2. Conflict Disclosure Info
• Speaker: Winston Tsui
• “Understanding Smoking Cessation Treatment Options
and Their Accessibility To Your Patients”.
• Financial Disclosure:
• Speaking engagements/honorarium: Pfizer, Servier,
Bayer, Boeringher

3. Disclosure
• I have full editorial control over the content
of this presentation and wish to advise and
that it may contain content that that is not
consistent with the approved Canadian
Product Monographs.

4. Objectives
• Review the latest clinical literature in smoking cessation and establish
the burden of smoking and its diseases as a serious health matter
• Understand tobacco dependence mechanisms and recognize the
fundamental problem of smoking as an addiction
• Outline and apply the most current and effective non-pharmacological
and pharmacological treatment strategies in a systematic approach in
terms of screening, diagnosis, intervention and follow-up of patients
who smoke
• Create an awareness and recognize smoking as a major modifiable
risk factor in the reduction of chronic diseases while addressing
challenging questions surrounding safety of smoking cessation
therapies

5. Burden of Disease

6. Tobacco use is the
leading preventable
cause of death in
the world.
World Health Organization: The World Health Report 2003
Courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

7. Tobacco will kill Over 175 million People Worldwide
Between 2005 and 2030
http://www.cancer.org/downloads/AA/TobaccoAtlas3/TA3_Chapt_10.pdf
Slide courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

8. Tobacco-Related Deaths
are Increasing1,2
Deaths Attributable to Tobacco
Tobacco may kill
one billion people
in the 21st century,
unless young
people avoid taking
up smoking and
current users quit.2
Deaths
(in Millions)
1
1
1
The 1950 death rate in developing countries was negligible.
ckay J, Eriksen M. The Tobacco Atlas, 2002.
ckay J, Eriksen M. The Tobacco Atlas, 2006.

13. Smoking Prevalence in Canada: 17%
~ 5 Million Smokers
Newfoundland
& Labrador
20%
B.C.
15%
Alberta
18%
Manitoba
18%
Saskatchewan
22%
Ontario
16%
Québec
20%
New
Brunswick
21%
Health Canada. Canadian Tobacco Use Monitoring Survey – Ages 25+ from Annual 2009.
http://www.hc-sc.gc.ca/hl-vs/tobac-tabac/research-recherche/stat/ctums-esutc_2007-eng.php
PEI
18%
Nova Scotia
19%

14. The Impact of Smoking on Canadians
Almost 5 Million Canadians Smoke1
♦ Smoking is the #1 preventable cause of death in Canada.2
– 22% of all deaths in Canada are attributable to smoking 2
– More than 45,000 Canadians die due to smoking each year2†
lculation based on data from the year 1998.
Health Canada. Canadian Tobacco Use Monitoring Survey 2005, Summary of Annual Results.
Makomaski Illing EM, Kaiserman, Can J Public Health 2004;95:38-44.

15. Slide courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

16. Smoking Saturates Nicotinic Receptors
MRI: Magnetic resonance image
kBq/mL
9
0
0.0 Cigarette
0.1 Cigarette
Brody AL. Arch Gen Psychiatry 2006;63:907-915.
0.3 Cigarette 1.0 Cigarette
3.0 Cigarette
Nondisplaceable

17. What’s in a Cigarette?
♦ Tobacco smoke: ≥ 4000 chemicals1, ≥ 50 carcinogenic2
Chemicals in
Tobacco Smoke1
Also Found In…
Acetone
Butane
Arsenic
Cadmium
Carbon monoxide
Toluene
Paint stripper
Lighter fluid
Ant poison
Car batteries
Car exhaust fumes
Industrial solvent
♦ Nicotine is responsible for the addiction, but other chemicals
are also involved.2
♦ Smoking cigarettes with lower tar and nicotine provides no
health benefit.2
1. World Health Organization. Tobacco: deadly in any form or disguise, 2006.
2. Health Canada. What’s in Cigarette smoke?, August 2005.

18. Why Quit? Potential Lifetime Health
Benefits of Quitting Smoking1-2
Cardiovascular heart disease (CHD) risk is similar to never smokers
Lung cancer risk is 30-50% that of continuing smokers
Stroke risk returns to the level of people who have never
smoked at 5-15 years post-cessation
1. CDC. Surgeon General Report 2004: American Cancer Society. Guide to Quitting Smoking.
2. US Department of Health & Human Services. The Health Benefits of Smoking Cessation: A Report of the Surgeon General. 1990.
15 years
10 years
5 years
1 year
3 months
Cessation
CHD: excess risk is reduced by 50%
among ex-smokers
Lung function may start to improve
with decreased cough, sinus
congestion, fatigue, and shortness of
breath

19. Tobacco Dependence Mechanisms

20. Mechanism of Action of Nicotine
in the Central Nervous System
♦ Nicotine binds
β2 β2
preferentially to nicotinic
α4 β2 α4
acetylcholine (nACh)
receptors in the central
nervous system; the
primary is the α4β2 nACh
receptor in the Ventral
α4β2
Tegmental Area (VTA)
Nicotinic
Receptor
♦ After nicotine binds to the
α4β2 nACh receptor in the
VTA, it results in a release
of dopamine in the
Nucleus Accumbens
(nAcc), which is believed
to be linked to reward
Foulds J. Int J Clin Pract 2006;60:571-576.

21. FOREBRAIN
Dopamine
BRAIN STEM
α4ß2 receptors
Slide courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

22. “Smokers smoke to maintain relative
constancy of nicotine, dopamine
and other neurotransmitter levels.”
Slide courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

23. The Cycle of Nicotine Addiction
♦ Nicotine binding causes an increase in
dopamine release 1
♦ Dopamine gives feelings of pleasure and
Nicotine
calmness 2
♦ The dopamine decrease between
cigarettes leads to withdrawal symptoms
of irritability and stress 3,4
♦ A smoker craves nicotine to release more
dopamine to restore pleasure and
calmness 2,3
1.
2.
3.
4.
Foulds J. Int J Clin Pract 2006;60:571-576.
Fagerstrom K. Drugs 2002;62(Suppl2):1-9.
Jarvis MJ. BMJ 2004; 328:277-279.
Rigotti NA. N Engl J Med 2002;346:506-512.
Dopamine

24. Quitting Smoking:
May be a Protracted Journey
♦ The majority of smokers are motivated to quit
1
♦ Most try to quit without pharmacological assistance
2
♦ 87% of current smokers have tried to quit smoking at least once before 3
♦ 19% of smokers report craving is the most common reason why quitting
smoking is considered difficult 4
♦ Relapse is common 5
♦ Many smokers make multiple attempts to quit
1.
2.
3.
4.
5.
♦ Only ~ 5% succeed without assistance
Hughes JR. CA Cancer J Clin 2000;50:143-151.
Anthenelli RM. Clin Neurosci Res 2005;5:175-183.
Pfizer Canada Inc., Data on file. 2006.
O'Donnell DE et al.Can Respir J 2004;11(SupplB):3B-59B.
Fiore MC et al.JAMA 2002;288:1768-1771.

25. Tobacco Dependence and
Environmental Reinforcement
♦ Pharmacologic effects
– Nicotine as an addictive drug
♦ Non-pharmacologic effects
– Environmental/social stimuli associated with smoking play a
role in reinforcing nicotine dependence
Caggiula AR et al.Psychol Behav 2002;77:683–687.

26. Withdrawal Syndrome: a Combination of
Physical and Psychological Conditions,
Making Smoking Hard to Treat1,2
Withdrawal Syndrome
Irritability,
frustration, or anger
Anxiety
Restlessness
or impatience
Insomnia/sleep
disturbance
Increased appetite
or weight gain
Dysphoric or
depressed mood
Difficulty concentrating
1. Diagnostic and Statistical Manual of Mental Disorders, IV-TR. Washington, DC: APA; 2006.
2. West RW et al. Fast Facts: Smoking Cessation. 1st ed. Oxford, United Kingdom. Health Press Limited, 2004.

27. Withdrawal Symptoms from Stopping Smoking
Incidence
Increased appetite
70%
Restlessness
60%
Depression
60%
Irritability/aggression
50%
Craving for nicotine
70%
Poor concentration
60%
Sleep disturbance
25%
Lightheadedness
10%
0
1
2
3
4
5
Duration (weeks)
Jarvis MJ. BMJ 2004;328:277-279.
6
7
8
9
10
or more

28. Select Withdrawal Symptoms Over Time
Placebo
Impatience
1.5
Nicotine Gum
Irritability/Anger
1.5
1.0
0.5
de s u d A nae M
t j
er oc Sl a w r dhi W
a t
1.0
0.5
0.0
0.0
1
2
3
4
5
6
7
8
1
9 10
Postcessation Weeks
3
4
5
6
7
8
9 10
Postcessation Weeks
Anxiety/Tension
Excessive Hunger
1.5
1.5
1.0
1.0
0.5
de s u d A nae M
t j
r oc Sl a w r dhi W
a t
2
0.5
0.0
0.0
1
2
3
4
5
6
7
8
Postcessation Weeks
9 10
1
2
3
4
5
6
7
8
9 10
Postcessation Weeks
N = 40. Mean adjusted withdrawal scores are from an analysis of covariance with baseline cigarettes per day
and baseline scores on the items shown as covariates.
Gross et al. Psychopharmacology. 1989;98:334-341.

29. Probability of Dependence After Trying a
Substance at Least Once
Tobacco
Heroin
Cocaine
Alcohol
Stimulants
Anxiolytics
Cannabis
Analgesics
Inhalants
32%
23%
17%
15%
11%
9%
9%
8%
4%
Stahl’s Essential Psychopharmacology, 3 rd ed. 2008
Courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

30. Pharmacological Smoking Cessation
Treatment Approaches

31. Pharmacotherapy
for Tobacco Dependence 1-4
3 First-Line Therapies:
♦ Nicotine replacement therapy (NRT)
– Long-acting -- Patch
– Short-acting -- Gum, Inhaler, Lozenges
♦ Bupropion SR
♦ Varenicline
1.
2.
3.
4.
O'Donnell DE et al.Can Respir J 2004;11(SupplB):3B-59B.
Foulds J. Int J Clin Pract 2006;60:571-576.
Challenge Quit to win. Pharmacological Aids. February 20, 2007.
CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.

32. Effectiveness and abstinence rates for various medications and
medication combinations compared to placebo at 6-months postquit
(n = 83 studies)a
Medication
Placebo
# of
Estimated odds
Estimated
arms
ratio (95% C.I.)
abstinence rate
80
1.0
Monotherapies
13.8
(95% C.I.)
Varenicline (2 mg/day)
5
3.1 (2.5–3.8)
33.2 (28.9–37.8)
Nicotine Nasal Spray
4
2.3 (1.7–3.0)
26.7 (21.5–32.7)
High-Dose Nicotine Patch ( > 25 mg) (Included
4
2.3 (1.7–3.0)
26.5 (21.3–32.5)
both standard or long-term duration)
Long-Term Nicotine Gum (> 14 weeks)
6
2.2 (1.5–3.2)
26.1 (19.7–33.6)
Varenicline (1 mg/day)
3
2.1 (1.5–3.0)
25.4 (19.6–32.2)
Nicotine Inhaler
6
2.1 (1.5–2.9)
24.8 (19.1–31.6)
Clonidine
3
2.1 (1.2–3.7)
25.0 (15.7–37.3)
Bupropion SR
26
2.0 (1.8–2.2)
24.2 (22.2–26.4)
Nicotine Patch (6–14 weeks)
32
1.9 (1.7–2.2)
23.4 (21.3–25.8)
Long-Term Nicotine Patch (> 14 weeks)
10
1.9 (1.7–2.3)
23.7 (21.0–26.6)
Nortriptyline
5
1.8 (1.3–2.6)
22.5 (16.8–29.4)
Nicotine Gum (6–14 weeks)
15
1.5 (1.2–1.7)
19.0 (16.5–21.9)
Go to www.surgeongeneral.gov/tobacco/gdlnrefs.htm for the articles used in this meta-analysis
Fiore MC et al. US Department of Health and Human Services. Public Health Service. May 2008.
a

33. Effectiveness of smoking
cessation interventions
Comparison
# studies
# participants
Pooled Odds Ratio
(95% CI)
Non-pharmacological intervention
Self-help1
vs. no intervention
11
>13,000
1.24 (1.07-1.45)
Individual counseling2
vs. minimal behaviour intervention
21
>7,000
1.56 (1.32-1.84)
Physician advice3
vs. no advice
17
>13,000
1.74 (1.48-2.05)
Group counseling4
vs. no intervention
7
815
2.17 (1.37-3.45)
Pharmacological intervention
NRTs5,6
vs. control
39,503
1.77 (1.66-1.88)
Bupropion SR7
vs. placebo
1.
2.
3.
4.
5.
6.
7.
103
19
>4,000
2.06 (1.77-2.40)
Lancaster T, Stead LF. Cochrane Database Syst Rev 2005;(3):CD001118.
Lancaster T. Stead LF. Cochrane Database Syst Rev 2005;(2):CD001292.
Lancaster T, Stead LF. Cochrane Database Syst Rev 2004;(4):CD000165.
Stead LF, Lancaster T. Cochrane Database Syst Rev 2005;(4):CD001007.
Silagy C et al. Cochrane Database Syst Rev 2004;(3):CD000146.
Stead L, Lancaster T. Int J Epidemiol 2005;34:1001–1003.
Hughes JR et al. Cochrane Database Syst Rev 2004;(4):CD000031.

34. Nicotine Replacement Therapy (NRT)
♦ NRT has been shown to be safe and effective in
helping people stop using cigarettes 1
♦ Delivers nicotine that binds to the nAChR
receptors 1
♦ NRTs does not deliver nicotine to the circulation
as rapidly as smoking; is delivered via the venous
system 2
1. American Heart Association website.
2. Sweeney CT et al.CNS Drugs 2001;15:453-467.

35. Nicotine Replacement Therapy (NRT): Nicotine
Delivery by Cigarettes and NRT Products
Cigarette (nicotine delivery, 1-2 mg)
Gum (nicotine delivery, 4 mg)
Nasal spray (nicotine delivery, 1 mg)
18
16
Plasma
Nicotine
Concentration
(μg/L)
Transdermal patch
14
12
10
8
6
4
2
0
0
Sweeney CT et al. CNS Drugs 2001;15:453-467.
10 20 30 40 50 60 70 80 90 100 110 120
Time post-administration (minutes)

36. Efficacy of Nicotine Replacement
Therapy (NRT)
Trials
(n)
Participants
(n)
Pooled RR
(95% CI)
Gum
53
19,090
1.43 (1.33–1.53)
Patch
41
18,237
1.66 (1.53–1.81)
Nasal spray
4
887
2.02 (1.49–3.73)
Inhaler
4
976
1.90 (1.36–2.67)
Tablets/lozenges
6
3109
2.00 (1.63–2.45)
Patch and inhaler
1
245
1.07 (0.57–1.99)
Choice of NRT product
2
496
2.26 (1.26–4.05)
110
43,040
1.58 (1.50–1.66)
Comparison
Any NRT vs. control
Stead L et al. Cochrane Database Syst Rev. 2008; Jan 23(1):CD000146.

37. Bupropion SR (Zyban®)
♦ ZYBAN® (bupropion SR hydrochloride) is a non-nicotine
sustained-release tablet for smoking cessation
♦ Initially developed as an antidepressant, later found to
have efficacy in smoking cessation1
♦ There are 2 potential MOAs:
– Blocks reuptake of dopamine 2,3
– Non-competitive inhibition of α3β2 and α4β2 nicotine
receptors4,5
Zyban® is a registered trademark of the GlaxoSmithKline Group of Companies and is used by Biovail under license.
1. Product Monograph. bupropion SR hydrocloride [Zyban®]. GlaxoSmithKline.
2. Henningfield JE et al.CA Cancer J Clin 2005;55:281–299.
3. Foulds J et al.Expert Opin Emerg Drugs 2004;9:39–53.
4. Slemmer JE et al.J Pharmacol Exp Ther 2000;295:321–327.
5. Roddy E. Br Med J 2004;328:509–511.
Pr

38. Comparison of Nicotine Replacement
Therapy (NRT) and Bupropion SR Therapy
for Quitting Smoking1
♦ Only cessation study comparing NRT and antidepressant therapy 2
Placebo (n=160)
Buproprion SR (n=244)
Nicotine Patch (n=244)
Bupropion SR + Patch (n=245)
*
*
*p≤0.001 vs. placebo and patch alone
1. Jorenby DE et al.N Engl J Med 1999;340:685–691.
2. Talwar A et al.Med Clin North Am 2004;88:1517–1534.

39. Bupropion SR for Tobacco
Dependence
Trials
(n)
Participants
(n)
Pooled OR†
(95% CI)
Bupropion SR alone vs.
Placebo
19
6443
2.06 (1.77–2.40)
Bupropion SR plus nicotine
patch vs. placebo
2
728
1.60 (1.09–2.34)
All bupropion SR vs.
placebo
21
7171
1.99 (1.73–2.30)
Comparison
OR= odds ratio
1. Hughes J, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2004;(4):CD000031.
2. Hughes JR, Stead LF, Lancaster T. Nortriptyline for smoking cessation: a review. Nicotine Tob Res 2005;7:491–499.
†
17

40. Varenicline: An α4β2 Nicotinic Acetylcholine
Receptor Partial Agonist and Antagonist
♦ ACTIVITY 1: Partial agonist
– Varenicline binds to the receptor,
partially stimulating dopamine release
♦ ACTIVITY 2: Antagonist
– Because varenicline is bound to the
receptor, it prevents the binding of
nicotine
Activation of the central nervous mesolimbic dopamine system is believed to be the
neuronal mechanism underlying reinforcement and reward experienced upon smoking
CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.

41. Varenicline Comparative Studies Design1,2
Treatment phase
Non-treatment phase
Varenicline 1 mg BID†
Bupropion 150 mg BID†
Placebo
Screening
visit
Baseline randomization
Week 12
Treatment Period
Week 52
Non-pharmacological Follow-up
B
L
W
1
W
2
W
3
W
4
W
5
W
6
W
7
W
8
W
9
W
10
W
11
W
12
W
13
W W
16 20
W
24
W
28
W
32
W W
36 40
W
44
W
48
W
52
C
C
C
C
C
C
C
C
C
C
C
C
C
C
T
C
T
T
C
C
T
C
Randomization Target quit date
Titrated during Week 1.
L = Baseline; W = Week;
C = Clinic visit; T = Telephone contact
1. Gonzales D et al.JAMA 2006;296:47-55.
2. Jorenby DE et al.JAMA 2006;296:56-63.
T
T
Two identically designed Phase 3 efficacy trials
Varenicline 1.0 mg BID vs placebo or
Bupropion SR150 mg BID
12 weeks of active treatment followed by
40 weeks of non-pharmacologic follow-up

42. Varenicline Comparative Studies
Primary/Secondary End Points
♦ Primary End Point1-3
– 4-Week Continuous Quit Rate (CQR), defined as the proportion of
individuals who maintained complete abstinence from cigarette
smoking and other nicotine use during the last 4 weeks (weeks 9
through 12) of the treatment period
– Abstinence was defined as self-report of no smoking (not even a
puff of a cigarette) and confirmed by exhaled CO measurements
≤10 ppm
♦ Key Secondary End Point1-3
– Continuous Abstinence (CA) rate from weeks 9 through 52
– Smoking Abstinence Point Prevalence verified by carbon monoxide
level at 7 days
1. Gonzales D et al.JAMA 2006;296:47-55.
2. Jorenby DE et al.JAMA 2006;296:56-63.
3. CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.

43. Varenicline Comparative Studies 4-Week
Continuous Quit Rates Weeks 9–121,2
50
45
40
35
30
25
20
15
10
5
0
44.0%
†
Study 2/Jorenby et al.2
†p<0.001 vs. bupro. and placebo
‡p<0.001 vs. placebo
29.5%
‡
17.7%
Varenicline
1 mg BID
n=352
Bupropion SR
150 mg BID
n=329
Placebo
n=344
Odds ratio
varenicline vs. placebo:
3.85; p<0.001
varenicline vs. bupropion SR: 1.93; p<0.001
1. Gonzales D et al.JAMA 2006;296:47-55.
2. Jorenby DE et al.JAMA 2006;296:56-63.
Continuous quit rate
Week 9-12 (%)
Continuous quit rate
Week 9-12 (%)
Study 1/Gonzales et al.1
50
45
40 43.9%
35 †
30
25
20
15
10
5
0
Varenicline
1 mg BID
n=344
†p<0.001 vs. bupro. and placebo
§p=0.001 vs. placebo
29.8%
§
17.6%
Bupropion SR
150 mg BID
n=342
Placebo
n=341
Odds ratio
varenicline vs. placebo:
3.85; p<0.001
varenicline vs. bupropion SR: 1.90; p<0.001

44. Varenicline Comparative Studies
Continuous Abstinence (CA) Rates Weeks 9–521,2
Study 1/Gonzales et al.1
Study 2/Jorenby et al.2
20
25
21.9%
†‡
15
† p=0.057 vs. bupropion SR
‡ p<0.001 vs. placebo
§p<0.001 vs. Placebo
16.1%
§
10
8.4%
5
0
Varenicline
1 mg BID
n=352
Bupropion SR
150 mg BID
n=329
Placebo
n=344
Odds ratio
varenicline vs. placebo:
3.09; p<0.001
varenicline vs. bupropion SR: 1.46; p=0.057
1. Gonzales D et al.JAMA 2006;296:47-55.
2. Jorenby DE et al.JAMA 2006;296:56-63.
Continuous abstinence rate
Week 9-52 (%)
Continuous abstinence rate
Week 9-52 (%)
25
23.0%
20 ¶ ††
15
¶p=0.004 vs. bupropion SR
†† p<0.001 vs. placebo
‡‡p<0.08 vs. Placebo
14.6%
‡‡
10
10.3%
5
0
Varenicline
1 mg BID
n=344
Bupropion SR
150 mg BID
n=342
Placebo
n=341
Odds ratio
varenicline vs. placebo:
2.66; p<0.001
varenicline vs. bupropion SR: 1.77; p=0.004

45. Varenicline Maintenance of Abstinence
(Extended Therapy) Study Design
Non-treatment
Double-blind phase follow-up phase
Open-label phase
Varenicline 1 mg BID
Varenicline 1 mg BID
(titrated)
Placebo
Baseline
Week 12
Week 24
Double-blind
treatment
Open-label treatment
B
L
C
W
1
C
W
2
C
W
3
C
W
4
C
W
5
C
W
6
C
W
7
C
W
8
C
Target quit date
L = Baseline; W = Week;
C = Clinic visit; T = Telephone contact
Tonstad S et al.JAMA2006;296:64-71.
W
10
C
W
12
C
W
13
C
W
14
C
W
16
C
Randomization
W
20
C
W
24
C
Week 52
Non-pharmacologic follow-up
(Double-blind)
W
25
C
W
26
T
W
28
C
W
32
T
W
36
C
W
40
T
W
44
C
W
48
T
W
50
C
Study goal:
To investigate the benefit of an additional 12-week
dosing for subjects who achieved abstinence during
the last 7 days of open-label varenicline treatment
(Week 12)

46. Varenicline Maintenance of Abstinence
Study Primary/Secondary End Points
♦ Primary End Point1,2
– Carbon monoxide (CO)-confirmed continuous abstinence (CA)† rate
from Week 13 through 24 (double-blind treatment phase)
♦ Key Secondary End Point1,2
– CA rate from Week 13 through 52
♦ Other Measure1
– 7-day point-prevalence of abstinence, during open-label phase and
from week 12 to week 52
The proportion of individuals who maintained complete abstinence for this specified
time period. Determined on a weekly basis, abstinence was defined as self-report of
no smoking (not even a puff of a cigarette) and confirmed by exhaled CO
measurements ≤10 ppm.
†
1.Tonstad S et al.JAMA 2006;296:64-71.
2.CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.

47. Maintenance of Abstinence (Extended Therapy)
in Quitters that had Previously Received
12 Weeks of Varenicline Therapy
1210 subjects who quit after 12 weeks of varenicline treatment
were then randomized to an additional 12 weeks.
p<0.001
vs. placebo
†
OR: varenicline vs. placebo 2.48, p<0.001
In the subsequent 28-week nontreatment follow-up of those who participated in the
double-blind phase of the study, the continuous abstinence rate for weeks
13 through 52 was 43.6% in the CHAMPIX-CHAMPIX group vs. 36.9% in the
CHAMPIX-placebo group (p=0.02)
Tonstad S et al. JAMA 2006;296:64-71

48. Varenicline Maintenance of
Abstinence Study: Adverse Events
Most Frequent AEs (Open-label Varenicline)
Open label
Varenicline
n
%
Newly emerging – Double blind
Varenicline
Placebo
n
%
n
%
Nausea
Mild
Moderate
Severe
645
452
162
31
33.5
70.1
25.1
4.8
7
5
2
0
1.2
4
4
0
0
0.7
Insomnia
377
19.6
16
2.7
17
2.8
Headache
304
15.8
17
2.8
12
2.0
Abnormal dreams
276
14.3
6
1.0
0
0.0
Tonstad S et al. JAMA 2006;296:64-71.

49. Comparison of Pharmacological
Interventions for Smoking Cessation
Comparison
# studies
# participants
Pooled
OddsRatio (95% CI)
Pharmacological interventions
NRTs
vs. control
103
39,503
1.77 (1.66-1.88)
Bupropion SR
vs. placebo
19
>4,000
2.06 (1.77-2.40)
CHAMPIX
vs. placebo
4
2,023
3.22 (2.43-4.27)
CHAMPIX
vs. bupropion SR
3
1,622
1.66 (1.28-2.16)
CHAMPIX
vs. NRT (all controls)
Indirect
comparison
Not
Applicable
1.73 (1.22-2.45)
For NRT and bupropion SR data: Cochrane Database Syst Rev 2004, 2005; Stead L, Lancaster T. Int J Epidemiol 2005;34:1001-1003.
For CHAMPIX pooled data: Cochrane Database Syst Rev 2007; Wu P et al.BMC Public Health 2006,6:300.

50. Long-Term Safety Study Conclusions
♦ Varenicline at a dose of 1 mg bid, can safely be taken for
periods up to one year
♦ AEs affecting tolerability were mostly related to gastrointestinal
symptoms or sleep disturbances
♦ Nausea was the most common AE, but was rarely rated as
severe and infrequently resulted in discontinuation of study
medication
♦ Sleep disturbances, in the form of insomnia or abnormal
dreams, also rarely resulted in discontinuation of study
medication
1. Tonstad S. Expert Rev Neurotherapeutics 2007;7:121-127.
2. Williams KE et al. Curr Med Res Opin 2007;23:793-801.

51. Varenicline Summary
♦ An innovative smoking cessation therapy believed to have simultaneous partial
agonist and antagonist activities at the α4β2 nACh receptor1
– Clinical significance is not fully confirmed1
♦ Demonstrated significantly superior continuous quit rates for weeks 9 through 12
vs. bupropion SR (Zyban®) and placebo in 2 pivotal head-to-head clinical trials:2,3
– ~4X greater odds of quitting smoking with varenicline (CHAMPIX) vs. placebo
(odds ratio=3.85, p<0.001; odds ratio=3.85, p<0.001)2,3
– ~2X greater odds of quitting smoking with varenicline (CHAMPIX) vs.
bupropion SR (odds ratio=1.93, p<0.001; odds ratio=1.90, p<0.001)2,3
♦ Established safety and tolerability profile in approximately 2,300 treated smokers1
Pr
Zyban® is a registered trademark of the GlaxoSmithKline Group of Companies and is used by Biovail under license.
1.CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.
2.Gonzales D et al.JAMA 2006;296:47-55.
3.Jorenby DE et al.JAMA 2006;296:56-63.

52. CHAMPIX (Varenicline)
Indication and Dosing Information
♦ Indicated for smoking cessation treatment in adults in conjunction with
smoking cessation counselling
♦ Treatment period is 12 weeks
♦ An additional course of 12 weeks of treatment may be considered for
patients who have successfully quit at the end of 12 weeks
♦ Varenicline is supplied for oral administration in 2 strengths: 0.5 mg and
1.0 mg
♦ After the first week of titration, there are two dosing options: the dose can
remain at 0.5 mg twice a day or go up to 1.0 mg twice a day.
Days 1 – 3:
0.5 mg once daily
Days 4 – 7:
0.5 mg twice daily
Day 8 – End of treatment: 0.5 mg twice daily OR 1 mg twice daily
CHAMPIX Product Monograph, Pfizer Canada Inc., May 2010

53. Varenicline Safety Information
♦ Established safety and tolerability profile assessed in approximately
2,300 subjects
♦ In general, onset of adverse events occurred in the first few weeks of
therapy and severity was generally mild to moderate
♦ The most commonly observed adverse events associated with varenicline
(>5% and twice the rate seen in placebo-treated patients) were nausea,
abnormal dreams, constipation, flatulence, and vomiting
Adverse event
Varenicline
0.5 mg BID
n=129
Nausea
Abnormal dreams
Constipation
Flatulence
Vomiting
Varenicline
1.0 mg BID
n=821
16%
9%
5%
9%
1%
Placebo
n=805
30%
13%
8%
6%
5%
10%
5%
3%
3%
2%
♦ Discontinuation rate due to nausea was only 2.7% (vs. 0.6% for placebo)
CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.

54. CHAMPIX (Varenicline)
Key Points to Keep in Mind:
♦ Identify patients who are motivated to quit smoking, since
motivated quitters are more likely to succeed1,2
♦ Prescribe a 12-week course of CHAMPIX treatment2
♦ Have patients set a target quit date 1-2 weeks into treatment 2-4
– The pivotal studies utilized a day 8 quit date3,4
♦ Reassess patients after 12 weeks
– For those who were successful, an additional course of 12 weeks may be
considered to help them stay quit2
1.West R. BMJ 2004;328:338-339.
2.CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.
3.Gonzales D et al.JAMA 2006;296:47-55.
4.Jorenby DE et al.JAMA 2006;296:56-63.

56. Cost of Champix
♦ Starter pack (week 1 & 2): $42
♦ Continuation: $47
♦ One month: $94
♦ Cigarettes (1 ppd) for 1 month: $261 - $287

57. Cardiovascular Concerns
♦ In 2011, the FDA issued an advisory that varenicline may
increase the risk of adverse cardiovascular events in patients
with known CVD.
♦ Efficacy and safety of varenicline for smoking cessation in
patients with cardiovascular disease: a randomized trial. Rigotti
NA et al. Circulation. 2010;121(2):221.
♦ Varenicline vs placebo: nonfatal myocardial infarction (2 vs 0.9
%), need for coronary revascularization (2.3 vs 0.9%), and a
new PAD (1.4 vs 0.9%), not statistically significant
♦ Overall and patients treated with varenicline had a lower rate of
cardiovascular mortality (0.6 versus 1.4%) also not statistically
significant.
♦ This same trial showed that varenicline is effective for smoking
cessation in patients with CVD.
♦ The FDA suggested that the known benefits of varenicline be
weighed against potential harms in patients with CVD.

58. Cardiovascular Concerns
♦ Risk of serious adverse cardiovascular events associated with
varenicline: a systematic review and meta-analysis. Singh S et
al. CMAJ. 2011;183(12):1359.
♦ meta-analysis of 14 randomized placebo-controlled trials of
Varenicline evaluated 8216 smokers with no or stable CVD
♦ Treatment with varenicline resulted in an increased risk of a
composite measure of adverse cardiovascular events including
myocardial ischemia, arrhythmia, heart failure, sudden death, or
cardiovascular-related death (1.06 versus 0.82 percent, OR
1.72, 95% CI 1.09-2.71).
♦ Although the absolute increase in events of 0.24%.

60. Cardiovascular Concern
♦ Risk of cardiovascular serious adverse events
associated with varenicline use for tobacco
cessation: systematic review and meta-analysis
♦ BMJ 2012; 344 doi: 10.1136/bmj.e2856 (Published 4
May 2012) BMJ 2012;344:e2856
♦ 22 trials, 2 with active CVD, 11 with Hx CVD
♦ 0.63% vs. 0.47%

61. ♦ Over the long term, even in a higher risk population
of patients with stable CVD, the benefits of smoking
cessation likely outweigh potential short-term harms
of varenicline.
♦ However, this increase in risk may be important in
choosing between medical therapies for smoking
cessation in patients at increased risk of
cardiovascular events.

62. People who quit
smoking after a
heart attack or
cardiac surgery
reduce their risk
of death by 36%
Cochrane Database of Systematic Reviews 2003;4:CD003041
Slide courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

63. Model of Deaths Prevented or Postponed
Through Risk-Factor Reduction
Coronary Heart Disease Deaths in England
Unal B et al.BMJ 2005;331:614.

64. Neuropsychiatric effects
♦ In 2008 FDA from post marketing reports suggested
patients should be monitored for neuropsychiatric
symptoms including changes in behavior, hostility,
agitation, depressed mood, suicidal ideation, and
suicide attempts.
♦ Vareniciline was responsible for 90 percent of 13,243
reported cases of suicidal/self-injurious behavior or
depression, followed by buproprion (7 percent), and
nicotine replacement (3 percent)
♦ Retrospective data collection that could be affected
by over-reporting of adverse events due to extensive
media coverage of varenicline.

65. Neuropyschiatric Affects
♦ In contrast, a pooled analysis of 10 randomized
placebo-controlled trials in 5096 smokers found no
association between varenicline and incidence of
psychiatric disorders or psychiatric adverse events
♦ Smokers themselves have an increased risk of
suicidal behavior, and similar neuropsychiatric
symptoms, also occur with nicotine withdrawal.
♦ Benefits of stopping smoking outweigh the uncertain
but potential risk of using varenicline in most patients.
♦ Need to take a careful psychiatric history prior to
prescribing the drug, avoiding it in smokers with a
history of suicidal ideation or a current unstable
psychiatric status.

66. BC Smoking Cessation Program
Effective September 30th, 2011, Pharmacare
launched the B.C. government’s Smoking
Cessation Program which is intended to
help eligible B.C residents stop smoking or
stop using other tobacco products by
assisting them with the cost of smoking
cessation aids.
♦
The program offers coverage for two treatment options:
1.
2.
prescription smoking cessation drugs or
non-prescription nicotine replacement therapy (NRT)
products.

67. Patient eligibility criteria
♦ To be eligible for nicotine replacement therapy program, patients must
have valid, active Medical Services Plan (MSP) coverage
♦ To be eligible for PharmaCare coverage of prescription smoking
cessation drugs, patients must be registered for Fair PharmaCare or
covered by one of the following PharmaCare plans:
– Permanent Residents of Licensed Residential Care Facilities (Plan
B)
– Recipients of B.C. Income Assistance plan (Plan C)
– No-Charge Psychiatric Medication plan (Plan G)
Source: BC Smoking Cessation Program-Information for Prescribers. Retrieved Oct 21, 2011 from
http://www.heath.gov.bc.ca/pharmacare/stop-smoking/mid-intro.html

68. Coverage Details
♦ Each calendar year, eligible B.C. residents may receive one or the
other of the following:
– Coverage for ONE of the designated prescription smoking
cessation drugs for a single continuous course of treatment lasting
up to 12 consecutive weeks (84 consecutive days). The actual
coverage patients receive depends on the rules of their
PharmaCare plan*.
OR
– 100% coverage for ONE of the designated nicotine replacement
therapy products for a single continuous course of treatment lasting
up to 12 consecutive weeks (84 consecutive days).
Source: BC Smoking Cessation Program-Information for Prescribers. Retrieved Oct 21, 2011 from
http://www.heath.gov.bc.ca/pharmacare/stop-smoking/mid-intro.html

69. Coverage details continued..
Handling requests for prescription drugs – key points
♦ You do NOT need to obtain Special Authority for an initial 12-week course of
treatment with bupropion (Zyban®) and varenicline (Champix®).
♦ Patients do NOT need to register for coverage through HealthLink BC for the
prescription drugs.
Handling requests for NRTs – key points
♦ Patients DO have to register for the smoking cessation program by phoning
HealthLink BC at 8-1-1 before they can obtain their NRT products.
♦ You do NOT need to write a prescription for either Habitrol® NRT patches or Thrive™
NRT gum. Patients can have these over-the-counter products fully covered under the
B.C. Smoking Cessation program without a prescription.
Source: BC Smoking Cessation Program-Information for Prescribers. Retrieved Oct 21, 2011 from
http://www.heath.gov.bc.ca/pharmacare/stop-smoking/mid-intro.html

70. For More Information…
♦ Visit the Ministry of health website at www.health.gov.ca/pharmacare/stopsmoking/ for more information about the BC Smoking Cessation Program

71. Non-Pharmacological Smoking Cessation
Treatment Approaches

72. A Comprehensive Approach
to Smoking Cessation
♦ Nicotine addiction has two main components:
– the pharmacological action of nicotine
– behavioural factors 1-3
♦ Current pharmacotherapies approximately double
the odds of quitting 4,5
♦ Advice and support increase the chances of
success 4,5
1.
2.
3.
4.
5.
Jarvis MJ. BMJ 2004;328:277-279.
Coleman T. BMJ 2004;328:397-399.
Rigotti NA. N Engl J Med 2002;346:506-512.
Hughes JR. CA Cancer J Clin 2000;50:143-151.
O'Donnell DE et al.Can Respir J 2004;11(SupplB):3B-59B.
Most effective methods of
smoking cessation combine
pharmacotherapy with
advice and support 2,4

73. Why May Some Smokers Need More
Help to Quit ?
♦ Higher level of dependence 1
– Cigarettes per day
– Time to first cigarette upon waking
♦ Living with a current smoker 1
♦ Fewer educational qualifications 2
♦ Lower socioeconomic class 2
♦ Co-morbid psychiatric disorders 3
1. Hyland A et al.Nicotine Tob Res 2004;6(Suppl3):S363-S369.
2. Chandola T et al.Addiction 2004;99:770-777.
3. Kalman D et al.Am J Addict 2005;14:106–123.

74. Non-pharmacologic Approaches
Advice and Support 1-3
♦ All smokers should be:
– Advised to quit
– Offered assistance
♦ Non-pharmacologic approaches can be helpful
– Strategic, tactical advice – ‘medicine management’
– Social support as part of treatment
– Securing social support outside of treatment
1. Pisinger C et al.Prev Med 2005;40:278-284.
2. Fiore MC et al.Clinical Practice Guideline: Treating Tobacco Use and Dependence. US Department of Health and Human Services. Public
Health Service; June 2000.
3. National Institute for Health and Clinical Excellence. Brief interventions and referral for smoking cessation in primary care.

75. Office-based Strategies for Helping
Patients Quit Smoking
♦ A systematic approach to identifying smokers1
♦ Sharing responsibility within a practice setting 2
– Ask – office staff can identify smoking status
– Advise, Assist – physician’s core tasks
– Assist and Arrange – office staff
“Make the most efficient use of time and resources”
1. Prochazka AV. Chest 2000;117(Suppl1):169S–175S.
2. Swartz SH, Hays JT. Med Clin North Am 2004;88:1623–1641.

76. Brief Tobacco Intervention
Using the 5 A’s
♦ Identify and document tobacco use
ASK
♦ In a clear, strong, personalized manner,
urge smoker to quit
ADVISE
♦ Is the smoker ready to make a quit
attempt?
ASSESS
♦ Use counselling and pharmacotherapy
to help him/her quit
ASSIST
♦ Schedule follow-up contact
ARRANGE
– Preferably within 1 week after the quit date
MC et al. Effective tobacco dependence treatment. JAMA 2002;288:1768-1771

77. Baseline assessment of the smoking status:
The Fagerström Test for Nicotine Dependence 1,2
Questions
Answers
1. How soon after you wake up do you smoke your first cigarette?
Points
After 60 minutes
0
31-60 minutes
1
6-30 minutes
2
Within 5 minutes
3
Yes
1
No
0
The 1st in the morning
1
All others
0
10 or less
0
11-20
1
21-30
2
31 or more
3
5. Do you smoke more frequently during the first hours after awakening than
during the rest of the day?
Yes
1
No
0
6. Do you smoke even if you are so ill that you are in bed most of the day?
Yes
1
No
0
2. Do you find it difficult to refrain from smoking in places where it is forbidden?
3. Which cigarette would you hate most to give up?
4. How many cigarettes per day do you smoke?
Dependence scores
0-2 Very low 3-4 Low
5 Medium
6-7 High
1. Heatherton TF et al.Br J Addict 1991;86:1119-27.
2. Heart and Stroke Foundation. The Fagerström Test for Nicotine Dependence.
8-10 Very high

78. The “5As”: Advise to Quit
♦ In a clear, strong, and personalized manner, urge every tobacco
user to quit at least once per year
♦ CLEAR
– “I think it is important for you to quit smoking now, and I can
help you.”
♦ STRONG
– “As your clinician, I need you to know that quitting smoking
is very important to protecting your health now and in the
future.”
♦ PERSONALIZED
– Tie tobacco use to health/illness (reason for office visit),
social/economic costs, motivation level, and impact on
others (children)
MC et al. US Department of Health and Human Services. Public Health Service. June 2000.

79. The “5As”: Assist in Quit Attempt
♦ For the patient willing to make a quit attempt, use counselling and
pharmacotherapy
– Provide practical counselling (problem solving and skills training)
– Provide social support
– Offer pharmacotherapy as appropriate
– Provide supplementary materials
 World Health Organization: www.who.int
 Centers for Disease Control and Prevention:
www.cdc.gov/tobacco
 Society for Research on Nicotine and Tobacco: www.srnt.org
– Consider need for referral to formal program
 In person
 Telephone or internet-based
e MC et al. US Department of Health and Human Services. Public Health Service. June 2000.

80. The “5As”: Arrange Follow-up
♦ Schedule follow-up contact, preferably within the first week after
the quit date
♦ Follow-up can occur either in person or via telephone
♦ Follow-up actions
– Congratulate success
– Review circumstances of lapse – elicit recommitment to
abstinence
– Identify and anticipate challenges
– Assess pharmacotherapy use
– Consider referral for more intensive treatment
MC et al. US Department of Health and Human Services. Public Health Service. June 2000.

81. Smoking Cessation Effectiveness
Increases with Treatment Intensity
Meta-analysis (2000): Effectiveness of and estimated abstinence rates for various
intensity levels of session length (n = 43 studies)a
Level of Contact
No Contact
Number of
Arms
Estimated Odds
Ratio (95% CI)
1.0
30
Estimated
Abstinence Rate†
(95% CI)
10.9
Minimal Counseling
(less than 3 minutes)
19
1.3 (1.01 – 1.6)
13.4 (10.9 – 16.1)
Low Intensity Counseling
(3 to 10 minutes)
16
1.6 (1.2 – 2.0)
16.0 (12.8 – 19.2)
Higher Intensity Counseling
(more than 10 minutes)
55
2.3 (2.0 – 2.7)
22.1 (19.4 – 24.7)
The abstinence rate is defined as the proportion of participants who reported no smoking.
Fiore MC et al. US Department of Health and Human Services. Public Health Service. May 2008.
†
a
Go to www.surgeongeneral.gov/tobacco/gdlnrefs.htm for the articles used in this meta-analysis