Psychiatric Adverse Events in Randomized, Double-Blind, Placebo-Controlled Clinical Trials of Varenicline
- 695 Downloads
Background: Varenicline (Chantix®, Champix®) has shown efficacy and tolerability as an aid to smoking cessation. In postmarketing surveillance, neuropsychiatric symptoms have appeared; however, their incidence and causal relationship to varenicline is not known.
Objective: We assessed the incidence and relative risk (RR) of psychiatric disorders in ten randomized, double-blind, placebo-controlled trials of varenicline for smoking cessation.
Methods: All smoking cessation phase II, III and IV randomized controlled clinical trials of varenicline versus placebo completed as of 31 December 2008, on file with the manufacturer (Pfizer, Inc.), were included. All studies have been published. All 3091 participants who received at least one dose of varenicline and all 2005 participants who received placebo were included in this analysis. These were men and women smoking ≥10 cigarettes/day, aged 18–75 years and without current psychiatric disease who received varenicline or placebo for 6 (one study), 12 (eight studies) or 52 (one study) weeks. Adverse events were recorded at each study visit and classified according to standard Medical Dictionary for Regulatory Activities (MedDRA®) terms (version 11.0).
Results: The incidence of psychiatric disorders other than solely sleep disorders and disturbances was 10.7% in subjects treated with varenicline and 9.7% in subjects treated with placebo, with an RR of 1.02 (95% CI 0.86, 1.22). The RRs (95% CI) versus placebo of psychiatric adverse events with an incidence ≥1% in the varenicline group were 0.86 (0.67, 1.12) for anxiety disorders and symptoms, 0.76 (0.42, 1.39) for changes in physical activity, 1.42 (0.96, 2.08) for depressed mood disorders and disturbances, 1.21 (0.79, 1.83) for mood disorders and disturbances not elsewhere classified and 1.70 (1.50, 1.92) for sleep disorders and disturbances. There were no cases of suicidal ideation or behaviour in varenicline-treated subjects in the ten placebo-controlled studies analysed. However, among three trials that were excluded from the analysis because of their open-label design, two cases of suicidal ideation and one completed suicide were reported in patients who had been treated with varenicline. With the exception of sleep disorders and disturbances, there was no evidence of dose-responsivity.
Conclusions: There was no significant increase in overall psychiatric disorders, other than sleep disorders and disturbances, in varenicline-treated subjects in this sample of smokers without current psychiatric disorders. Ongoing studies are testing the use of varenicline in psychiatric patients.
- 3.Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2008; (3): CD006103Google Scholar
- 4.Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2007; (1): CD000031Google Scholar
- 5.Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008; (1): CD000146Google Scholar
- 16.US FDA. Early communication about an ongoing safety review of varenicline (marketed as Chantix). US FDA, 2007 Nov [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070765.htm [Accessed 2010 Jan 26]
- 17.US FDA. Public health advisory: important information on Chantix (varenicline). US FDA, 2008 May [online]. Available from URL: http://www.fda.gov/drugs/drugsafety/publichealthadvisories/ucm051136 [Accessed 2010 Jan 26]
- 18.US FDA. Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics) [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169986.htm [Accessed 2009 Jul 10]
- 20.Nakamura M, Oshima A, Fujimoto Y, et al. Efficacy and tolerability of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther 2007 Jun; 29(6): 1040–56PubMedCrossRefGoogle Scholar
- 22.Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006 Aug 14–28; 166(15): 1561–8PubMedCrossRefGoogle Scholar
- 30.Pfizer Inc. A3051048: a double-blind, placebo-controlled, multicenter study evaluating the safety of repeated use of varenicline in smokers who failed to remain abstinent in study A3051046 [online]. Available from URL: http://pdf.clinicalstudyresults.org/documents/company-study_2500_0.pdf [Accessed 2009 Jul 10]
- 31.Clinical study results for protocol no. A3051046 and A3051048 [online]. Available from URL: http://www.clinicalstudyresults.org/drugdetails/?inn_name_id=494&sort=c.company_name&page=1&drug_id=2500 [Accessed 2009 Apr 7]
- 32.MedDRA, Maintenance and Support Services Organization [online]. Available from URL: http://www.meddramsso.com/MSSOWeb/index.htm [Accessed 2008 Aug 21]
- 33.Pfizer Inc. US prescribing information: CHANTIX (varenicline) tablets [online]. Available from URL: http://www.pfizer.com/files/products/uspi_chantix.pdf [Accessed 2009 Jul 10]
- 38.Charney D, Nestler E, editors. Neurobiology of mental illness. 2nd ed. New York: Oxford University Press, 2005Google Scholar
- 44.American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text revision. Washington, DC: American Psychiatric Association, 2000Google Scholar
- 49.Gunnell D, Irvine D, Wise L, et al. Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database. BMJ 2009; 339: 1072Google Scholar
- 50.FDA drug safety newsletter. Vol. 2, No. 1. 2009 Oct 8 [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm110235.htm [Accessed 2010 Feb 10]