smoking cessation presentation dr. tsui - abbotsford, june 6, 2012

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

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.

ObjectivesObjectives

• 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

Burden of DiseaseBurden of Disease

Tobacco use is the Tobacco use is the leading preventable leading preventable

cause of death in cause of death in the world.the world.

Tobacco use is the Tobacco use is the leading preventable leading preventable

cause of death in cause of death in the world.the world.

World Health Organization: The World Health Report 2003World Health Organization: The World Health Report 2003Courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

http://www.cancer.org/downloads/AA/TobaccoAtlas3/TA3_Chapt_10.pdf

Tobacco will kill Over 175 million People Worldwide Tobacco will kill Over 175 million People Worldwide Between 2005 and 2030Between 2005 and 2030

Tobacco will kill Over 175 million People Worldwide Tobacco will kill Over 175 million People Worldwide Between 2005 and 2030Between 2005 and 2030

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

Tobacco-Related Deaths are Increasing1,2

Tobacco-Related Deaths are Increasing1,2

Tobacco may kill one billion people in the 21st century, unless young people avoid taking up smoking and current users quit.2

Deaths Attributable to Tobacco

Deaths (in Millions)

The 1950 death rate in developing countries was negligible.

1. Mackay J, Eriksen M. The Tobacco Atlas, 2002.2. Mackay J, Eriksen M. The Tobacco Atlas, 2006.

1 1 1

Smoking Prevalence in Canada: 17%Smoking Prevalence in Canada: 17%~ 5 Million Smokers~ 5 Million Smokers

Smoking Prevalence in Canada: 17%Smoking Prevalence in Canada: 17%~ 5 Million Smokers~ 5 Million Smokers

B.C.

15%

Ontario

16%

Québec

20%

Newfoundland & Labrador

20%

Alberta

18%

Saskatchewan

22%

Manitoba

18%

New Brunswick

21%

PEI

18%

Nova Scotia

19%

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

The Impact of Smoking on CanadiansThe Impact of Smoking on Canadians

Smoking is the #1 preventable cause of death in Canada.2

– 22% of all deaths in Canada are attributable to smoking2

– More than 45,000 Canadians die due to smoking each year2†

Almost 5 Million Canadians Smoke1

†Calculation based on data from the year 1998.1. Health Canada. Canadian Tobacco Use Monitoring Survey 2005, Summary of Annual Results.2. Makomaski Illing EM, Kaiserman, Can J Public Health 2004;95:38-44.

Smoking Saturates Nicotinic ReceptorsSmoking Saturates Nicotinic Receptors

0.0 Cigarette 0.1 Cigarette 0.3 Cigarette 1.0 Cigarette 3.0 Cigarette Nondisplaceable

MRI: Magnetic resonance image

kBq/mL 9

0

Brody AL. Arch Gen Psychiatry 2006;63:907-915.

What’s in a Cigarette?What’s in a Cigarette?

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

AcetoneButaneArsenicCadmiumCarbon monoxideToluene

Paint stripperLighter fluidAnt poisonCar batteriesCar exhaust fumesIndustrial solvent

Chemicals inTobacco Smoke1 Also Found In…

1. World Health Organization. Tobacco: deadly in any form or disguise, 2006. 2. Health Canada. What’s in Cigarette smoke?, August 2005.

Tobacco smoke: 4000 chemicals1, 50 carcinogenic2

Why Quit? Potential Lifetime Health Benefits of Quitting Smoking1-2

Why Quit? Potential Lifetime Health Benefits of Quitting Smoking1-2

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.

Lung function may start to improve with decreased cough, sinus

congestion, fatigue, and shortness of breath

3 m

on

ths

Lung cancer risk is 30-50% that of continuing smokers

Ce

ss

ati

on

CHD: excess risk is reduced by 50% among ex-smokers

Cardiovascular heart disease (CHD) risk is similar to never smokers

Stroke risk returns to the level of people who have never smoked at 5-15 years post-cessation

1 ye

ar

5 ye

ars

10 y

ears

15 y

ears

Tobacco Dependence MechanismsTobacco Dependence Mechanisms

Mechanism of Action of Nicotine in the Central Nervous System

Mechanism of Action of Nicotine in the Central Nervous System

Nicotine binds preferentially to nicotinic acetylcholine (nACh) receptors in the central nervous system; the primary is the α4β2 nACh receptor in the Ventral Tegmental Area (VTA)

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

4 2224

42Nicotinic Receptor

Foulds J. Int J Clin Pract 2006;60:571-576.

BRAIN STEMBRAIN STEMαα44ßß2 2 receptorsreceptors

FOREBRAINFOREBRAINDopamineDopamine


““Smokers smoke to maintain relative Smokers smoke to maintain relative constancy of nicotine, dopamine constancy of nicotine, dopamine and other neurotransmitter levels.”and other neurotransmitter levels.”


The Cycle of Nicotine AddictionThe Cycle of Nicotine Addiction

Nicotine binding causes an increase in dopamine release 1

Dopamine gives feelings of pleasure and 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

DopamineDopamine

NicotineNicotine

1. Foulds J. Int J Clin Pract 2006;60:571-576.2. Fagerstrom K. Drugs 2002;62(Suppl2):1-9.3. Jarvis MJ. BMJ 2004; 328:277-279.4. Rigotti NA. N Engl J Med 2002;346:506-512.

Quitting Smoking: May be a Protracted Journey

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

Only ~ 5% succeed without assistance1. Hughes JR. CA Cancer J Clin 2000;50:143-151.2. Anthenelli RM. Clin Neurosci Res 2005;5:175-183.3. Pfizer Canada Inc., Data on file. 2006.4. O'Donnell DE et al.Can Respir J 2004;11(SupplB):3B-59B.5. Fiore MC et al.JAMA 2002;288:1768-1771.

Tobacco Dependence and Environmental Reinforcement

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.

Withdrawal Syndrome: a Combination of Physical and Psychological Conditions,

Making Smoking Hard to Treat1,2

Withdrawal Syndrome: a Combination of Physical and Psychological Conditions,

Making Smoking Hard to Treat1,2

Restlessness or impatience

Increased appetite or weight gain

Withdrawal Syndrome

Anxiety

Dysphoric or depressed mood

Irritability, frustration, or anger

Difficulty concentrating

Insomnia/sleep disturbance

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.

Withdrawal Symptoms from Stopping SmokingWithdrawal Symptoms from Stopping Smoking

0 1 2 3 4 5 6 7 8 9 10

Duration (weeks)or more

Jarvis MJ. BMJ 2004;328:277-279.

Incidence

Increased appetite

Restlessness

Depression

Irritability/aggression

Craving for nicotine

Poor concentration

Sleep disturbance

Lightheadedness

70%

60%

60%

50%

70%

60%

25%

10%

0.0

0.5

1.0

1.5

1 2 3 4 5 6 7 8 9 10

1 2 3 4 5 6 7 8 9 10

Anxiety/Tension

Irritability/Anger

Excessive Hunger

Select Withdrawal Symptoms Over TimeSelect Withdrawal Symptoms Over Time

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.

Impatience

0.0

0.5

1.0

1.5

1 2 3 4 5 6 7 8 9 10

Placebo Nicotine Gum

Mea

n A

dju

sted

Wit

hd

raw

al S

core

Mea

n A

dju

sted

Wit

hd

raw

al S

core

Postcessation Weeks

0.0

0.5

1.0

1.5

0.0

0.5

1.0

1.5

1 2 3 4 5 6 7 8 9 10

Postcessation Weeks

Postcessation WeeksPostcessation Weeks

Stahl’s Essential Psychopharmacology, 3rd ed. 2008

Probability of Dependence After Trying a Substance at Least Once

Probability of Dependence After Trying a Substance at Least Once

Tobacco 32%

Heroin 23%

Cocaine 17%

Alcohol 15%

Stimulants 11%

Anxiolytics 9%

Cannabis 9%

Analgesics 8%

Inhalants 4%

Courtesy of Andrew Pipe, CM, MD, LLD(Hon), DSc(Hon)

Pharmacological Smoking Cessation Pharmacological Smoking Cessation Treatment ApproachesTreatment Approaches

Pharmacotherapy for Tobacco Dependence 1-4

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. O'Donnell DE et al.Can Respir J 2004;11(SupplB):3B-59B.2. Foulds J. Int J Clin Pract 2006;60:571-576.3. Challenge Quit to win. Pharmacological Aids. February 20, 2007.4. CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.

Medication # of arms

Estimated odds ratio (95% C.I.)

Estimated abstinence rate

(95% C.I.) Placebo 80 1.0 13.8

Monotherapies

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 both standard or long-term duration)

4 2.3 (1.7–3.0) 26.5 (21.3–32.5)

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)

aGo to www.surgeongeneral.gov/tobacco/gdlnrefs.htm for the articles used in this meta-analysisFiore MC et al. US Department of Health and Human Services. Public Health Service. May 2008.

Effectiveness and abstinence rates for various medications and medication combinations compared to placebo at 6-months postquit

(n = 83 studies)a

Effectiveness of smoking cessation interventions

Effectiveness of smoking cessation interventions

Comparison # studies # participants Pooled Odds Ratio (95% CI)

Non-pharmacological intervention

Self-help1

vs. no intervention11 >13,000 1.24 (1.07-1.45)

Individual counseling2

vs. minimal behaviour intervention21 >7,000 1.56 (1.32-1.84)

Physician advice3

vs. no advice17 >13,000 1.74 (1.48-2.05)

Group counseling4

vs. no intervention7 815 2.17 (1.37-3.45)

Pharmacological intervention

NRTs5,6

vs. control103 39,503 1.77 (1.66-1.88)

Bupropion SR7

vs. placebo19 >4,000 2.06 (1.77-2.40)

1. Lancaster T, Stead LF. Cochrane Database Syst Rev 2005;(3):CD001118.2. Lancaster T. Stead LF. Cochrane Database Syst Rev 2005;(2):CD001292.3. Lancaster T, Stead LF. Cochrane Database Syst Rev 2004;(4):CD000165.4. Stead LF, Lancaster T. Cochrane Database Syst Rev 2005;(4):CD001007.5. Silagy C et al. Cochrane Database Syst Rev 2004;(3):CD000146.6. Stead L, Lancaster T. Int J Epidemiol 2005;34:1001–1003.7. Hughes JR et al. Cochrane Database Syst Rev 2004;(4):CD000031.

Nicotine Replacement Therapy (NRT)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.

Nicotine Replacement Therapy (NRT): Nicotine Delivery by Cigarettes and NRT Products

Nicotine Replacement Therapy (NRT): Nicotine Delivery by Cigarettes and NRT Products

0

2

4

6

8

10

12

14

16

18

0 10 20 30 40 50 60 70 80 90 100 110 120

Cigarette (nicotine delivery, 1-2 mg)

Gum (nicotine delivery, 4 mg)

Nasal spray (nicotine delivery, 1 mg)

Transdermal patch

Time post-administration (minutes)

Plasma Nicotine Concentration (μg/L)

Sweeney CT et al. CNS Drugs 2001;15:453-467.

Efficacy of Nicotine Replacement Therapy (NRT)

Efficacy of Nicotine Replacement Therapy (NRT)

ComparisonTrials

(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)

Any NRT vs. control 110 43,040 1.58 (1.50–1.66)

Stead L et al. Cochrane Database Syst Rev. 2008; Jan 23(1):CD000146.

Bupropion SR (Zyban®)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 32 and 42 nicotine receptors4,5

PrZyban® 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.

Comparison of Nicotine Replacement Therapy (NRT) and Bupropion SR Therapy

for Quitting Smoking1

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)

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.

**

*p≤0.001 vs. placebo and patch alone

Bupropion SR for Tobacco Dependence

Bupropion SR for Tobacco Dependence

ComparisonTrials

(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)

†OR= odds ratio1. 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

Varenicline: An α4β2 Nicotinic Acetylcholine Receptor Partial Agonist and Antagonist

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.

C C C C C C C C C C C C C C T T C T T C T C T C

L 1 2 3 4 5 6 7 8 9 10 11 12 13 16 20 24 28 32 36 40 44 48 52W

Varenicline Comparative Studies Design1,2Varenicline Comparative Studies Design1,2

W W W W W W W W W W W WB W W W W W W W W W W

Treatment phase Non-treatment phase

Varenicline 1 mg BID†

Bupropion 150 mg BID†

Placebo

Screening visit

Baseline randomization Week 12 Week 52

RandomizationTwo identically designed Phase 3 efficacy trialsVarenicline 1.0 mg BID vs placebo orBupropion SR150 mg BID12 weeks of active treatment followed by40 weeks of non-pharmacologic follow-up

Target quit date

†Titrated during Week 1.BL = Baseline; W = Week;C = Clinic visit; T = Telephone contact

Treatment Period Non-pharmacological Follow-up

1. Gonzales D et al.JAMA 2006;296:47-55.2. Jorenby DE et al.JAMA 2006;296:56-63.

Varenicline Comparative Studies Primary/Secondary End Points

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.

Varenicline Comparative Studies 4-Week Continuous Quit Rates Weeks 9–121,2

Varenicline Comparative Studies 4-Week Continuous Quit Rates Weeks 9–121,2

50454035302520151050

50454035302520151050

Varenicline 1 mg BIDn=352

44.0%†

29.5%‡

17.7%

43.9%†

29.8%§

17.6%

Cont

inuo

us q

uit r

ate

Wee

k 9-

12 (%

)

Odds ratiovarenicline vs. placebo: 3.85; p<0.001varenicline vs. bupropion SR: 1.93; p<0.001

Odds ratiovarenicline vs. placebo: 3.85; p<0.001varenicline vs. bupropion SR: 1.90; p<0.001

†p<0.001 vs. bupro. and placebo

‡p<0.001 vs. placebo

Bupropion SR150 mg BID n=329

Placebon=344



Placebon=341

†p<0.001 vs. bupro. and placebo

§p=0.001 vs. placebo

Cont

inuo

us q

uit r

ate

Wee

k 9-

12 (%

)

Study 1/Gonzales et al.1 Study 2/Jorenby et al.2


Varenicline Comparative Studies Continuous Abstinence (CA) Rates Weeks 9–521,2

Varenicline Comparative Studies Continuous Abstinence (CA) Rates Weeks 9–521,2


21.9%†‡

16.1%§

8.4%

23.0%¶ ††

14.6%‡‡

10.3%

Cont

inuo

us a

bstin

ence

rate

Wee

k 9-

52 (%

)

Odds ratiovarenicline vs. placebo: 3.09; p<0.001varenicline vs. bupropion SR: 1.46; p=0.057

Odds ratiovarenicline vs. placebo: 2.66; p<0.001varenicline vs. bupropion SR: 1.77; p=0.004

† p=0.057 vs. bupropion SR

‡ p<0.001 vs. placebo

§p<0.001 vs. Placebo


Placebon=344



Placebon=341

Cont

inuo

us a

bstin

ence

rate

Wee

k 9-

52 (%

)

25

20

15

10

5

0

25

20

15

10

5

0

¶p=0.004 vs. bupropion SR

†† p<0.001 vs. placebo

‡‡p<0.08 vs. Placebo


Study 1/Gonzales et al.1 Study 2/Jorenby et al.2

Double-blindtreatment

Varenicline 1 mg BID

Placebo

Varenicline Maintenance of Abstinence (Extended Therapy) Study Design

Varenicline Maintenance of Abstinence (Extended Therapy) Study Design

WWWB W W W W W W W WWW W W W W W W W W W W W

321L 4 5 6 7 8 10 12 161413 20 24 25 26 28 32 36 40 44 48 50

CCCC C C C C C C C CCC C C C T C T C T C T C

Open-label phase Double-blind phaseNon-treatmentfollow-up phase

Varenicline 1 mg BID(titrated)

Baseline Week 12 Week 24 Week 52

Open-label treatment Non-pharmacologic follow-up(Double-blind)

RandomizationTarget quit date

Tonstad S et al.JAMA2006;296:64-71.

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)

BL = Baseline; W = Week;C = Clinic visit; T = Telephone contact

Varenicline Maintenance of Abstinence Study Primary/Secondary End Points

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.

Maintenance of Abstinence (Extended Therapy) in Quitters that had Previously Received

12 Weeks of Varenicline Therapy

Maintenance of Abstinence (Extended Therapy) in Quitters that had Previously Received

12 Weeks of Varenicline Therapy1210 subjects who quit after 12 weeks of varenicline treatment were then randomized to an additional 12 weeks.

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

OR: varenicline vs. placebo 2.48, p<0.001

†p<0.001 vs. placebo

Varenicline Maintenance ofVarenicline Maintenance ofAbstinence Study: Adverse EventsAbstinence Study: Adverse Events

Varenicline Maintenance ofVarenicline Maintenance ofAbstinence Study: Adverse EventsAbstinence Study: Adverse Events

Most Frequent AEs (Open-label Varenicline)

NauseaMildModerateSevere

Insomnia

Headache

Abnormal dreams

64545216231

377

304

276

33.570.125.14.8

19.6

15.8

14.3

Open label

Varenicline

n %

7520

16

17

6

1.2

2.7

2.8

1.0

Newly emerging – Double blind

Varenicline

n %

4400

17

12

0

0.7

2.8

2.0

0.0

Placebo

n %

Tonstad S et al. JAMA 2006;296:64-71.

Comparison of Pharmacological Interventions for Smoking Cessation

Comparison of Pharmacological Interventions for Smoking Cessation

NRTs vs. control Bupropion SRvs. placebo CHAMPIXvs. placebo CHAMPIXvs. bupropion SR CHAMPIXvs. NRT (all controls)

39,503 >4,000 2,023 1,622 NotApplicable

103 19 4 3 Indirect comparison

Pharmacological interventions

1.77 (1.66-1.88) 2.06 (1.77-2.40) 3.22 (2.43-4.27) 1.66 (1.28-2.16)

1.73 (1.22-2.45)

Comparison # studies # participants Pooled OddsRatio (95% CI)

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.

Long-Term Safety Study ConclusionsLong-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.

Varenicline SummaryVarenicline Summary

An innovative smoking cessation therapy believed to have simultaneous partial

agonist and antagonist activities at the 42 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

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.

PrZyban® is a registered trademark of the GlaxoSmithKline Group of Companies and is used by Biovail under license.

CHAMPIX (Varenicline) Indication and Dosing Information

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:Days 4 – 7:Day 8 – End of treatment:

0.5 mg once daily0.5 mg twice daily0.5 mg twice daily OR 1 mg twice daily

CHAMPIX Product Monograph, Pfizer Canada Inc., May 2010

Varenicline Safety Information 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

Discontinuation rate due to nausea was only 2.7% (vs. 0.6% for placebo)

NauseaAbnormal dreamsConstipationFlatulenceVomiting

16%9%5%9%1%

Adverse event

Varenicline 0.5 mg BIDn=129

30%13%

8%6%5%

Varenicline1.0 mg BIDn=821

10%5%3%3%2%

Placebon=805

CHAMPIX Product Monograph, Pfizer Canada Inc., January 2007.

CHAMPIX (Varenicline)Key Points to Keep in Mind:

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 treatment2-4

– 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.

Cost of ChampixCost of Champix

Starter pack (week 1 & 2): $42 Continuation: $47 One month: $94

Cigarettes (1 ppd) for 1 month: $261 - $287

Cardiovascular ConcernsCardiovascular 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.

Cardiovascular ConcernsCardiovascular 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%.

Cardiovascular ConcernCardiovascular 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%

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.

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


Model of Deaths Prevented or Postponed Through Risk-Factor Reduction

Model of Deaths Prevented or Postponed Through Risk-Factor Reduction

Coronary Heart Disease Deaths in England

Unal B et al.BMJ 2005;331:614.

Neuropsychiatric effects 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.

Neuropyschiatric AffectsNeuropyschiatric 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.

BC Smoking Cessation ProgramBC 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. prescription smoking cessation drugs or

2. non-prescription nicotine replacement therapy (NRT) products.

Patient eligibility criteriaPatient 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

Coverage DetailsCoverage 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).


Coverage details continued..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.


For More Information…For More Information…

Visit the Ministry of health website at www.health.gov.ca/pharmacare/stop-smoking/ for more information about the BC Smoking Cessation Program

Non-Pharmacological Smoking Cessation Non-Pharmacological Smoking Cessation Treatment ApproachesTreatment Approaches

A Comprehensive Approachto Smoking Cessation

A Comprehensive Approachto 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

Most effective methods of smoking cessation combine pharmacotherapy with advice and support 2,4

1. Jarvis MJ. BMJ 2004;328:277-279.2. Coleman T. BMJ 2004;328:397-399.3. Rigotti NA. N Engl J Med 2002;346:506-512.4. Hughes JR. CA Cancer J Clin 2000;50:143-151. 5. O'Donnell DE et al.Can Respir J 2004;11(SupplB):3B-59B.

Why May Some Smokers Need More Help to Quit ?

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.

Non-pharmacologic Approaches Advice and Support 1-3

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.

Office-based Strategies for Helping Patients Quit Smoking

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

1. Prochazka AV. Chest 2000;117(Suppl1):169S–175S. 2. Swartz SH, Hays JT. Med Clin North Am 2004;88:1623–1641.

““Make the most efficient use of time and resources”Make the most efficient use of time and resources”

Brief Tobacco InterventionUsing the 5 A’s

Brief Tobacco InterventionUsing the 5 A’s

Identify and document tobacco use

In a clear, strong, personalized manner, urge smoker to quit

Is the smoker ready to make a quit attempt?

Use counselling and pharmacotherapy to help him/her quit

Schedule follow-up contact– Preferably within 1 week after the quit date

Fiore MC et al. Effective tobacco dependence treatment. JAMA 2002;288:1768-1771

ASKASK

ADVISEADVISE

ASSESSASSESS

ASSISTASSIST

ARRANGEARRANGE

Baseline assessment of the smoking status: The Fagerström Test for Nicotine Dependence1,2

Baseline assessment of the smoking status: The Fagerström Test for Nicotine Dependence1,2

Questions Answers Points

1. How soon after you wake up do you smoke your first cigarette? After 60 minutes 0

31-60 minutes 1

6-30 minutes 2

Within 5 minutes 3

2. Do you find it difficult to refrain from smoking in places where it is forbidden? Yes 1

No 0

3. Which cigarette would you hate most to give up?

The 1st in the morning 1

All others 0

4. How many cigarettes per day do you smoke? 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

Dependence scores0-2 Very low 3-4 Low 5 Medium 6-7 High 8-10 Very high

1. Heatherton TF et al.Br J Addict 1991;86:1119-27.2. Heart and Stroke Foundation. The Fagerström Test for Nicotine Dependence.

The “5As”: Advise to QuitThe “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)

Fiore MC et al. US Department of Health and Human Services. Public Health Service. June 2000.

The “5As”: Assist in Quit AttemptThe “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


The “5As”: Arrange Follow-upThe “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


Smoking Cessation Effectiveness Increases with Treatment IntensitySmoking Cessation Effectiveness Increases with Treatment Intensity

Level of ContactNumber of

ArmsEstimated Odds Ratio (95% CI)

Estimated Abstinence Rate†

(95% CI)

No Contact30

1.010.9

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.

Meta-analysis (2000): Effectiveness of and estimated abstinence rates for various intensity levels of session length (n = 43 studies)a

a Go to www.surgeongeneral.gov/tobacco/gdlnrefs.htm for the articles used in this meta-analysis

smoking cessation presentation dr. tsui - abbotsford, june 6, 2012

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