverseneuropsychiatriceffectsreportedduringvareniclineuse(casereports). PriordiagnosesConcomitantmedicationsDurationof varenicline use Smoking outcome Neuropsychiatric symptoms Outcome Popkin(2008)[30]Majordepression, recurrent Fluoxetine,aspirin,niacin andmetoprolol 6weeksReducedfrom 20to3--4cpd Hypersomnia,‘unusual’ dreams,decreasedappetite, irritability,sadnessandguilt Vareniclinestopped; symptomsresolvedin2weeks Freedman (2007)[31] SchizophreniaThiothixene5days20--40cpd,no change Worseningpsychosis, psychomotoragitation Vareniclinestopped; symptomsresolved Kohen(2007)[32]BipolardisorderValproicacid1weekStoppedsmokingManiaVareniclinestopped; symptomsresolvedin1week butwasalsotreatedwith olanzapine Kutscher (2009)[33] NoneOralcontraceptives10weeksStoppedsmokingParanoia,anxietyandsuicidal ideation Vareniclinestopped; symptomsresolvedin3days butwasalsotreatedwith zolpidemandclonazepam DiPaula(2009)[34]Bipolardisorder, mixedwithpsychotic features Lamotrigine,trifluoperazine, diphenhydramine, olanzapine,haloperidol, lorazepam 2days20--40cpdto 0duetotobacco- freeinpatient hospitalization Worseningpsychosisand agitation Vareniclinestopped;mental statusreturnedtobaseline Lyons(2008)[35]Majordepression, GAD,borderline personalitydisorder, dailymarijuana, h/ometamphetamine abuse Topiramate,duloxetine, modafinil,andclonazepam Notreported20cpd;varenicline helpedherquit ParanoiaandirritabilityVareniclinestopped; symptomsresolvedin 2weeks;Rechallengewith vareniclinecausedsymptoms torecur Pumariega (2008)[36] Depression(family historyofbipolar disorderinbrother) Sertraline3monthsNotreportedDecreasedsleep,racing thoughts,psychomotor activation,irritability,rapid andpressuredspeechand paranoia Vareniclinestopped; symptomsresolvedbutwas alsotreatedwitharipiprazole Raidoo(2009)[37]PTSD,depression, alcoholdependence Fluoxetine,nortriptyline, quetiapine,prazosin, pramipexole,terazosin, atenolol,spironolactone 19days40cpdto2cpdVisualhallucinationsVareniclinestopped; symptomsresolvedin3days Ismail(2010)[38]SchizophreniaOralanddepotrisperidone18days15cpdto2cpdPolydipsiaandhyponatremia, worseningpsychosis Vareniclinestopped; symptomsresolvedin5days Morstad(2008)[39]BipolarII,h/oalcohol andmetamphetamine abuse Bupropion,clonazepam, oxcarbazepine,quetiapine, montelukast,pantoprazole 1month40cpd,decreased smoking Irritability,reducedsleep, suicidalideation,feelingsof hopelessness,agitationand racingthoughts Vareniclinestopped; symptomsresolvedin3days butwasalsotreatedwith quetiapine UDSpositiveforcannabis Pirmoradi (2008)[40] Majordepression, alcoholdependence 7days4--5cpdSevereanxiety,nausea, vertigo,blurredvisionand dizziness Vareniclinestopped; symptomsresolvedin3days cpd:Cigarettesperdaysmoked;GAD:Generalizedanxietydisorder;h/o:Historyof;UDS:Urinedrugscreen. Varenicline for tobacco dependence 4 Expert Opin. Pharmacother. [Early Online] ExpertOpin.Pharmacother.Downloadedfrominformahealthcare.combyUniversityofMedicine&Dentistryon06/07/11 Forpersonaluseonly.
  • 5. learning and memory, and no increases in psychopathology, depression or suicidal ideation [44]. Other case reports indicate good tolerability and no clinical worsening in smokers with schizophrenia, several of whom were successful in quitting smoking [45-48]. On its website the FDA acknowledges the limitations of case reports including the lack of medical validation, possible influence by the media and other sources, potential for errors in reporting and possible complication of nicotine withdrawal symptoms. For these reasons systematically coll
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