Varenicline Update. Serena Tonstad, MD, PhD Dept of Preventive Cardiology Ullevål University Hospital Oslo, Norway

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1 Varenicline Update Serena Tonstad, MD, PhD Dept of Preventive Cardiology Ullevål University Hospital Oslo, orway October 23, 2015 Disclosures related to smoking cessation: Pfizer, Mceil, ovartis

2 Binding of Varenicline to euronal icotinic Acetylcholine Receptors H H Receptor Subunits Cell membrane β2 V V β2 V V V V icotine α4 α4 α4 α4 V β2 β2 V V Varenicline

3 Partial Agonist Effect on Dopamine Release in Rat ucleus Accumbens in. Accumbens l ±SEM Dopamine Release % of Basal Varenicline 1 mg/kg po Time (minutes) icotine 0.32 mg/kg icotine 0.32 mg/kg sc Varenicline 1 mg/kg po + icotine 0.32 mg/kg sc Varenicline 1 mg/kg po

4 Changes in Urge To Smoke Mean Change From Baseline Study Period, Week p <.001 p <.01 p <.05 Varenicline Tartrate 0.5 mg BID Pooled (n=245) Varenicline Tartrate 1.0 mg BID Pooled (n=249) Placebo (n=111) Oncken C et al. Arch Intern Med.2006; 166: 1575

5 Changes in Cigarette Evaluation Questionnaire Scores A. Psychological Reward Study Period, wk B. Satisfaction Study Period, wk C. Enjoyment of respiratory tract sensations Study Period, wk Mean changes in modified Cigarette Evaluation Questionnaire scores in the psychological reward (A), satisfaction (B), and enjoyment subscales from week 1 to week 12. BID indicates twice daily In comparison with placebo:p<0.001; p<0.01 ; p<0.05 Oncken C et al. Arch Intern Med.2006;166(15):

6 JAMA First Studies: Continuous Abstinence Rates vs B and P CA Responde ers (%) 50 Varenicline Bupropion Study 1 50 Study 2 45 Placebo Week Responders s (%) Week Varenicline Bupropion Placebo Gonzales, Jorenby JAMA 2006

7 Meta-analysis All Comparisons Varenicline vs RT indirect comparison by network analysis Cochrane Database Syst Rev 2013 Cahill et al

8 Varenicline Maintenance Study Tonstad et al. JAMA 2006

9 Studies in Patients with Chronic Mental Illness 2-4 times the smoking rates of the general population High dependence 50% of deaths are due to tobacco-related conditions Smoking thought to act as a treatment Varied diagnoses and biopsychosocial mechanisms Schizophrenia Unipolar and bipolar depression Anxiety disorders Post-traumatic stress disorder

10 Maintenance Varenicline in Patients with Schizophrenia and Bipolar Disorder 247 screened 203 treated with v for 12 weeks 87 abstinent last 2 weeks 61 completed 40 more weeks of varenicline Abstinence rates 60% vs 19% Evins et al JAMA 2014; 311:

11 Maintenance Treatment With Varenicline in Patients With Schizophrenia and Bipolar Disorder

12 Varenicline in Smokers w/ Stably Treated Current or Past (2 y) Major Depression 50 % OR=3.35 (2.16, 5.21) P< % 15.6% OR=2.53 (1.56, 4.10) P= % 12.3% Varenicline Placebo OR=2.36 (1.40, 3.98) P= % 10.4% 0 CQR 9-12 CAR 9-24 CAR 9-52 Anthenelli et al. Ann Intern Med 2013; 159:

13 Varenicline Re-treatment Study Generally healthy adult smokers (10 cigs or more/day) 1 or more previous quit attempts with varenicline lasting 2 or more weeks o quit attempts in the last 3 months Gonzales D et al. Clin Pharmacol Therapeutics 2014; 96:

14 Quit Rates Re-treatment Study 45.0% 28.9% 20.1% 11.8% 7.8% 3.3%

15 Flexible Quit Date Study Generally healthy adult smokers (10 cigs or more/day) o quit attempts in the last 3 months Usual start of varenicline or placebo, but free to quit at any time between days 8 and 35 after starting treatment Most tried within this window Rennard S et al. icotine Tob Res 2012;14:343-50

16 Quit Rates Flexible Quit Date Study Rennard S et al. icotine Tob Res 2012;14:

17 Other Studies Clinical diagnoses CVD COPD Various parts of the world Asia China Latin America/Middle East

18 Efficacy of Varenicline in Phase 3 and 4 Studies (Weeks 9 12) Gonzales et al. JAMA, 2006; 296:47-55.; Jorenby et al. JAMA, 2006; 296:56-63.; Tsai et al. Clin Ther2007;29: ; Wang et al. Respirology2009;14: ; Bolliger et al. Clin Ther 2011;33: ; Rigotti et al. Circulation 2010; 121: ; Tashkin et al. Chest2011;139: ; Anthenelli et al. Ann Int Med2013; 159: ; Rennard et al. ic Tob Research 2012;14: ; Gonzales et al. Clin Pharm Therap 2014;96:

19 Efficacy of Varenicline in Phase 3 and 4 Studies (Weeks 9 24) Publications: Gonzales et al. JAMA, 2006; 296:47-55.; Jorenby et al. JAMA, 2006; 296:56-63.; Tsai et al. Clin Ther2007;29: ; Wang et al. Respirology 2009;14: ; Bolliger et al. Clin Ther 2011;33: ; Rigotti et al. Circulation 2010; 121: ; Tashkin et al. Chest 2011;139: ; Anthenelli et al. Ann Int Med 2013; 159: ; Rennard et al. ic Tob Research 2012;14: ; Gonzales et al. Clin Pharm Therap 2014;96:

20 Efficacy of Varenicline in Phase 3 and 4 Studies (Weeks 9 52) Gonzales et al. JAMA 2006; 296:47-55.; Jorenby et al. JAMA2006; 296:56-63.;Rigotti et al. Circulation 2010; 121: ; Tashkin et al. Chest2011;139: ; Anthenelli et al. Ann Int Med 2013; 159: ; Gonzales et al. Clin Pharm Therap 2014;96:

21 Interactions of sex and medication efficacy at the end of treatment (12 wks), 24 wks, and 52 wks Sherry A. McKee et al. icotine Tob Res 2015;ntr.ntv207

22 Effect of Varenicline on Cessation through Reduction RCT Varenicline vs placebo for 24 weeks 28-week follow-up 1510 smokers not willing or able to quit smoking within the next month willing to reduce, and make a quit attempt within the next 3 months Reduction targets: 50% by week 4 75% by week 8 Quit attempt by week 12 Abstinence: weeks Ebbert et al JAMA 2015

23 Quit Rates Cessation Through Reduction Ebbert JO et al. JAMA. 2015; 313:

24 Combination Studies Varenicline & bupropion: high uncontrolled cessation rates in small study (Ebbert JO et al, 2009); no effect in larger study (Ebbert JO et al. JAMA 2014) Varenicline & nicotine patch: icotine patch or placebo patch started 2 weeks before TQD and continued for 12 more weeks Varenicline started 1 week before TQD and continued for 12 more weeks (Koegelenberg et al JAMA 2014; 312: ) Meta-analysis Chang PH et al. BMC Public Health 2015

25 Increasing Varenicline Dose RCT 503 smokers started varenicline 3 weeks before TQD Of those 200 had little nausea, no reduction in enjoyment of smoking and less than 50% reduciton in their baseline smoking These 200 were then randomized to double blind additional treatment with varenicline up to a maxiumum of 5 mg/day or placebo The high dose reduced smoking enjoyment during the prequit period did not help urges to smoke Smoking cessation rates after 1,4 and 12 weeks after the quit date were numerically lower in the dose-increase group (S) 1 wk: 37% vs 48% 4 wk: 51% vs 59% 12 wk: 23% vs 26% More vomiting and nausea in the increased dose group Hajek P et al. JAMA Intern Hajek Med 2015; et 175: al

26 Varenicline for RT or Smokeless Tobacco Cessation Stop RT study >11 month users of flexible RT Varenicline effective after 12 weeks but not 52 weeks Stop smokeless tobacco studies 3 published RCTs 88% males 12-week results 48% vs 33% 26-week results S but numerically higher for varenicline 1) Tonnesen & Mikkelsen icotine Tob Res ) Schwartz J et al. icotine Tob Res 2015

27 Varenicline Safety Depression, suicidal ideation and behaviour, and suicide attempts have been reported in patients attempting to quit smoking with Champix in the post-marketing experience Clinicians should be aware of the possible emergence of significant depressive symptomatology in patients undergoing a smoking cessation attempt, and should advise patients accordingly Champix should be discontinued immediately if agitation, depressed mood or changes in behaviour that are of concern for the doctor, the patient, family or caregivers are observed, or if the patient develops suicidal ideation or suicidal behaviour. Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine withdrawal In addition, smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (eg, depression). 1Champix (Summary of Product Characteristics). Pfizer Ltd, Sandwich, UK

28 Independent Meta-analysis of europsychiatric Events 39 RCTs ( participants) o increased risk of suicide or attempted suicide o risk suicidal ideation o risk depression o risk irritability o risk aggression o risk death More sleep disorders, insomnia, abnormal dreams, and fatigue Reduced anxiety Thomas et al BMJ 2015; 350:h1109

29 EAGLES Study Design RCT FDA mandated Efficacy secondary endpoint Safety primary endpoint europsychiatric CVD Randomization groups Smokers without psychiatric diagnosis Varenicline (12 wks) Bupropion (12 wks) icotine patch (11 wks) Triple dummy placebo Smokers with psychiatric diagnosis Varenicline (12 wks) Bupropion (12 wks) icotine patch (11 wks) Triple dummy placebo clinicaltrials.gov

30 Good to Know about Pharmacokinetics Half-life ~ 24 hours C max within 3 4 hours Steady state reached within 4 days o effect of food on concentrations Undergoes minimal metabolism 92% excreted unchanged in urine and <10% as metabolites Days 1 3: Days 4 7: Day 8 End of treatment: 0.5 mg once daily 0.5 mg twice daily 1 mg twice daily Champix (Summary of Product Characteristics). Pfizer LTD, Sandwich, UK, 2008.

31 Practical Tips (1) The smoker Time course Ready to set a quit date Physically dependent on cigarettes ot pregnant o contraindications (sensitivity to varenicline or other tablet components) Drug interactions not a concern Start varenicline 8-35 days before the quit date Do not promise an effect before the quit date A few but not many people may wish to quit before quit date Takes 4 days to steady state acute use not studied

32 Timing of Varenicline ovember 2015 Su M Tu W Th F Sa First 3 Days: 0.5mg/day December 2015 Su M Tu W Th F Sa ext 4 Days: 0.5mg 2x/day January 2016 Su M Tu W Th F Sa After First 7 Days: Dose should increase to 1 mg 2x/day SMOKIG QUIT DATE Last Day of Treatment: 12 weeks later

33 Practical Tips (2) Drug administration Support BID dosing to reduce nausea and expectancy The tablets cannot be divided or crushed Dose within 30 min of a meal or snack to diminish nausea Reduce dose if intolerant or severe renal dysfunction Take second dose early in afternoon Encourage 1 2 more quit attempts if target date not met Give motivational tips and follow-up Most people could benefit from advice about diet and exercise

34 Practical Tips (3) Tolerance End of treatment Very vivid dreams ausea occurs within minutes of dosing (more in women) Short time course of nausea (1 st two weeks) Prescribe antiemetics if needed Give the smoker a clear idea what to do if neuropsychiatric side effects Tapering may be useful Offer another 12 weeks of treatment if smoker feels unsure or if he/she has not been continuously abstinent from the quit date

35 Frequent Questions How much and what kind of follow-up is needed? What if the smoker does not feel a subjective effect of the drug? What if the smoker quits taking the drug before the end of 12 weeks? Dose adjustment Light or intermittent smokers