Search

BACKGROUND: The alcohol cue reactivity paradigm is increasingly used to screen medications for the treatment of alcohol use disorder (AUD) and other substance use disorders. Yet, its prospective association with craving and naturalistic drinking outcomes in clinical trials remains unknown. This study embedded repeated human laboratory assessments of alcohol cue reactivity within the context of a randomized controlled trial to examine the effects of varenicline tartrate (Chantix(®)), a partial agonist of α4β2 nicotinic acetylcholine receptors, on alcohol craving among treatment-seeking heavy drinkers with AUD. Our main objectives were to test whether varenicline, as compared to placebo, blunts alcohol-cue elicited craving and test whether alcohol cue reactivity observed in the human laboratory predicts subsequent alcohol craving and use during the remainder of the trial. DESIGN AND METHODS: This double-blind, randomized, two-site study compared the effects of varenicline (up to 2 mg/day) and placebo on responses to in vivo alcohol cue and affective picture cue exposure in the human laboratory. Forty-seven volunteers (18 females, 29 males), ages 23 to 67 years (M = 43.7, SD = 11.5), were recruited from the community via advertisements to participate in a clinical trial designed to study the effects of varenicline on alcohol use. Participants were randomized to either varenicline or placebo for 6 weeks. RESULTS: Varenicline did not attenuate cue-induced alcohol craving relative to placebo, but craving captured during the cue reactivity paradigm significantly predicted subsequent alcohol use in real-world settings during the clinical trial. Higher craving predicted heavier alcohol use. CONCLUSIONS: Our results are among the first to show alcohol cue-induced craving captured during a human laboratory paradigm predicts drinking outcomes in the context of a clinical trial.

The crystal structure of varenicline hydrogen tartrate Form B (Chantix®) has been refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Varenicline hydrogen tartrate Form B crystallizes in space group P212121 (#19) with a = 7.07616(2), b = 7.78357(2), c = 29.86149(7) Å, V = 1644.706(6) Å3, and Z = 4. The hydrogen bonds were identified and quantified. Hydrogen bonds link the cations and anions in zig-zag chains along the b-axis. The powder pattern has been submitted to ICDD® for inclusion in the Powder Diffraction File™ (PDF®).

IntroductionVarenicline tartrate is superior for smoking cessation to other tobacco cessation therapies by 52 weeks, in the outpatient setting. We aimed to evaluate the long-term (104 week) efficacy following a standard course of inpatient-initiated varenicline tartrate plus Quitline-counselling compared to Quitline-counselling alone.MethodsAdult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to one of three hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling, (n = 196) or Quitline-counselling alone, (n = 196), with continuous abstinence from smoking assessed at 104 weeks.ResultsA total of 1959 potential participants were screened for eligibility between August 2008 and December 2011. The proportion of participants who remained continuously abstinent (intention-to-treat) at 104 weeks were significantly greater in the varenicline tartrate plus counselling arm (29.2% n = 56) compared to counselling alone (18.8% n = 36; p = 0.02; odds ratio 1.78; 95%CI 1.10 to 2.86, p = 0.02). Twenty-two deaths occurred during the 104 week study (n = 10 for varenicline tartrate plus counselling and n = 12 for Quitline-counselling alone). All of these participants had known or developed underlying co-morbidities.ConclusionsThis is the first study to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting. Varenicline tartrate plus Quitline-counselling was found to be an effective opportunistic treatment when initiated for inpatient smokers who had been admitted with tobacco-related disease.

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 (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) as well as AUC from time zero to infinity (AUCinf). ANOVA for pharmacokinetic equivalence was assessed using log-transformed Cmax 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 Cmax, AUClast, and AUCinf 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 Cmax, AUClast, and AUCinf 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.

BackgroundSARS-CoV-2 infections have resulted in a global pandemic, but an antiviral therapy for this novel strain of coronavirus does not currently exist. The objective of our study was to investigate the antiviral potential of the nicotinic acetylcholine receptor (nACHR) agonist varenicline tartrate against SARS-CoV-2.MethodsWe assessed antiviral activity using in vitro human cell assays and we assessed in vivo efficacy in a rhesus macaque model.ResultsIn vitro studies found that varenicline tartrate, over a range of concentrations, reduced the infectivity of SARS-CoV-2 wildtype, alpha, and beta variants in Calu-3 cells and Caco-2 cells, with maintenance of cell viability. In vivo studies found that varenicline tartrate, administered as a nasal spray to rhesus macaques, reduced SARS-CoV-2 wildtype viral load and inhibited viral replication in the nasal mucosa and upper airway.ConclusionAlthough the study reported here was exploratory, we have confirmed that the nAChR agonist varenicline has the potential to interact with and inhibit SARS-CoV-2 infection and replication.

Objective Varenicline is an efficacious aid for smoking cessation. In this study, the pharmacokinetics and safety were compared between film-coated tablets of varenicline tartrate (reference drug) and the newly developed orally disintegrating films of varenicline salicylate (test drug), both of them contained 1 mg of varenicline. Materials and methods A randomized, open-label, single-dose, two-sequence, two-period crossover study was conducted in healthy male subjects. Serial blood samples were obtained for up to 72 hours in each period, with a washout period of 7 days or more. The pharmacokinetic parameters were calculated using the noncompartmental method. Safety profiles were assessed throughout the study. Results A total of 28 subjects completed the study. The plasma varenicline concentration-time profiles were similar for the two study drugs. The maximum plasma varenicline concentration (Cmax) was 5,768.95 ng/L (mean) and 5,780.55 ng/L for the test drug and reference drug, respectively. The areas under the concentration-time curve from time 0 to the last measurable time point (AUC0-t) were 94,086.30 h×ng/L and 89,958.55 h×ng/L for the test drug and reference drug, respectively. The geometric mean ratios (90% confidence intervals) of the test drug to the reference drug for Cmax and AUC0-t were 0.9955 (0.9488 - 1.0444) and 1.0449 (0.9848 - 1.1088), respectively, which fell within the bioequivalence range of 0.8 - 1.25. There was no difference in safety between the study drugs. Conclusion The pharmacokinetics and safety profiles were similar between the two study drugs. The orally disintegrating film of varenicline salicylate can be an alternative to varenicline tartrate tablets.

Aaron D Drovandi,Sherryl G Robertson,Bunmi S Malau-Aduli,Peta Ann Teague,Beverley D Glass College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia Background: Ensuring adherence to prescribed smoking cessation medications, such as Champix® (varenicline), is essential during a quit attempt as non-adherence can significantly reduce the likelihood of achieving prolonged smoking abstinence. The use of dose administration aids may improve adherence, though medication stability on repackaging is not guaranteed, due to a lack of available data from manufacturers supporting this practice. Objective: To determine the suitability for repackaging varenicline tartrate tablets into a dose administration aid, by assessing its physical and chemical stability after being repackaged and stored at ambient conditions for 6 weeks. Methods: Varenicline tartrate (1.0 mg) tablets were repackaged into commercially available Webster-pak® blister compartments and stored for 42 days at ambient conditions characteristic of a Zone IVB climate (30 ± 2°C and 75 ± 5% relative humidity) according to the World Health Organization (WHO) guidelines on pharmaceutical stability testing. Physical and chemical tests were performed on the repackaged and control tablets, including an assessment of: tablet thickness, hardness, weight uniformity, friability, dissolution, disintegration, and content uniformity after exposure to ambient conditions and light according to International Council on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use guideline Q1B. Results: Weight, friability, and thickness of the tablets complied with compendial standards. A validated high performance liquid chromatography method was used to confirm that after exposure to light, and repackaging at 30°C/75% relative humidity, the tablets remained within the required 95%–105% of the stated drug content. However, tablet hardness and disintegration decreased over time, with tablets becoming softer and undergoing more rapid disintegration in water. Conclusion: Repackaging 1.0 mg varenicline tartrate tablets into a dose administration aid can be undertaken to improve adherence rates and therefore smoking abstinence rates. This can be performed without compromising either the physical or chemical stability of the tablets. Keywords: stability, compliance, degradation

Sarıoğlu, Nurhan (Balikesir Author), In this study, we investigated the effects of certain respiratory drugs, which are mainly used on human serum paraoxonase-1 (hPON1; EC 3.1.8.1). hPON1 was purified from human serum, with 354.91 fold and 45% yield by using two simple step procedures including, first, ammonium sulfate precipitation, then, Sepharose-4B-l-tyrosine-1-naphthylamine hydrophobic interaction chromatography. SDS-polyacrylamide gel electrophoresis showed a single protein band belonging to hPON1 with 43 kDa. All the pharmaceutical compounds inhibited the PON1 enzyme highly at the micromolar level. The obtained IC50 values for nine different pharmaceutics ranged from 0.219 mu M (salbutamol sulfate) to 67.205 mu M (montelukast sodium). So, all drugs could be considered as potent hPON1 inhibitors. K-i values and inhibition types were determined by Lineweaver-Burk graphs. While varenicline tartrate and moxifloxacin hydrochloride inhibited the enzyme in a noncompetitive manner, others inhibited it in a mixed manner.

Cigarette smoking costs Australia and New Zealand billions of dollars per year and is the single most preventable risk to health. Though governments have initiated numerous public health policies which have reduced the incidence of smoking, current usage remains around 15 percent. Making further inroads is likely to require augmenting these interventions with action at the individual level. The hospital setting provides a unique opportunity to assess the efficacy of individual attention. The aim of this study is to make an initial assessment of this efficacy by collating the existing evidence of outcomes achieved by health professionals working with individuals in hospital settings. The systematic literature search resulted in 69 studies (72 citations) for evaluation. Results indicated that a multicomponent intervention comprised of high intensity counselling with a minimum of one month of post-discharge follow-up in addition to either nicotine replacement therapy or varenicline tartrate is the most effective combination of individual treatments for improving smoking abstinence, particularly for general inpatients. Further, there was an indication that patients admitted to specialist wards (e.g. cardiovascular) would benefit most from high intensity interventions, regardless of the use of adjunct pharmacotherapy. The evidence for a positive effect on sustained quit smoking rates for peri-operative patients is not definite, but as smoking adversely affects surgical success, implementing multicomponent interventions should still be considered. This review found no clear evidence to support implementation of smoking cessation interventions in the emergency department setting. Overall, interventions throughout the review were heterogeneous, making the estimate of a true effect difficult. Furthermore, there were only low numbers of local studies, with the findings of this review relying mostly upon extrapolation from overseas studies. Given the severity of the burden placed on the health system by smoking, there is a need for continuing endeavours by researchers with the support of the government to identify innovative and effective interventions for smokers that can be delivered by health professionals caring for smokers in the hospital setting. Refereed/Peer-reviewed

In this study, analyses were carried out in a fused-silica capillary (i.d. 50.0 µm, total length 48.5 cm and effective length 40.0 cm), in normal mode, applying a voltage of 20 kV. Sample injections were made in a hydrodynamic mode over 7 seconds under a pressure of 50 mbar. Capillary temperature was set at 35 °C and the detection was performed at 205 nm wavelenght. Background electrolyte was 40 mM citrate buffer at pH 6.0 and the internal standard was labetalol HCl. Total analysis time was shorter than 5 minutes. The method was validated according to the ICH guidelines and it was found to be linear, precise, accurate, specific, robust and rugged. Linearity range was found to be 1.0 – 60.0 µg mL-1 and the limit of detection and quantitation were found as 0.5 and 1.0 µg mL-1, respectively.

Background: Quitting smoking is key for patients with Chronic Obstructive Pulmonary Disease (COPD). Standard recommendations for quitting smoking are implemented for COPD as well. Varenicline Tartrate (VT) is the most effective drug to help quit smoking, but few studies have analysed its effectiveness. Aim of the study: To determine the Abstinence Rate (AR) at 12 months, in COPD and non-COPD smokers. Methods: Observational study in 31 COPD (post bronchodilator-BD FEV1/FVC

Nicotinic acetylcholine receptors (nAChRs) are implicated in the pathogenesis of Parkinson's disease (PD). Varenicline tartrate is a partial agonist at ?4ß2 and full agonist at ?7 neuronal nAChR subunits. A unilateral lesion of the substantia nigra (SN) has been used as a reliable model of PD. This study aimed to investigate the effect of varenicline on locomotor and nonlocomotor behavioral deficits induced by a unilateral lesion of the SN induced by 6-hydroxydopamine (6-OHDA) (8 g/4 l). Varenicline (1 mg/kg) was administered to the lesioned rats daily for 2 weeks, which commenced 3 weeks after 6-OHDA administration. The results showed that varenicline improved motor deficits induced by 6-OHDA. It improved locomotor and nonlocomotor activities such as forelimb use, rotarod performance, and forelimb asymmetry. Varenicline did not change rearing or vibrissae-elicited forelimb placing but did increase apomorphine-induced rotation. In conclusion, the present results suggest that drugs with specific partial/full agonistic activity on nAChR subunits could be of value in the treatment of neurodegenerative disorders such as PD. © 2018 Wolters Kluwer Health, Inc. All rights reserved.

An LC-QTOF-MS method was developed for the separation and characterization of related substances in varenicline tartrate. The separation was established on an InertSustain C18 column (4.6 mm × 150 mm, 5 μm) by liner gradient elution using 0.05% trifluoroacetic acid as mobile phase A and acetonitrile as mobile phase B. The degradation studies were conducted under the ICH prescribed stress conditions. Varenicline tartrate was found to be unstable to alkaline, oxidative, thermal and photolytic stresses, while relatively stable under acid stress condition. Thirteen related substances were detected all together in varenicline tartrate and its stressed samples. Their structures were identified mainly through positive ESI high resolution QTOF mass spectrometric analysis of the parent and product ions' accurate masses and the calculated elemental compositions. Among the 13 related substances, seven were process-related and six were degradation products, and two of them were further verified by chemical synthesis and NMR spectroscopic determination. Their formation mechanisms were also discussed, and the key steps in the manufacturing processes were also determined to provide varenicline tartrate with high purity.

Importance Cigarette smoking is the leading cause of preventable morbidity and mortality in the United States and worldwide, and most tobacco users begin smoking in adolescence. Although advances have yielded efficacious pharmacotherapies to complement smoking cessation counseling in adults, far less progress has been made in addressing tobacco use in adolescence. Objective To evaluate the efficacy and safety of varenicline tartrate for smoking cessation in adolescents and young adults. Design, Setting, and Participants This 2-group randomized, placebo-controlled, double-blind intention-to-treat clinical trial enrolled a volunteer sample of treatment-seeking adolescent and young adult cigarette smokers (n = 157) aged 14 to 21 years at an outpatient clinical site in Charleston, South Carolina, from August 15, 2012, to October 20, 2017. Follow-up was completed on January 25, 2018. Data were analyzed from March 19, 2018, to August 11, 2018, with further revisions completed April 10, 2019. Interventions Participants were randomized in a 1:1 ratio to a 12-week course of varenicline (n = 77) or placebo (n = 80). All participants received weekly smoking cessation counseling. Main Outcomes and Measures The preselected primary efficacy outcome was urine cotinine level–confirmed 7-day abstinence at the end of treatment. Secondary efficacy outcomes included weekly abstinence throughout active treatment, abstinence at posttreatment follow-up visits, and time to first 7-day abstinence. The primary safety outcome was the frequency of treatment-emergent adverse events. Results A total of 157 participants were enrolled (94 male [59.9%]; mean [SD] age, 19.1 [1.5] years). The varenicline and placebo groups did not differ in the primary outcome of cotinine-confirmed self-reported 7-day abstinence at the end of treatment (varenicline group, 4 of 45 [8.9%]; placebo group, 4 of 45 [8.9%]; risk ratio [RR], 0.97; 95% CI, 0.29-2.99;P = .96). However, among secondary outcomes, the varenicline group achieved self-reported earlier abstinence of at least 7 days (hazard ratio, 1.91; 95% CI, 1.12-3.27) and demonstrated higher rates of self-reported weekly abstinence during the full course of treatment (RR, 1.81; 95% CI, 1.09-2.99;P = .02) and at posttreatment follow-up (RR, 1.82; 95% CI, 1.01-3.28;P = .02). Study medication was generally well tolerated, and treatment-emergent adverse events did not differ between groups (any adverse events, 55 [71.4%] in the varenicline group vs 60 [75.0%] in the placebo group; RR, 0.95; 95% CI, 0.79-1.15;P = .61). Conclusions and Relevance When added to weekly cessation counseling for adolescent cigarette smokers, varenicline, compared with placebo, was well tolerated but did not improve end-of-treatment abstinence. However, varenicline may hasten abstinence and yield improvements in posttreatment abstinence outcomes. Trial Registration ClinicalTrials.gov identifier:NCT01509547

SUMMARY Worldwide, lung cancer contributes to over 1.4 million deaths per year. Smoking cessation is strongly recommended in clinical practice guidelines for lung cancer management, yet evidence suggests a translational gap between evidence and practice. There are significant health benefits following smoking cessation even after a short period of time. Long-term implications for lung cancer patients include improvements in quality of life, reductions in postoperative complications and reductions in 12-month mortality. Evidence suggests that combining pharmacotherapy, in particular varenicline tartrate (varenicline), with cognitive and behavioral interventions offers the best opportunity for successful long-term abstinence. This review summarizes the latest evidence for smoking cessation interventions in lung cancer patients, identifies gaps in current clinical practice and highlights priority areas for future research.

Background: VT is currently the most effective smoking cessation pharmacotherapy available, yet its cost-effectiveness is unknown.Aims: To conduct a cost-effectiveness analysis for the use of VT in the inpatient setting.Methods: Adult smokers (n=392, 20-75 years) admitted to three metropolitan tertiary hospitals, were randomised to receive either 12-weeks of VT (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline- a phone counselling service (C)(n=196) or C alone (n=196) with completion of the 12 week intervention post discharge. Two year follow-up information was combined with Markov model forecasts to quantify long-term impacts of trial outcome (i.e. observed quit rates) on costs and quality adjusted life year (QALY) gained.Results: At 2 years, there was a cost of $3,278 per additional person classified as an ex-smoker for the VT+C arm compared to the C arm. Incremental cost-effectiveness of hospital costs over a lifetime for VT+C compared to C was $26,688 per QALY. For the outcome of continuous abstinence at 12-months, the proportion of successful subjects in the VT+C arm was significantly greater with 31.1% (n=61) compared to 21.4% (n=42) in the QCA arm (RR 1.45, 95%CI 1.03 to 2.04, p=0.03). Statistical significance was maintained at 24 month follow-up (28.6 for VT+C group compared to 18.4% for QCA group; p=0.01).Conclusion: The trial effects modelled over a lifetime indicated that VT+C compared to C costs an estimated $28,688/QALY gained, which is cost-effective compared to many conventionally accepted therapies.

BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist).OBJECTIVES: To review the efficacy of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, and PsycINFO using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in May 2015, although we have included a few key trials published after this date. We also searched online clinical trials registers.SELECTION CRITERIA: We included randomised controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment.DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomisation procedure, concealment of allocation, and completeness of follow-up.The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model.MAIN RESULTS: Two trials of cytisine (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled risk ratio (RR) of 3.98 (95% confidence interval (CI) 2.01 to 7.87; low-quality evidence). One recent trial comparing cytisine with NRT in 1310 people found a benefit for cytisine at six months (RR 1.43, 95% CI 1.13 to 1.80).One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). This drug is no longer in development.We identified 39 trials that tested varenicline, 27 of which contributed to the primary analysis (varenicline versus placebo). Five of these trials also included a bupropion treatment arm. Eight trials compared varenicline with nicotine replacement therapy (NRT). Nine studies tested variations in varenicline dosage, and 13 tested usage in disease-specific subgroups of patients. The included studies covered 25,290 participants, 11,801 of whom used varenicline.The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.24 (95% CI 2.06 to 2.43; 27 trials, 12,625 people; high-quality evidence). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.08 (95% CI 1.56 to 2.78; 4 trials, 1266 people). The pooled RR for varenicline versus bupropion at six months was 1.39 (95% CI 1.25 to 1.54; 5 trials, 5877 people; high-quality evidence). The RR for varenicline versus NRT for abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 trials, 6264 people; moderate-quality evidence). Four trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The number needed to treat with varenicline for an additional beneficial outcome, based on the weighted mean control rate, is 11 (95% CI 9 to 13). The most commonly reported adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Our analysis of reported serious adverse events occurring during or after active treatment suggests there may be a 25% increase in the chance of SAEs among people using varenicline (RR 1.25; 95% CI 1.04 to 1.49; 29 trials, 15,370 people; high-quality evidence). These events include comorbidities such as infections, cancers and injuries, and most were considered by the trialists to be unrelated to the treatments. There is also evidence of higher losses to follow-up in the control groups compared with the intervention groups, leading to a likely underascertainment of the true rate of SAEs among the controls. Early concerns about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008. However, subsequent observational cohort studies and meta-analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour. The evidence is not conclusive, however, in people with past or current psychiatric disorders. Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses. Current evidence neither supports nor refutes such an association, but we await the findings of the CATS trial, which should establish whether or not this is a valid concern.AUTHORS' CONCLUSIONS: Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and three-fold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion or with NRT. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The most frequently recorded adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Early reports of possible links to suicidal ideation and behaviour have not been confirmed by current research.Future trials of cytisine may test extended regimens and more intensive behavioural support.

Preoperative smoking cessation is important for recovery from surgery without complications. Available evidence suggests nicotine replacement therapy could be safe and effective in the perioperative period. On the other hand, the newly developed selective nicotinic acetylcholine (ACh) receptor partial agonist, varenicline tartrate, is also effective as an aid for smoking cessation and helps people to stop smoking. During the transitional phase between the decision to stop smoking and actual smoking cessation, patients could use varenicline before undertaking smoking cessation. We have previously reported that acute cigarette smoking can cause impairment of endothelium-dependent vasodilation in cerebral vessels; thus, the use of varenicline before surgery in a patient who is still a smoker may not be safe with regard to endothelial function. Therefore, to assess the safety of varenicline in terms of endothelial function, we evaluated its effect on the acute smoking-induced impairment of endothelium-dependent cerebral vasodilation. In anesthetized Sprague-Dawley rats, we applied ACh topically to pial vessels; then, after administering intravenous varenicline or saline injection, we reexamined the ACh-induced vasodilator response both before and after smoking. Under control conditions, cerebral pial arterioles were dose-relatedly dilated by ACh. After smoking, 10(-5) M ACh constricted the arterioles following saline pretreatment (diameter -7.6 ± 1.8 %, n = 6), but induced dilation following varenicline pretreatment (diameter +15.3 ± 3.3 %, n = 6). Thus, varenicline may prevent the smoking-induced impairment of endothelium-dependent vasodilation in cerebral pial arterioles.

A simple, rapid and stability-indicating reversed-phase liquid chromatographic method was developed for the assay of varenicline tartrate (VRT) in the presence of its degradation products generated from forced decomposition studies. The HPLC separation was achieved on a C18 Inertsil column (250 mm x 4.6 mm i.d. particle size is 5 μm) employing a mobile phase consisting of ammonium acetate buffer containing trifluoroacetic acid (0.02M, pH 4) and acetonitrile in gradient program mode with a flow rate of 1.0 mL min−1. The UV detector was operated at 237 nm while column temperature was maintained at 40 °C. The developed method was validated as per ICH guidelines with respect to specificity, linearity, precision, accuracy, robustness and limit of quanti-fication. The method was found to be simple, specific, precise and accurate. Selectivity of the proposed method was validated by subjecting the stock solution of VRT to acidic, basic, photolysis, oxidative and thermal degradation. The calibration curve was found to be linear in the concentration range of 0.1–192 μg mL−1 (R2 = 0.9994). The peaks of degradation products did not interfere with that of pure VRT. The utility of the developed method was examined by analyzing the tablets containing VRT. The results of analysis were subjected to statistical analysis.

The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix(®), Pfizer, Saint-Laurent, QC, Canada or Chantix(®), Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p = 0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9-12 was 42% (95% confidence interval [CI]: 26-58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline.

Background Smoking is the most important risk factor for COPD and accelerates its progression. Despite the health implications, a large proportion of patients with COPD continue to smoke, so finding effective smoking cessation interventions for this population is paramount. To our knowledge, this is the first randomized clinical trial to compare the efficacy and safety of varenicline tartrate vs placebo in smokers with mild to moderate COPD. Methods In a 27-center, double-blind, multinational study, 504 patients with mild to moderate COPD (postbronchodilator FEV 1 /FVC, 1 percent predicted normal value, ≥ 50%) and without known psychiatric disturbances were randomized to receive varenicline (n = 250) or placebo (n = 254) for 12 weeks, with a 40-week nontreatment follow-up. The primary end point was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. A secondary end point was CAR for weeks 9 to 52. Results CAR for weeks 9 to 12 was significantly higher for patients in the varenicline group (42.3%) than for those in the placebo group (8.8%) (OR, 8.40; 95% CI, 4.99-14.14; P P Conclusions Varenicline was more efficacious than placebo for smoking cessation in patients with mild to moderate COPD and demonstrated a safety profile consistent with that observed in previous trials. Trial registry ClinicalTrials.gov ; No.: NCT00285012 ; URL: www.clinicaltrials.gov

Rationale: Treatment of the most widely abused drugs, nicotine and alcohol, is hampered by high rates of relapse. Varenicline tartrate, an α4β2 nicotinic receptor partial agonist, is currently prescribed as a smoking cessation aid. However, there is emerging evidence that it may also modulate alcohol seeking and cognitive functioning in rats. Objectives: As preclinical data on alcohol taking and relapse are limited, we used a self-administration- reinstatement model to evaluate the effects of varenicline on operant responding for alcohol (12%, v/v), intravenous nicotine (40 μg/kg/inf.), sucrose (10%, w/v) and on cue-induced relapse to alcohol and nicotine seeking in rats. At the cognitive level, we assed varenicline's effects on 5-choice serial reaction time task (5-CSRTT) performance with a focus on correct responses (attention) and premature responding (impulsivity), modalities that have previously been associated with addictive behaviour. Results: Varenicline, at doses of 1.5 and 2.5 mg/kg, reduced alcohol and nicotine self-administration and enhanced operant responding for sucrose. At these doses, varenicline reduced cue-induced relapse to alcohol, but not nicotine seeking. In contrast, at 0.5 mg/kg, varenicline facilitated cue-induced nicotine seeking. Similar to nicotine, varenicline increased premature responding at low doses, but had no effect on any of the other behavioural parameters in the 5-CSRTT. Conclusions: Our data indicate that varenicline specifically reduced responding for nicotine and alcohol, but not for natural reinforcers such as sucrose. Interestingly, varenicline strongly attenuated cue-induced relapse to alcohol seeking, but not nicotine seeking. Varenicline may therefore be a promising aid in the treatment of alcohol addiction. © 2011 The Author(s).

Summary A new ultra-performance liquid chromatographic (UPLC) method has been developed and validated for quantification of substances related to varenicline tartrate, process-related and degradation products, in pharmaceutical formulations. Chromatographic separation of six impurities was performed on a reversed phase column. The method was validated for linearity, limits of detection and quantification, accuracy, precision, and selectivity. The calibration plots obtained for the six impurities were linear over the range 0.005–0.30%. The relative standard deviations (sr) of intra and inter-day experiments were less than 1.0%. The detection limits ranged between 0.002 and 0.004%, depending on the impurity. The proposed UPLC method was successfully applied to quantification of varenicline impurities in its pharmaceutical formulation.

Varenicline tartrate (Champix), a new smoking cessation medicine, was launched in the UK in December 2006. Varenicline is a highly selective partial agonist of the alpha(4)beta(2) nicotinic acetylcholine receptor (alpha(4)beta(2) receptor). The partial agonistic binding leads to alleviation of symptoms of craving and withdrawal, and simultaneously prevents nicotine from binding to the alpha(4)beta(2) receptor thereby causing reduction in the rewarding and reinforcing effects of smoking. Regulatory concerns have arisen about psychiatric events associated with varenicline, including depression, suicidal ideation and changes in behaviour/emotion.To present the interim results of an ongoing study by the Drug Safety Research Unit (DSRU) monitoring the safety of varenicline.The observational cohort study is being conducted to study the postmarketing safety of varenicline, using modified prescription-event monitoring (PEM) methodology. Patients are identified from dispensed prescriptions issued by general practitioners (GPs) from December 2006. Demographic, clinical event (during the course and 1 month after stopping varenicline, reasons for discontinuing and suspected adverse drug reactions [ADRs] to varenicline) and drug utilization data are collected from detailed study-specific questionnaires posted to GPs at least 4 months after the date of first prescription for each patient. Event incidence densities (IDs; number of first reports of an event/1000 patient-months of exposure) are calculated.The interim cohort comprises 2,682 patients: median age 47 years (interquartile range [IQR] 38-56), 60.7% females (n = 1627). Nausea/vomiting was the most frequent clinical reason for stopping varenicline (n = 91; 35.3% of clinical reasons) and the most frequently reported suspected ADR to varenicline (n = 60, 50.9% of patients for whom an ADR was reported). The most frequently reported psychiatric events (causality not implied) during treatment included (n; % of cohort): sleep disorder (43; 1.6%), anxiety (33; 1.2%), depression (29; 1.1%), abnormal dreams (26; 1.0%) and mood change (17; 0.6%). Two cases of attempted suicide were reported during treatment with varenicline (one patient took an overdose of a benzodiazepine with alcohol, the other slashed their wrist). Both these patients had previous history of psychiatric illness and precipitating factors for the event.This study reflects 'real life' use of varenicline. Nausea/vomiting - the event most frequently reported as an ADR and as reason for stopping treatment - is listed in the UK Summary of Product Characteristics (SPC). The most frequently reported psychiatric events are listed in the UK SPC. All patients with suicidal events either had a past medical history of psychiatric illness prior to starting varenicline and/or a precipitating factor for the event. Clinicians should closely monitor patients with pre-existing psychiatric illness who are taking varenicline. Further evaluation of events of interest including psychiatric events is ongoing. Results presented are expected to change as the cohort size increases. Results of this study should be taken into account together with other clinical and pharmacoepidemiological studies.

To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation.320 healthy, motivated-to-quit smokers (or =10 cigarettes/day) aged 18-65 years, entered a multicenter, randomized, double-blind, placebo-controlled study - conducted between December 26, 2001 and June 24, 2003 - with a 12-week treatment phase and 40-week, double-blind, non-treatment follow-up. Treatment consisted of varenicline or placebo in fixed doses (Week 1: titrated from 0.5 to 1.0 mg/day) followed by a self-regulated flexible schedule (Weeks 2-12: 0.5-2.0 mg/day).Primary outcomes included carbon monoxide-confirmed continuous abstinence rate (CAR) from smoking for Weeks 4 through 7, 9 through 12, and 9 through 52. Secondary outcomes included CAR from Weeks 9 through 24, 7-day point prevalence of abstinence, safety assessments, and measures of craving, withdrawal, and smoking reward.Superior CARs were observed in varenicline-treated (n = 157) versus placebo participants (n=155) for Weeks 4 through 7 (38.2 vs. 11.6%), 9 through 12 (40.1 vs. 11.6%), 9 through 24 (28.0 vs. 9.0%), and 9 through 52 (22.3 vs. 7.7%) (all p0.001). Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 (46.5 vs. 14.2%; p0.001), 24 (32.5 vs. 13.5%; p0.001), and 52 (28.0 vs. 13.5%; p=0.001). Overall, medication compliance was high, although varenicline-treated, but not placebo, participants tended to taper down their dosage over time. Total treatment-emergent AEs were 77.1% (varenicline: 121/157) and 65.8% (placebo: 102/155). Few AEs led to treatment discontinuation (varenicline: 11/157, 7.0% and placebo: 7/155, 4.5%). Participants were primarily healthy Caucasians, so more research is necessary to determine how applicable these findings are to other populations.A self-regulated, flexible dosing regimen of varenicline is well tolerated, with superior effectiveness versus placebo for smoking cessation.

Significant degradation of the amine-based smoking cessation drug varenicline tartrate in an early development phase osmotic, controlled-release (CR) formulation yields predominantly two products: N-methylvarenicline (NMV) and N-formylvarenicline (NFV). NMV is produced by reaction of the amine moiety with both formaldehyde and formic acid in an Eschweiler-Clarke reaction, while NFV is formed by reaction of formic acid alone with varenicline. This represents the first report of these reactions occurring on storage of solid pharmaceutical formulations. Both formaldehyde and formic acid are formed from oxidative degradation of polyethylene glycol (PEG) used in an osmotic coating through a process heavily dependent on the physical state of the PEG. When the concentration of PEG in the coating is sufficiently low, the PEG remains phase compatible with the other component of the coating (cellulose acetate) such that its degradation (and the resulting drug reactivity) is effectively eliminated. Antioxidants in the coating and oxygen scavengers in the packaging also serve to prevent the PEG degradation, and consequently provide for drug stability.

Varenicline tartrate (Champix) is the first in a new class of therapy for smoking cessation and has been available on NHS prescription since December 2006. It has received approval from The National Institute for Health and Clinical Excellence (NICE) and the Scottish Medicines Consortium and NICE final guidance was issued in July 2007. Varenicline is a partial agonist of the nicotinic receptor (·4, 2 subtype) and also prevents nicotine from binding to it. Studies comparing safety and efficacy with bupropion (Zyban) have been favourable and efficacy with varenicline has been shown to be greater than that with bupropion. A study comparing the nicotine patch is due for publication this year. Varenicline has a good safety profile with nausea being the most common side effect in about a third of those who take it. Despite the treatment's advantages there have been numerous issues which have affected its use. These include funding and administrative issues and this paper looks at ways of overcoming those barriers to prescribing what is a valuable addition to the range of treatments on offer to smokes who want to stop.

Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.

The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with α4 nicotinic subunits containing a single point mutation, Leu 9′ → Ala 9′ in the pore-forming M2 domain, rendering α4* receptors hypersensitive to nicotine. Selective activation of α4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of α4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.

Importance Individuals with alcohol use disorder have high rates of cigarette smoking. Varenicline tartrate, an approved treatment for smoking cessation, may reduce both drinking and smoking. Objectives To test the efficacy of varenicline with medical management for patients with alcohol use disorder and comorbid smoking seeking alcohol treatment, and to evaluate the secondary effects on smoking abstinence. Design, Setting, and Participants This phase 2, randomized, double-blind, parallel group, placebo-controlled trial was conducted at 2 outpatient clinics from September 19, 2012, to August 31, 2015. Eligible participants met alcohol-dependence criteria and reported heavy drinking (≥5 drinks for men and ≥4 drinks for women) 2 or more times per week and smoking 2 or more times per week; 131 participants were randomized to either varenicline or placebo stratified by sex and site. All analyses were of the intention-to-treat type. Data analysis was conducted from February 5, 2016, to September 29, 2017. Interventions Varenicline tartrate, 1 mg twice daily, and matching placebo pills for 16 weeks. Medical management emphasized medication adherence for 4 weeks followed by support for changing drinking. Main Outcomes and Measures Percentage of heavy drinking days (PHDD) weeks 9 to 16, no heavy drinking days (NHDD) weeks 9 to 16, and prolonged smoking abstinence weeks 13 to 16. Results Of 131 participants, 39 (29.8%) were women and 92 (70.2%) were men, the mean (SD) age was 42.7 (11.7) years, and the race/ethnicity self-identified by most respondents was black (69 [52.7%]). Sixty-four participants were randomized to receive varenicline, and 67 to receive placebo. Mean change in PHDD between varenicline and placebo across sex and site was not significantly different. However, a significant treatment by sex by time interaction for PHDD ( F 1,106 = 4.66; P = .03) revealed that varenicline compared with placebo resulted in a larger decrease in log-transformed PHDD in men (least square [LS] mean difference in change from baseline, 0.54; 95% CI, −0.09 to 1.18; P = .09; Cohen d = 0.45) but a smaller decrease in women (LS mean difference, −0.69; 95% CI, −1.63 to 0.25; P = .15; Cohen d = −0.53). Thirteen of 45 men (29%) had NHDD taking varenicline compared with 3 of 47 men (6%) taking placebo (Cohen h = 0.64; 95% CI, 0.22-1.03), whereas 1 of 19 women (5%) had NHDD compared with 5 of 20 women (25%) taking placebo (Cohen h = −0.60; 95% CI, −1.21 to 0.04). Taking varenicline, 8 of 64 participants (13%) achieved prolonged smoking abstinence; no one (0 of 67) quit smoking taking placebo ( P = .003; Cohen h = 0.72; 95% CI, 0.38-1.07). Conclusions and Relevance Varenicline with medical management resulted in decreased heavy drinking among men and increased smoking abstinence in the overall sample. Varenicline could be considered to promote improvements in men with these dual behavioral health risks. Trial Registration clinicaltrials.gov Identifier:NCT01553136

Two simple, sensitive, rapid, and stability-indicating liquid chromatographic (LC) methods have been developed for the determination of varenicline tartrate. They comprised the determination of varenicline (VRC) in the presence of its oxidative degradates and related impurity (N-formyl varenicline) (NFV). The first method was a LC with diode array detection (DAD) at 235 nm using Ristek-Ultra® C18 column (100 mm × 2.1 mm, 5 µm). Isocratic elution of VRC was employed using a mobile phase consisting of buffer mixture (1.2% potassium dihydrogen phosphate and 0.08% octane sulphonic acid): acetonitrile (86:14, v/v), pH (5.0). In the second method; a fluorimetric detection technique was developed, based on precolumn derivatization of VRC using 7-chloro-4-nitrobenzo-2-oxa-1, 3-diazole (NBD-Cl). The fluorescence detector (FLD) was operated at 474 nm for excitation and 539 nm for emission. Isocratic elution was applied with a mobile phase consisting of methanol-distilled water (70:30, v/v). Separation was achieved using Symmetry® Waters C18 column (150 mm × 4.6 mm, 5 µm). Linearity, accuracy and precision were found to be acceptable over the concentration ranges of 0.5-20.0 µg mL(-1) and 0.2-20.0 µg mL(-1) with the first and the second method, respectively. The optimized methods were validated and proved to be specific, simple, and accurate for the quality control of the drug in its pharmaceutical preparation.

IMPORTANCE Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. OBJECTIVE To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. DESIGN, SETTING, AND PARTICIPANTS Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. MAIN OUTCOME AND MEASURES A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. RESULTS The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P

Introduction: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies; however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitlinecounseling compared to quitline-counseling alone in the inpatient medical setting. Methods: Adult patients (n = 392, 20–75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 weeks of varenicline tartrate (titrated from 0.5 mg daily to 1 mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline-counseling alone (n = 196). Results: VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8 ± 2.89 and 53.7 ± 2.77 years in the VT+C and counseling alone groups, respectively). The most common self-reported adverse event during the 12-week treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities. Conclusions: VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting. Refereed/Peer-reviewed

OBJECTIVES To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial α4β2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence. METHODS Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13. RESULTS The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild. CONCLUSIONS Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence.

The use of varenicline tartrate alleviates postquit withdrawal discomfort, but it also seems to reduce the "reward" associated with smoking. The current treatment schedule, which commences 1 week before quitting, relies primarily on the first mechanism. We set out to determine whether increasing the prequit medication period renders cigarettes less satisfying and facilitates quitting.One hundred one smokers attending a stop-smoking clinic in London, United Kingdom, were randomly allocated to receive varenicline for 4 weeks before the target quit date (TQD) or to receive placebo for 3 weeks before the TQD, followed by varenicline for 1 week before the TQD. In both groups, standard varenicline treatment was given for 3 months after the TQD. Measures included smoking satisfaction and smoke intake before quitting, urges to smoke and withdrawal discomfort after quitting, and sustained abstinence from the TQD to 3 months.Varenicline preloading reduced prequit enjoyment of smoking (P = .004) and smoke intake (P.001), with 36.7% of participants reducing their cotinine concentrations by more than 50% (reducers). Varenicline preloading did not affect postquit withdrawal symptoms, but it increased 12-week abstinence rates (47.2% in the varenicline arm vs 20.8% in the placebo arm, P = .005). The effect was particularly strong among the reducers in the varenicline arm (66.7% in reducers vs 22.6% in nonreducers, P = .002). Varenicline preloading was well tolerated.Although several issues remain to be clarified, varenicline preloading can generate a substantial reduction in ad lib smoking and enhance 12-week quit rates. Current treatment schedules may lead to suboptimal treatment results. Trials with longer follow-up periods are needed to corroborate these findings. Trial Registration clinicaltrials.gov Identifier: NCT00789074.

Varenicline tartrate, a selective partial agonist of the α4β2 nicotinic receptor, has been shown to be an effective smoking cessation aid with an acceptable safety profile in a number of randomized, controlled trials. The aim of the CHOICES (Champix Observational Investigation in the Cessation of Smoking) study was to investigate the effectiveness and safety of varenicline in real-world clinical practice.The CHOICES study was a 12-week, prospective, observational, non-comparative study of varenicline conducted in four European countries (Belgium, Greece, Hungary, and Slovenia) between November 21, 2007 and August 3, 2009. Participants were prescribed varenicline according to the recommendations on the European Summary of Product Characteristics (SmPC). Smoking abstinence rates in the 7 days between week 11 and 12 were determined based on verbal reporting using a nicotine use inventory. The safety profile of varenicline was also assessed.Of 566 participants enrolled in this study, 551 received varenicline and were evaluated for effectiveness and safety. At baseline, the overall study population had a mean age of 45.5 years; a mean history of smoking of 27.0 years; and a mean score on the Fagerström Test of Nicotine Dependence (FTND) of 6.1. Overall, 64.6% (95% CI 60.1, 68.3) of participants successfully quit smoking by the end of the treatment phase at week 12. The most frequent treatment-emergent (all causality) adverse events were nausea (8.9%), insomnia (2.9%), and sleep disorder (2.2%) of mostly mild or moderate intensity. Discontinuations from the study due to treatment-related adverse events occurred in 3.4% of participants.Abstinence rates were not validated by carbon monoxide measurements, as this is not a practice uniformly used in European countries.The CHOICES study shows that in a real-world clinical practice setting outside a clinical trial environment, varenicline is an effective smoking cessation aid with an acceptable safety profile.

Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α(4)β(2) nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in adult smokers aged 18-55 years, elderly smokers and nonsmokers aged ≥ 65 years, adolescent smokers aged 12-17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3-4 hours after dosing. Protein binding of varenicline is low (≤ 20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steady-state conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of varenicline. In vitro, varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤ 55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in varenicline clinical trials, with an incidence that was sex-related and increased with varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of varenicline simplify its use in clinical practice.