CC-1 Orlistat OTC Joint Endocrinologic and Metabolic Drugs – Nonprescription Drugs Advisory Committee Meeting January 23, 2006.
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Orlistat OTC
Joint Endocrinologic and Metabolic Drugs – Joint Endocrinologic and Metabolic Drugs – Nonprescription Drugs Advisory Committee MeetingNonprescription Drugs Advisory Committee Meeting
January 23, 2006January 23, 2006
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Orlistat for Over-the-Counter Use
John Dent, PhDGlaxoSmithKline
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Unmet Need – American Health CrisisOTC Target Population
64% overweight64% overweight11
$100 billion annual healthcare cost$100 billion annual healthcare cost22
34% trying to lose weight34% trying to lose weight3 3
1. National Center for Health Statistics (CDC), National Health and Nutrition Examination Survey.2. U.S. Food and Drug Administration Working Group on Obesity. “Counting Calories.”3. Mintel Weight Loss U.S. Report, April 2005.
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Orlistat Promotes Gradual, Sensible Weight Loss
Not a “magic pill”Not a “magic pill”
Targets people committed to losing weightTargets people committed to losing weight
Different from any other weight loss drugDifferent from any other weight loss drug
Works best with low-fat dietWorks best with low-fat diet
Consistent with NIH recommendationsConsistent with NIH recommendations
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Orlistat Development History
April 1983April 1983 Molecule synthesizedMolecule synthesized
Early 1998Early 1998 Launched in New Zealand Launched in New Zealand and and ArgentinaArgentina
Sept. 1998Sept. 1998 Launched in EULaunched in EU
April 1999April 1999 Approved in United StatesApproved in United States
June 2001June 2001 Roche begins OTC Roche begins OTC developmentdevelopment
April 2003April 2003 Roche conducts AUTRoche conducts AUT
July 2004July 2004 GSK licenses rights to GSK licenses rights to OTC orlistatOTC orlistat
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Orlistat Has Extensive Clinical & Post-Marketing History
More than 100 clinical studiesMore than 100 clinical studies
30,000 clinical trial patients30,000 clinical trial patients
Data in up to 4 years of treatmentData in up to 4 years of treatment
22 million people used orlistat 22 million people used orlistat
Available in more than 145 countriesAvailable in more than 145 countries
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Label: OTC Orlistat
Target User: Overweight adults Target User: Overweight adults
Dose: 60 mgDose: 60 mg
Directions: 1-2 capsules 3X a dayDirections: 1-2 capsules 3X a daywith meals containing fatwith meals containing fat
Indication: Weight lossIndication: Weight loss
Duration: Up to 6 monthsDuration: Up to 6 months
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Consumer Understanding of Overweight
Overweight defined as BMI between 25-29.9Overweight defined as BMI between 25-29.9
Obesity defined as BMI Obesity defined as BMI 3030
Consumers can’t calculate BMIConsumers can’t calculate BMI
Clinically obese consider themselves Clinically obese consider themselves overweight overweight
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“The OTC population can include a wide range of BMIs ranging from
slightly overweight to obese.”
FDA Minutes, Pre-NDA Meeting December 8, 2004
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Orlistat Development Program
Iterative process informed label developmentIterative process informed label development
Warning statements improvedWarning statements improved
Key communications stayed the sameKey communications stayed the same
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More Than a Pill… a Program
In-pack educational materialsIn-pack educational materials
Tailored, Web-based support programTailored, Web-based support program
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GSK Success with Behavioral Therapies
1996 nicotine replacement therapy (NRT) switch1996 nicotine replacement therapy (NRT) switch
Support program proven to enhance quit ratesSupport program proven to enhance quit rates
Successful program to manage potential risks Successful program to manage potential risks
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Agenda
Public Health Rationale Caroline Apovian, MDAssoc. Professor of Medicine/PediatricsBoston University School of Medicine
Safety & Efficacy Vidhu Bansal, PharmD Director of Medical Affairs GlaxoSmithKline
Consumer Behavior Saul Shiffman, PhDProfessor of Health Psychology University of
Pittsburgh
Consumer Education Steve BurtonVice-President of Weight Control
GlaxoSmithKline
Summary & Commitments John Dent, PhDSr. Vice-President CHRDGlaxoSmithKline
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Expert Consultants Joel S. Bennett, MD (Hematology)
Physician and Professor of MedicineDivision of Hematology-Oncology, University of Pennsylvania Hospital
Gary D. Foster, PhD (Weight Loss)Clinical Director of the Weight and Eating Disorders Program
University of Pennsylvania School of Medicine
Marsha D. Marcus, PhD (Eating Disorders)Chief of Eating Disorders and Behavioral MedicineWestern Psychiatric Institute & Clinic, University of Pittsburgh Medical Center
Ron Shapiro, MD (Transplant)Professor of Surgery, Director, Kidney, Pancreas, Islet TransplantationThomas E. Starzl Transplantation Institute,University of Pittsburgh School of Medicine
Holly R. Wyatt, MD (Obesity/Metabolism)National Program Director for the Centers for Obesity Research and EducationDenver, Colorado
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Caroline Apovian, MDCaroline Apovian, MD
Associate Professor of Medicine & Pediatrics, Associate Professor of Medicine & Pediatrics, Boston University School of MedicineBoston University School of Medicine
Director, Center for Nutrition & Weight Management, Director, Center for Nutrition & Weight Management, Boston Medical CenterBoston Medical Center
Co-Principal, New England Centers for Obesity Research & EducationCo-Principal, New England Centers for Obesity Research & Education
Vice Chair, Massachusetts Medical Society Committee on NutritionVice Chair, Massachusetts Medical Society Committee on Nutrition
The Public Health Need forFDA-Approved Weight Loss Tools
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Prevalence of Overweight and Obesity Among US Adults, Age 20-74 Years
JO Hill, HR Wyatt, GW Reed, JC Peters, Obesity and theEnvironment: Where do we go from here? Science 299:853-855 (2003).
Obese OverweightP
erce
nt
NHANES II1976-80
(n=11207)
NHANES III1988-94
(n=14468)
NHANES 1999
(n=1446)
NHANES III1999-2000(n=4115)
47
65
5661
0
10
20
30
40
50
60
70
80
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Risk of Developing Obesity Higher Than Previously Thought
Data are for people free of obesity at baseline.Vasan RS et al. Ann Intern Med. 2005;143:473-80.
10 20 300
YearsAd
jus
ted
cu
mu
lati
ve
inci
den
ce,
% o
bes
ity
0
10
20
30
40Men
10 20 300
Years
0
10
20
30
40Women
Age 30-34 y Age 40-44 y Age 50-54 y
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4
6
5
3
2
1
0<21 22 23 24 25 26 27 28 29 30
Low Levels of Overweight AssociatedWith Negative Health Consequences
WomenWomen MenMen
4
6
5
3
2
1
0<21 22 23 24 25 26 27 28 29 30
Body Mass Index (kg/m2)Body Mass Index (kg/m2)
Rel
ativ
e R
isk
Rel
ativ
e R
isk
Willett WC, et al.Willett WC, et al. N Engl J Med. N Engl J Med. 1999;341:427– 434.1999;341:427– 434.
CholelithiasisCholelithiasisType 2 diabetesType 2 diabetes HypertensionHypertension Coronary heart Coronary heart diseasedisease
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Even Small Weight Losses Have Positive Impact on Risk Factors
HbA1cHbA1c
HDL cholesterolHDL cholesterol
Blood pressureBlood pressure
TriglyceridesTriglycerides
Total cholesterolTotal cholesterol
5%-10% 5%-10% Weight LossWeight Loss
~~5% 5% Weight LossWeight Loss
1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753.2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278.3. Blackburn G. Obes Res. 1995;3(Suppl 2):211S-216S.4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270.
1
2
3
3
----
1
2
3
3
4
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Every 1 kg of Weight Loss Can Provide Improvements in Risk Factors
Change per kilogram Change per kilogram of weight lossof weight loss
MeanMean
MeasureMeasure % change% change
CholesterolCholesterol11 -0.99-0.99 -2.28 mg/dL-2.28 mg/dL
LDL cholesterolLDL cholesterol11 -0.68-0.68 -0.91 mg/dL-0.91 mg/dL
TriglyceridesTriglycerides11 -1.93-1.93 -1.54 mg/dL-1.54 mg/dL
HDL cholesterolHDL cholesterol11 0.150.15 0.07 mg/dL0.07 mg/dL
Systolic blood pressure*Systolic blood pressure*22 -0.49-0.49 -0.68 mm Hg-0.68 mm Hg
Diastolic blood pressureDiastolic blood pressure††22 -0.38-0.38 -0.34 mm Hg-0.34 mm Hg
* Baseline systolic blood pressure = 140 mm Hg.† Baseline diastolic blood pressure = 90 mm Hg.
1. Dattilo AM, Kris-Etherton PM. AM J Clin Nutr. 1992;56:320-8.2. MacMahon SW, Cutler J, Brittain E, Higgins M. Eur Heart J. 1987;8:57-70.
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Modest Weight Loss ImprovesQuality of Life Co-Morbidities
Sleep apneaSleep apnea11
OsteoarthritisOsteoarthritis22
GERDGERD33
Back painBack pain44
InfertilityInfertility55
Urinary incontinenceUrinary incontinence5,65,6
1. Grassi G, Facchini A, Trevano FQ et al. Hypertension 2005;46:321-5.2. Focht BC, Rejeski WJ, Ambrosius WT, Katula JA, Messier SP. Arthritis Rheum. 2005;53:659-65.3. Hampel H, Abraham NS, El Serag HB. Ann Intern Med. 2005;143:199-211.4. Liuke M, Solovieva S, Lamminen A et al. Int J Obes (Lond) 2005;29:903-8.5. Villareal DT, Apovian CM, Kushner RF, Klein S. Obes Res. 2005;13:1849-63.6. Dwyer PL, Lee ET, Hay DM. Br J Obstet Gynaecol. 1988;95:91-6.
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Even Small Amounts ofWeight Can Be Difficult to Lose
Staying motivated is a challengeStaying motivated is a challenge
Frustration can lead to giving upFrustration can lead to giving up
Result can be further weight gain, obesity Result can be further weight gain, obesity and co-morbiditiesand co-morbidities
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Most Overweight People Don’t See Physicians For Weight Management
People may be embarrassed to discuss People may be embarrassed to discuss overweight with doctoroverweight with doctor
Weight management often not coveredWeight management often not coveredby insuranceby insurance
Many people can’t afford doctor visitsMany people can’t afford doctor visits
In general, doctors not accustomed to In general, doctors not accustomed to counseling patients on weight management counseling patients on weight management
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U.S. Consumers Spend $1 Billion/YearOn Weight Control Drugs and Supplements
Source: Ipsos-Insight PharmTrends Report, 2004
$1 Billion Spent Annually
Herbal & Dietary
Supplements(DSHEA products)
Rx WeightControl
10% 90%
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The Lure of Unproven“Weight Loss” Supplements
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Summary and Conclusion
Overweight / obesity a growing epidemicOverweight / obesity a growing epidemic
Modest weight loss provides important Modest weight loss provides important benefitsbenefits
People rely on unproven non-prescription People rely on unproven non-prescription productsproducts
We need a wide variety of FDA-approved We need a wide variety of FDA-approved prescription and OTC weight loss tools prescription and OTC weight loss tools
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Safety and Efficacy Orlistat 60-120 mg
Vidhu Bansal, PharmDVidhu Bansal, PharmDDirector, Medical Affairs Director, Medical Affairs
GlaxoSmithKline GlaxoSmithKline
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Agenda
OverviewOverview EfficacyEfficacy– Mechanism of actionMechanism of action
– Efficacy of 120 mg doseEfficacy of 120 mg dose
– Efficacy of 60 mg doseEfficacy of 60 mg dose
– Improvements in risk factorsImprovements in risk factors
SafetySafety– TolerabilityTolerability
– Abuse/misuseAbuse/misuse
– Drug interactionsDrug interactions
ConclusionsConclusions
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60 mg Dose Meets Weight Loss Criterion
Orlistat 120 mg Rx dose FDA-approved in Orlistat 120 mg Rx dose FDA-approved in 1999 based on weight loss criterion1999 based on weight loss criterion
– Significantly greater proportion of subjects on Significantly greater proportion of subjects on 60 mg treatment achieved a 5% weight loss after 60 mg treatment achieved a 5% weight loss after one year, compared to placeboone year, compared to placebo
60 mg also meets this criterion at both60 mg also meets this criterion at both6 months and 1 year6 months and 1 year
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absorptionabsorption
Passes through GI Tract
Fat absorption blocked25-30%
Orlistat: A Unique Mechanism of Action
tryglyceridelipaseorlistatMonoglycerides
Small intestine wall
Fatty acids
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Orlistat Mechanism of ActionProvides Unique Benefits
Non-systemic actingNon-systemic acting
Non-CNS actingNon-CNS acting
Non-addictiveNon-addictive
No negative impact on cardiovascular systemNo negative impact on cardiovascular system
Minimally absorbedMinimally absorbed
No residual effectNo residual effect
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Orlistat Dose-Response Curve%
fec
al f
at e
xcre
tio
n
Orlistat dose (mg) tid
30 120 240 40060
60
50
40
30
20
10
0
Zhi J et al. Clin Pharmacol Ther 1994; 56: 82–85.
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60 mg Ideal Starting Dose for OTCStudy BM14150 – Dose Ranging Study
6 month randomized, double-blind, placebo-controlled, 6 month randomized, double-blind, placebo-controlled, multi-center, confirmatory dose ranging study multi-center, confirmatory dose ranging study
Weight Loss Results:Weight Loss Results:
Orlistat 60 mg is minimum effective doseOrlistat 60 mg is minimum effective dose
Dose tid NPlacebo-Subtracted
Weight Loss (kg) SE
P-value Active vs. Placebo
30 mg 122 - 0.95 0.59 p=0.106
60 mg 123 - 1.86 0.59 p=0.002
120 mg 120 - 2.55 0.60 p<0.001
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Orlistat 60 mg Controlled Clinical Studies
Study # LocationN
ITTDuration BMI Dose
BM14149 Europe 716 2 years 28-43 Plc, 60, 120 mg
NM14161 U.S. 635 2 years 30-43 Plc, 60, 120 mg
NM17247 U.S. 378 4 months 25-28 Plc, 60 mg
Total 1,729 25-43 Plc, 60, 120 mg
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Low Level of Interventionin Controlled Studies
Study #Dietary Instructions
and InterventionBehavioral
ModificationExercise
BM14149Counseling by dietitians 1X/month for first year
NoneSubjects advised to exercise
NM14161AHA adapted diet sheets
Subjects were offered 4 videos for viewing on their own
No formal counseling; subjects encouraged to walk more
NM17247Self-instructional materials
Self-instructional materials
Reading materials on exercise
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Low Level of Interventionin Controlled Studies
Study #Dietary Instructions
and InterventionBehavioral
ModificationExercise
BM14149Counseling by dietitians 1X/month for first year
NoneSubjects advised to exercise
NM14161AHA adapted diet sheets
Subjects were offered 4 videos for viewing on their own
No formal counseling; subjects encouraged to walk more
NM17247Self-instructional materials
Self-instructional materials
Reading materials on exercise
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Low Level of Interventionin Controlled Studies
Study #Dietary Instructions
and InterventionBehavioral
ModificationExercise
BM14149Counseling by dietitians 1X/month for first year
NoneSubjects advised to exercise
NM14161AHA adapted diet sheets
Subjects were offered 4 videos for viewing on their own
No formal counseling; subjects encouraged to walk more
NM17247Self-instructional materials
Self-instructional materials
Reading materials on exercise
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Design of Two Well-Controlled StudiesStudies NM14161 and BM14149
Placebo
Single-blind dietary lead-in period
Double-blind randomized treatment period
- 4 weeks 0 52 weeks
Orlistat 120 mg tid
Orlistat 60 mg tid Placebo
Hypocaloric Diet
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Orlistat + Diet Significantly More Weight Loss Than Placebo + Diet (BM14149)
-10
-9
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-1
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
% c
ha
ng
e f
rom
bas
elin
e
Placebo
60 mg tid
120 mg tid
Treatment week
Significant relative weight change from baseline at 6 months for 60 mg vs. placebo and 120 mg vs. placebo, P<0.001 - ITT population, observed data; mean +/-- SE
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Orlistat + Diet Significantly More Weight Loss Than Placebo + Diet (NM14161)
Placebo
60 mg tid
120 mg tid
-10
-9
-8
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-4
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-1
0
% c
ha
ng
e f
rom
bas
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Treatment week
Significant relative weight change from baseline at 6 months for 60 mg vs. placebo and 120 mg vs. placebo, P<0.001 - ITT population, observed data; mean +/-- SE
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Orlistat 60 mg is Effective at 6 Months (BM14149)
Treatment N
Weightloss SE
(kg)
Orlistat effect SE
(kg)
Responderrate (%)
Placebo 204 3.1 0.34 –– 30.9
60 mg tid 216 5.3 0.33 2.2* 0.46 54.6*
120 mg tid 221 5.6 0.33 2.5* 0.45 54.8*
*Significant difference with respect to placebo (P<0.05)responder: 5% weight loss from baseline to month 6
ITT, observed
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Orlistat 60 mg is Effectiveat 6 Months (NM14161)
*Significant difference with respect to placebo (P<0.05)responder: 5% weight loss from baseline to month 6
Treatment N
Weightloss SE
(kg)
Orlistat effect SE
(kg)
Responderrate (%)
Placebo 173 1.1 0.35 –– 21.3
60 mg tid 182 3.8 0.34 2.7* 0.48 37.7*
120 mg tid 178 4.6 0.34 3.5* 0.48 42.8*
ITT, observed
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Design of Lower BMI (25-28 BMI) Study(NM17247)
Placebo, N=195
Orlistat 60 mg tid, N=196
Double-blind randomized treatment period
0 16 weeks
Hypocaloric Diet
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Weight Loss Consistent With Pivotal Studies (NM17247)
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-3
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-1
0
0 4 8 12 16Treatment week
Rel
ativ
e ch
ang
e fr
om
bas
elin
e (%
)
Placebo
60 mg tid
* Significant relative weight change from baseline at 16 weeks for 60 mg vs. placebo,ITT population, observed data; mean +/-- SE
*P=0.002
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Orlistat 60 mg Improves Risk Factors at 4 Months in Overweight
* Significance from baseline at 4 months for 60 mg vs. placebo, p<0.05ITT population, observed data
Total-C LDL-C Systolic BP Diastolic BP
*
*
**
-6
-5
-4
-3
-2
-1
0
1%
ch
ang
e fr
om
ran
do
miz
atio
n
Placebo
60 mg tid
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60 mg and 120 mg Doses Achieve Criteria for Responder Analysis at 6 Months in Overweight and Obese Populations
BMI Treatment NResponder
rate (%)
26.7- 29.9 Placebo 28/83 33.7
60 mg tid 43/70 61.4*
120 mg tid 46/78 59.0*
30 Placebo 108/488 22.1
60 mg tid 188/505 37.2*
120 mg tid 218/493 44.2*
ITT, LOCF. Studies included: NM14161, BM14149, NM14150
* Significant difference with respect to placebo (P<0.05)Responder: 5% weight loss from baseline to month 6
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Orlistat Shows Significant and Consistent Weight Loss Across All Studies
Placebo 60 mg tid 120 mg tid
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24
Pooled BM14149 and NM14161
% c
han
ge
fro
m b
asel
ine
Study Week
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24
NM17247
% c
han
ge
fro
m b
asel
ine
Study Week
ITT population, observed data; mean +/-- SE
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Orlistat Has Well Established Safety Profile
Extensive clinical trial data and Extensive clinical trial data and post-marketing experiencepost-marketing experience
Overall good tolerabilityOverall good tolerability
Low withdrawal ratesLow withdrawal rates
Few drug interactionsFew drug interactions
Minimal impact on fat soluble vitaminsMinimal impact on fat soluble vitamins
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GI Side Effects Predictable and Manageable
6 Months
Placebo 60 mg tid 120 mg tid
Adverse event N=634 N=623 N=632
Fecal urgency 7.9% 18.8% 23.4%
Oily spotting 1.1% 17.7% 21.7%
Flatus with discharge 1.9% 17.3% 19.9%
Fatty/Oily stool 2.7% 17.2% 21.7%
Oily evacuation 0.6% 11.6% 13.4%
Increased defecation 2.7% 7.1% 8.2%
Fecal incontinence 0.8% 4.7% 7.8%
* Significantly different 60 mg compared 120 mg (p<0.05)
*
*
*
*
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Orlistat 60 mg vs. 120 mg
Advantages of 60 mg vs. 120 mg:Advantages of 60 mg vs. 120 mg:
– Fewer GI events with 60 mg doseFewer GI events with 60 mg dose
– Significantly lower chance of GI events in Significantly lower chance of GI events in first four weeks of treatment first four weeks of treatment
– One third fewer GI events within first week One third fewer GI events within first week
– Lower withdrawal rate due to GI events Lower withdrawal rate due to GI events
60 mg dose provides flexibility to potentially 60 mg dose provides flexibility to potentially enhance compliance enhance compliance
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Low Withdrawal Rates at 6 Months
0
5
10
15
20
25
Placebo 60 mg tid 120 mg tid
% o
f su
bje
cts
Non-AE Non-GI AE GI AE
19.7% 10.4% 10.8%
1.4%
1.8% 2.0%
0.8%
3.2%
5.4%
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Orlistat Has Low Potential for Misuse
No abuse liability No abuse liability
– Not centrally actingNot centrally acting
– No subjective effectNo subjective effect
Low misuse potentialLow misuse potential
– 4 published cases of misuse reported worldwide 4 published cases of misuse reported worldwide
– No published reports of misuse by anorexics/teensNo published reports of misuse by anorexics/teens
– No dose dependent effectNo dose dependent effect
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Rate of 2 Consecutive Below-NormalVitamin Levels in 6 Months of Treatment
* Significant difference between 60-mg and 120-mg doses; Fisher’s Exact Test at p<0.05
This analysis includes all U.S. Studies (NM14336, NM14161, and NM14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation
Placebo (%) 60 mg tid (%) 120 mg tid (%)
Vitamin A 3/580 (0.5) 1/203 (0.5) 15/962 (1.6)
Vitamin D 13/558 (2.3) 2/209 (1.0)* 50/954 (5.2)
Vitamin E 2/565 (0.4) 7/196 (3.6) 29/944 (3.1)
Beta-carotene 2/576 (0.3) 3/207 (1.4) 40/977 (4.1)
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WarningsDo not use • if you are taking cyclosporine (a drug given after organ transplant) • if you have been diagnosed with problems absorbing food• if you are allergic to any of the ingredients in orlistat capsules• if you are not overweight
Orlistat Has LowPotential for Drug Interactions
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Ask a doctor or pharmacist before use if you are • taking medicine for diabetes. Your medication dose may need to be adjusted during weight loss.• taking warfarin (blood thinning medicine)• taking other weight loss drugs
Orlistat Has LowPotential for Drug Interactions
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Summary
Orlistat 60 mg, 1-2 capsules tid:Orlistat 60 mg, 1-2 capsules tid:
Orlistat plus diet always significantly better Orlistat plus diet always significantly better than placebo and diet alonethan placebo and diet alone
Safety and tolerability suitable for OTCSafety and tolerability suitable for OTC
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Consumer Understanding and Use in OTC Setting
Saul Shiffman, PhD
Research Professor of Health Psychology and Pharmaceutical Sciences
University of Pittsburgh
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Key Consumer Behavior Questionsfor Appropriate OTC Use
Can people recognize the condition?Can people recognize the condition?
Do people understand the label?Do people understand the label?
Do people self-select appropriately? Do people self-select appropriately?
Do people use the product correctly?Do people use the product correctly?
Can people use the product safely?Can people use the product safely?
Are people satisfied with the product?Are people satisfied with the product?
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Summary: Key Consumer Behavior Questions for Appropriate OTC Use
People recognize overweightPeople recognize overweight
People understand the orlistat labelPeople understand the orlistat label
Self-selection for orlistat was initially poorSelf-selection for orlistat was initially poor
– Label changes improved self-selectionLabel changes improved self-selection
– Potential risk will be managed through programsPotential risk will be managed through programs
People used orlistat correctly, according to labelPeople used orlistat correctly, according to label
People used orlistat safelyPeople used orlistat safely
People lost weight and were satisfiedPeople lost weight and were satisfied
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Behavioral ResearchProgram for OTC Orlistat
StudyStudy TimingTiming ObjectiveObjective
Label Comp #1Label Comp #1 20022002 ComprehensionComprehension
Label Comp #2Label Comp #2 20022002 ComprehensionComprehensionSelf-selectionSelf-selection
Actual Use Trial (AUT)Actual Use Trial (AUT) 20032003 Self-selectionSelf-selectionUsageUsage
Label Comp #3Label Comp #3 20042004 ComprehensionComprehensionSelf-selectionSelf-selection
Label Comp #4Label Comp #4 20052005 ComprehensionComprehension
Cyclosporine self-selectionCyclosporine self-selection 20052005 Self-selectionSelf-selection
Warfarin self-selectionWarfarin self-selection 20052005 Self-selectionSelf-selection
Teen self-selection Teen self-selection 20052005 Self-selectionSelf-selection
Weight survey Weight survey 20052005 Self-recognitionSelf-recognition
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Behavioral ResearchProgram for OTC Orlistat
StudyStudy TimingTiming ObjectiveObjective
Label Comp #1Label Comp #1 20022002 ComprehensionComprehension
Label Comp #2Label Comp #2 20022002 ComprehensionComprehensionSelf-selectionSelf-selection
Actual Use Trial (AUT)Actual Use Trial (AUT) 20032003 Self-selectionSelf-selectionUsageUsage
Label Comp #3Label Comp #3 20042004 ComprehensionComprehensionSelf-selectionSelf-selection
Label Comp #4Label Comp #4 20052005 ComprehensionComprehension
Cyclosporine self-selectionCyclosporine self-selection 20052005 Self-selectionSelf-selection
Warfarin self-selectionWarfarin self-selection 20052005 Self-selectionSelf-selection
Teen self-selection Teen self-selection 20052005 Self-selectionSelf-selection
Weight survey Weight survey 20052005 Self-recognitionSelf-recognition
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Behavioral ResearchProgram for OTC Orlistat
StudyStudy TimingTiming ObjectiveObjective
Actual Use Trial (AUT)Actual Use Trial (AUT) 20032003
Self-selection in Self-selection in special populationsspecial populations
Focused self-selection Focused self-selection studies:studies:
- Cyclosporine users- Cyclosporine users- Warfarin users- Warfarin users- Teens- Teens
20052005
Self-selectionSelf-selectionUsageUsage
Label Comp #4Label Comp #4 20052005 ComprehensionComprehension
Weight surveyWeight survey 20052005 Self-recognitionSelf-recognition
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Key Consumer Behavior Questionsfor Appropriate OTC Use
Can people recognize the condition?Can people recognize the condition?
Do people understand the label?Do people understand the label?
Do people self-select appropriately? Do people self-select appropriately?
Do people use the product correctly?Do people use the product correctly?
Can people use the product safely?Can people use the product safely?
Are people satisfied with the product?Are people satisfied with the product?
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Self-Recognition: People Can Judge if They are Overweight
US random-digit dial survey, N=1,629 adultsUS random-digit dial survey, N=1,629 adults
– Roper Survey Center, University of Connecticut Roper Survey Center, University of Connecticut
Compare self-classified weight status vs. BMI Compare self-classified weight status vs. BMI
– Self-classified “overweight”Self-classified “overweight”
– BMI based on self-reported height, weightBMI based on self-reported height, weight
88% of consumers who consider themselves 88% of consumers who consider themselves overweight have BMI overweight have BMI 2525
– 11% BMI 20-2511% BMI 20-25
– 1% BMI <201% BMI <20
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Key Consumer Behavior Questionsfor Appropriate OTC Use
Can people recognize the condition?Can people recognize the condition?
Do people understand the label?Do people understand the label?
Do people self-select appropriately? Do people self-select appropriately?
Do people use the product correctly?Do people use the product correctly?
Can people use the product safely?Can people use the product safely?
Are people satisfied with the product?Are people satisfied with the product?
CC-66
Label Comprehension Study 4: Design
13 facilities, geographically dispersed 13 facilities, geographically dispersed
Presented with labelPresented with label
Presented with hypothetical usage scenarios, asked “okay” or Presented with hypothetical usage scenarios, asked “okay” or “not okay to use?” “not okay to use?”
Responses coded as correct, acceptable, incorrectResponses coded as correct, acceptable, incorrect
Study Population Study Population
– 304 general population (from mall intercept)304 general population (from mall intercept)
– 160 low literacy (from research databases)160 low literacy (from research databases)
– 18 years or older, English speaking, interested in weight loss18 years or older, English speaking, interested in weight loss
– 65% female, 62% White, 30% African-American, 65% female, 62% White, 30% African-American, 9% Hispanic9% Hispanic
CC-67
Label Comprehension Study 4: Objective
Assess consumers’ ability to understand key Assess consumers’ ability to understand key labeling communications on proposed labellabeling communications on proposed label
– Indication – Use Indication – Use
– Target populationTarget population
– Dosing directionsDosing directions
– Warnings – Warnings – Do Not UseDo Not Use and and Ask A DoctorAsk A Doctor
CC-68
Consumers Understand LabelIndication & Directions – LC#4
General General PopulationPopulation
N=304N=304Low LiteracyLow Literacy
N=160N=160
Indication & population
Used to lose weight 100% 100%
Not OK to use if not overweight 79% 78%
Directions for use
Recommended dosage 95% 91%
Maximum daily dose (6) 86% 67%
When to increase dose 89% 80%
Stop at 6 months 78% 74%
Diet & vitamins
Need to change diet 96% 93%
How to control GI effects 86% 69%
Take vitamin daily 93% 88%
Take vitamin 2 hrs from orlistat 79% 66%
CC-69
Consumers Understand Label Warnings – LC#4
General General PopulationPopulation
N=304N=304Low LiteracyLow Literacy
N=160N=160
Do not use
Using cyclosporine 96% 90%
Under 18 years 98% 98%
Problems absorbing food 92% 89%
Allergic to ingredients 99% 97%
Breast feeding 96% 93%
Ask a doctor (or pharmacist) if…
Taking warfarin 94% 93%
Had kidney stones 97% 97%
Had gallbladder problems 99% 97%
Taking medicine for diabetes 97% 96%
Taking other weight loss drug 98% 98%
CC-70
Key Consumer Behavior Questionsfor Appropriate OTC Use
Can people recognize the condition?Can people recognize the condition?
Do people understand the label?Do people understand the label?
Do people self-select appropriately? Do people self-select appropriately?
Do people use the product correctly?Do people use the product correctly?
Can people use the product safely?Can people use the product safely?
Are people satisfied with the product?Are people satisfied with the product?
CC-71
Actual Use Trial Design:Self-selection Phase
18 community pharmacies, geographically dispersed 18 community pharmacies, geographically dispersed
Recruited by in-pharmacy and newspaperRecruited by in-pharmacy and newspaperads for weight lossads for weight loss
Reviewed label, asked if appropriateReviewed label, asked if appropriate
Completed medical historyCompleted medical history
Asked to purchaseAsked to purchase
Evaluate by labeled conditionsEvaluate by labeled conditions
Inclusion: Age Inclusion: Age 1818
CC-72
Actual Use Trial Sample
79% female 79% female
Mean age: 45 yearsMean age: 45 years
Race:Race:
– 79% Caucasian79% Caucasian
– 6% African American6% African American
– 8% Hispanic8% Hispanic
– 6% Other6% Other
CC-73
Actual Use Trial Subject Disposition
681 evaluable681 evaluable
543 said “appropriate” 543 said “appropriate”
CC-74
Warnings on Actual Use Trial Label and Current Proposed Label
Warnings on Actual Use Trial Label
Actual Use Trial label only Current proposed label
More than 30 lbs to lose Allergic to ingredients
High blood pressure Medicine for diabetes
High cholesterol/triglycerides Other weight loss drugs
On a doctor recommended diet Gallbladder problems
Problems absorbing food
Warfarin
Cyclosporine
CC-75
Self-selection Results Among People with Exclusions
Percent of people who have label conditions Percent of people who have label conditions who make correct selection decisionswho make correct selection decisions
23% Actual Use Trial label23% Actual Use Trial label
29% current proposed label 29% current proposed label
CC-76
Self-selection Results AmongAll People Current Proposed Label
Exclusions & Self-Selection Status
N=681
No label exclusion, correct 560 82%
Exclusion, correct selection 35 5%
Exclusion, incorrect selection 86 13%18%
87%
CC-77
Percent Incorrect SelectorsCurrent Proposed Label
Percent Who Incorrectly Selected Orlistat
13%
Total N=681
n %
Allergic to ingredients 0 0
Other weight loss drugs 294.3
Gallbladder problems 152.2
Problems absorbing food 101.5
Medicine for diabetes 304.4
Warfarin 71.0
Cyclosporine 10.3
CC-78
Revised Cyclosporine Warning
Actual Use Trial Label
Proposed Label
CC-79
Cyclosporine Self-selection Study
Cyclosporine self-selection studyCyclosporine self-selection study
– Recruited transplant patients from national Recruited transplant patients from national consumer research panelconsumer research panel
– 46 cyclosporine users interested in 46 cyclosporine users interested in losing weightlosing weight
89% appropriately selected not to use89% appropriately selected not to use
Cyclosporine education/prevention programCyclosporine education/prevention program
CC-80
Revised Warfarin Warning
Actual Use Trial Label
Proposed Label
CC-81
Warfarin Self-selection Study
Warfarin self-selection studyWarfarin self-selection study
– Recruited warfarin users from clinical Recruited warfarin users from clinical databasesdatabases
– 54 warfarin interested in losing weight54 warfarin interested in losing weight
72% appropriately selected not to use72% appropriately selected not to use
Warfarin education/prevention programWarfarin education/prevention program
CC-82
Teens and Those Not Overweight
TeensTeens
Not overweightNot overweight
CC-83
Teen Recruitment
Teen self-selection study Teen self-selection study
Teens (14-17) interested in Teens (14-17) interested in weight lossweight loss
Recruitment in 8 cities via flyers Recruitment in 8 cities via flyers for weight loss for weight loss
Locations frequented by teens: Locations frequented by teens: teen-oriented mall stores (e.g., teen-oriented mall stores (e.g., Abercrombie, Hollister, Claire’s), Abercrombie, Hollister, Claire’s), video arcades, high schools, etc.video arcades, high schools, etc.
Recruited 147 teensRecruited 147 teens
CC-84
Teen Self-selection
147 ad respondents (14-17) shown package 147 ad respondents (14-17) shown package
– 59% appropriately selected not to use59% appropriately selected not to use
– 87% not interested in purchase 87% not interested in purchase
Of 13% interested in purchase:Of 13% interested in purchase:
67% overweight or at risk for overweight; 67% overweight or at risk for overweight; 8585thth percentile BMI percentile BMI
33% normal weight; 8533% normal weight; 85thth percentile BMI percentile BMI– 4% of those who responded to ads4% of those who responded to ads
0% underweight0% underweight
CC-85
“What Led You To Make That Decision?”Teens Who Incorrectly Selected Orlistat
““I want to lose just a small amount of weight and this seems I want to lose just a small amount of weight and this seems to be a sensible way to do it.”to be a sensible way to do it.”
““It’s because it’s for people who know you can’t just take a It’s because it’s for people who know you can’t just take a pill you have to diet as well.” pill you have to diet as well.”
““The box says the program helps you and teaches you to eat The box says the program helps you and teaches you to eat healthy foods in moderation. That’s good for losing or healthy foods in moderation. That’s good for losing or maintaining weight which is what I need for my life.”maintaining weight which is what I need for my life.”
““The label said that you have to follow a well balanced diet The label said that you have to follow a well balanced diet while using this product and I feel that I would be able to do while using this product and I feel that I would be able to do that.”that.”
CC-86
BMI Distribution of Orlistat Self-Selectors in Actual Use Trial
0
5
10
15
20
25
30
35
18.5 18.5-22 22-25 25-30 30-35 35
Baseline BMI (kg/m2)
% o
f su
bje
cts
(N=
543)
Under Normal Over Obese
CC-87
Key Consumer Behavior Questionsfor Appropriate OTC Use
Can people recognize the condition?Can people recognize the condition?
Do people understand the label?Do people understand the label?
Do people self-select appropriately?Do people self-select appropriately?
Do people use the product correctly?Do people use the product correctly?
Can people use the product safely?Can people use the product safely?
Are people satisfied with the product?Are people satisfied with the product?
CC-88
Actual Use Trial Design: Usage Phase
3 month open label 3 month open label
Required product purchaseRequired product purchase
Exclusions: Absolute ‘Do Not Use’ conditions, Exclusions: Absolute ‘Do Not Use’ conditions, pregnancy, under 18, prior use of orlistatpregnancy, under 18, prior use of orlistat
543 said “appropriate” 543 said “appropriate” 494 included494 included262 purchased262 purchased237 used and assessed237 used and assessed
CC-89
Actual Use Trial Design:Usage Phase Procedures
Dispensing Dispensing
– Orlistat + behavioral materialsOrlistat + behavioral materials
– No instruction/counselingNo instruction/counseling Data collection by phone Data collection by phone
– Days 14, 30, 60, 90Days 14, 30, 60, 90 Usage patternsUsage patterns
– AEsAEs
– Weight lossWeight loss
– SatisfactionSatisfaction Duration of useDuration of use
– Median 77.5 daysMedian 77.5 days
– 46% still using at 90 days46% still using at 90 days
CC-90
Consumers Took Orlistat 2-3 Times a Day
0
10
20
30
40
50
60
70
0 1 2 3 4+Occasions per day
% o
f su
bje
cts
Day 14 (N=217) Day 90 (N=148)
95% took 95% took orlistat orlistat
with mealswith meals
CC-91
Consumers Took 1-2 Capsules per Occasion
0
10
20
30
40
50
60
70
80
0 1 2 3+Capsules per occasion
% o
f su
bje
cts
Day 14 (N=217) Day 90 (N=148)
CC-92
Consumers FollowedLabel Recommendations
74% took multivitamin during study74% took multivitamin during study
87% followed a diet 87% followed a diet
– 74% followed a low fat diet 74% followed a low fat diet
– 90% “successful” following diet90% “successful” following diet
51% exercised more51% exercised more
79% used weight loss materials79% used weight loss materials
– 80% rated materials as useful80% rated materials as useful
CC-93
Key Consumer Behavior Questionsfor Appropriate OTC Use
Can people recognize the condition?Can people recognize the condition?
Do people understand the label?Do people understand the label?
Do people self-select appropriately? Do people self-select appropriately?
Do people use the product correctly?Do people use the product correctly?
Can people use the product safely?Can people use the product safely?
Are people satisfied with the product?Are people satisfied with the product?
CC-94
Consumers Use Orlistat Safelyand Tolerate Side Effects
Safety population = 284Safety population = 284
SAEsSAEs
– 4 unrelated, resolved4 unrelated, resolved
Urinary tract infection (2), syncope, pregnancy with Urinary tract infection (2), syncope, pregnancy with miscarriagemiscarriage
– 2 possibly related, resolved without consequence2 possibly related, resolved without consequence
Esophageal spasmEsophageal spasm
Abdominal painAbdominal pain
15% discontinued due to AEs15% discontinued due to AEs
72% had AE72% had AE
50% had defecation pattern changes50% had defecation pattern changes
CC-95
Users Managed Orlistat-specific GI Effects
No orlistat-specificGI effects
50%Discontinue
9%
Continue
33%Interrupt
8%
CC-96
Key Consumer Behavior Questionsfor Appropriate OTC Use
Can people recognize the condition?Can people recognize the condition?
Do people understand the label?Do people understand the label?
Do people self-select appropriately? Do people self-select appropriately?
Do people use the product correctly?Do people use the product correctly?
Can people use the product safely?Can people use the product safely?
Are people satisfied with the product?Are people satisfied with the product?
CC-97
Users Are Satisfied with Orlistat
Interviewed Day 30 (N=219)Interviewed Day 30 (N=219)
– 74% reported losing weight74% reported losing weight
– 5 lbs. median self-reported weight loss 5 lbs. median self-reported weight loss
– 83% satisfied or very satisfied with orlistat83% satisfied or very satisfied with orlistat
Interviewed Day 90 (N=148)Interviewed Day 90 (N=148)
– 91% reported losing weight91% reported losing weight
– 10 lbs. median self-reported weight loss 10 lbs. median self-reported weight loss
– 81% satisfied or very satisfied with orlistat81% satisfied or very satisfied with orlistat
CC-98
Summary: Key Consumer Behavior Questions for Appropriate OTC Use
People recognize overweightPeople recognize overweight
People understand the orlistat labelPeople understand the orlistat label
Self-selection was initially poor in AUTSelf-selection was initially poor in AUT
– Label changes improved self-selectionLabel changes improved self-selection
– Potential risk will be managed through programsPotential risk will be managed through programs
People used orlistat correctly, according to labelPeople used orlistat correctly, according to label
People used orlistat safelyPeople used orlistat safely
People lost weight and were satisfiedPeople lost weight and were satisfied
CC-99
Orlistat’s Consumer Education and Behavioral Support Program
Steve BurtonVice-President of Weight Control
GlaxoSmithKline
CC-100
OTC Orlistat – Need for Candid Communications
GSK is committed to a program that helps GSK is committed to a program that helps people adopt a healthy eating planpeople adopt a healthy eating plan
Set realistic expectations – gradualSet realistic expectations – gradualweight lossweight loss
Promote low-fat diet to manage Promote low-fat diet to manage treatment effectstreatment effects
Encourage other lifestyle changes, Encourage other lifestyle changes, e.g., exercisee.g., exercise
CC-101
OTC Orlistat: More Than a Pill…It’s a Program
CC-102
Behavioral Support with Purchase
CC-103
Additional Behavioral Support Online
Weight Losswith Orlistat
Maintenancewithout Orlistat
First 6 months Second 6 months
Online Support for 1 Year
+
CC-104
Additional Behavioral Support Online
Weight Losswith Orlistat
Maintenancewithout Orlistat
First 6 months Second 6 months
Online Support for 1 Year
Customized Weight Loss Plan
Weekly Monitoring
Customized Exercise Plan
Monthly Follow-Up
Weight
Calories/Fat
Treatment Effects
Label Heeding
Rx Drug Use Surveillance& Follow-Up
Multivitamin Use
Exercise
Diet Reminder
Multivitamin Use
Weight
CC-105
Engaging the Healthcare Professional
Help HCP become Help HCP become more engaged more engaged
– PhysiciansPhysicians
– PharmacistsPharmacists
– NursesNurses
– DietitiansDietitians
Provide tools and Provide tools and resources to HCPsresources to HCPs
– Counseling kits
– Patient leaflets
– Continuing education
– HCP website
CC-106
GSK’s Commitments in Smoking Control
Surveillance programs in place up to 6 years Surveillance programs in place up to 6 years after the switch to OTC statusafter the switch to OTC status
– Surveillance to detect signals of misuse/abuseSurveillance to detect signals of misuse/abuse
– Quarterly reports and extra measures deemed Quarterly reports and extra measures deemed unnecessary after 6 yearsunnecessary after 6 years
– Continue to monitor/report as like other OTCsContinue to monitor/report as like other OTCs
CC-107
Summary
Promote healthy behavior change and be Promote healthy behavior change and be candid about what to expect from orlistatcandid about what to expect from orlistat
Education and behavioral support to help Education and behavioral support to help sustain lifestyle changes sustain lifestyle changes
A new treatment option that can improve the A new treatment option that can improve the health and well-being of overweight adultshealth and well-being of overweight adults
CC-108
Summary and Proposed CommitmentsOrlistat OTC
John Dent, PhDJohn Dent, PhD
GlaxoSmithKlineGlaxoSmithKline
CC-109
Cyclosporine and Warfarin Safety Nets
Enhanced warnings on labelEnhanced warnings on label
Targeted educational outreach to pharmacistsTargeted educational outreach to pharmacists
Orlistat warning stickers on warfarinOrlistat warning stickers on warfarinand cyclosporine bottles and cyclosporine bottles
Educational materials at patient discharge Educational materials at patient discharge
CC-110
Responsible Marketingto Committed Adults
Marketing orlistat as a program, not a pillMarketing orlistat as a program, not a pill
Ensuring consumers understand importance Ensuring consumers understand importance of behavior changeof behavior change
Advertising through age-appropriate mediaAdvertising through age-appropriate media
CC-111
Orlistat Unlike Any Other Weight Loss Drug
Non-systemicNon-systemic
Minimally absorbedMinimally absorbed
Not CNS-actingNot CNS-acting
No negative effects on cardiovascular systemNo negative effects on cardiovascular system
Not addictiveNot addictive
Not an appetite suppressantNot an appetite suppressant
Not a stimulantNot a stimulant
CC-112
Orlistat Summary
Reduces absorption of fat caloriesReduces absorption of fat calories
Clinically proven, safe and effective Clinically proven, safe and effective
Provides effective weight loss Provides effective weight loss
Consumers use safely and are satisfied Consumers use safely and are satisfied
Benefit outweighs potential riskBenefit outweighs potential risk
CC-113
Conclusion
Orlistat 60 mg is an appropriate Orlistat 60 mg is an appropriate
OTC weight loss aidOTC weight loss aid
CC-114
Backups Shown
CC-115
Mean Percent Change from Baseline Body Weight, LOCF – ITT Population, XENDOS
Ch
ang
e in
wei
gh
t (k
g)*
26 156 2080
-12
0
-10
-6
-2
-4
-8
Week
52 78 104 130 182
-4.1 kg
-6.9 kg
p<0.001
Placebo + lifestyle Orlistat + lifestyle
*Mean ± SEM
JH-25
CC-116
Effect of Orlistat on Fat-soluble Vitamin Levels
Vitamin D 25-hydroxy
Vitamin D 1, 25-dihydroxy
0
20
40
60
80
100
120
140
BL 6 12 18 24 30 36 40 48
Months
Placebo
120 mg tid
nm
ol/
L
0
40
80
120
160
200
BL 6 12 18 24 30 36 40 48
Months
pm
ol/
L
JH-6
CC-117
Vitamin D Metabolism
NN25-OHD25-OHD(ng/ml)(ng/ml)
1,25 (OH)1,25 (OH)22DD(pg/ml)(pg/ml)
PTHPTH(pg/ml)(pg/ml)
ObeseObese 1212 88 3737 518518
Non-obeseNon-obese 1414 2020 2929 243243
P-valueP-value <0.001<0.001 <0.01<0.01 <0.001<0.001
From Bell, et al. JCI, 76, 1985.
JH-44
CC-118
Effect of Orlistat on Fat-soluble Vitamin Levels
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
BL 6 12 18 24 30 36 40 48
μm
ol/L
Months
Vitamin A Placebo
120 mg tid
Vitamin K1
Placebo
120 mg tid
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
BL 6 12 18 24 30 36 40 48
Months
nm
ol/L
JH-7
CC-119
Labels for BMI Research
AT-286
CC-120
Results of BMI Research –Target Population
Across all 4 BMI labels, <45% consumers Across all 4 BMI labels, <45% consumers correctly reported BMIcorrectly reported BMI11
1 For those respondents whose BMI was included in the chart.
AT-287
CC-121
XENDOS Study: Marked Laboratory Abnormalities in Bone Markers
ParameterParameterYear 1Year 1 Year 2Year 2 Year 3Year 3 Year 4Year 4
NN nn %% NN nn %% NN nn %% NN nn %%
Calcium Calcium LowLow
PlaceboPlacebo
OrlistatOrlistat
16551655
16491649
33
22
(0.2)(0.2)
(0.1)(0.1)
12681268
14771477
00
22
(0.0)(0.0)
(0.1)(0.1)
992992
12911291
00
00
(0.0)(0.0)
(0.0)(0.0)
636636
958958
00
11
(0.0)(0.0)
(0.1)(0.1)
Parathyroid Parathyroid hormone hormone HighHigh
PlaceboPlacebo
OrlistatOrlistat
16551655
16491649
66
22
(0.4)(0.4)
(0.1)(0.1)
12681268
14771477
1010
77
(0.8)(0.8)
(0.5)(0.5)
992992
12911291
1313
2121
(1.3)(1.3)
(1.6)(1.6)
636636
958958
1515
1919
(2.4)(2.4)
(2.0)(2.0)
Osteocalcin Osteocalcin HighHigh
PlaceboPlacebo
OrlistatOrlistat
16551655
16491649
11
00
(0.1)(0.1)
(0.0)(0.0)
12681268
14771477
11
11
(0.1)(0.1)
(0.1)(0.1)
992992
12911291
11
22
(0.1)(0.1)
(0.2)(0.2)
636636
958958
11
00
(0.2)(0.2)
(0.0)(0.0)
Urine N-T Urine N-T HighHigh
PlaceboPlacebo
OrlistatOrlistat
16551655
16491649
33
77
(0.2)(0.2)
(0.4)(0.4)
12681268
14771477
55
55
(0.4)(0.4)
(0.3)(0.3)
992992
12911291
22
00
(0.2)(0.2)
(0.0)(0.0)
636636
958958
33
44
(0.5)(0.5)
(0.4)(0.4)
JH-25
CC-122
XENDOS Study: Bone Mineral Density (g/cm2)
NN MeanMean SDSD MedianMedian
PlaceboPlacebo Day 1Day 1 7777 1.241.24 0.070.07 1.241.24
Year 1Year 1 5454 1.251.25 0.070.07 1.241.24
Year 2Year 2 5555 1.261.26 0.070.07 1.261.26
Year 3Year 3 5555 1.261.26 0.070.07 1.261.26
Year 4Year 4 5555 1.261.26 0.070.07 1.251.25
OrlistatOrlistat Day 1Day 1 7272 1.251.25 0.070.07 1.241.24
Year 1Year 1 6565 1.241.24 0.080.08 1.241.24
Year 2Year 2 6565 1.261.26 0.070.07 1.261.26
Year 3Year 3 6565 1.261.26 0.070.07 1.251.25
Year 4Year 4 6565 1.261.26 0.070.07 1.251.25
JH-27
CC-123
Serum 25-OH Vitamin D Levels in Post-menopausal Women Not Receiving Estrogen Replacement Therapy
Placebo(n=29)
120 mg(n=59) p-value
Baseline serum 25-OH vitamin D ± SD (nmol/L)
52.5 ± 26.5 52.6 ± 20.4
2-year change from baseline ± SD (nmol/L)
-5.5 ± 14.1 -8.6 ± 24.1 NS
Incidence of 2 consecutive low serum 25-OH vitamin D values (%)
14.3% 8.7% NS
JH-43
PH-124
Intermittent vs. Continuous Weight Loss Therapy Intermittent vs. Continuous Weight Loss Therapy Provide Comparable EfficacyProvide Comparable Efficacy
Wirth A, Krause J. Long-term weight loss with sibutramine: a randomized controlled trial. Jama. 2001;286:1331-1339.
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 4 8 12 16 20 24 28 32 36 40 44 48
Randomized Treatment
Ch
an
ge
in
Bo
dy
We
igh
t (k
g)
Run-in
Week
Placebo (n=201)
Intermittent Sibutramine Therapy (n=395)
Continuous Sibutramine Therapy (n=405)
All Patients (n=1001)
PH-43
EF-125
Orlistat Shows Significant and Consistent Orlistat Shows Significant and Consistent Weight Loss Across All Studies Weight Loss Across All Studies
-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24-10
-8
-6
-4
-2
0
0 4 8 12 16 20 24
Placebo 60 mg tid 120 mg tid
Pooled BM14149 and NM14161 NM17247
% C
han
ge
Fro
m B
asel
ine
% C
han
ge
Fro
m B
asel
ine
Study Week Study Week
ITT population, observed data; mean ± SE.EF-20
EF-126
3% Weight Loss at 4 Months is Predictive of 5% 3% Weight Loss at 4 Months is Predictive of 5% Weight Loss at 6 Months – NM14161, BM14149Weight Loss at 6 Months – NM14161, BM14149
76.3% of subjects who lost 76.3% of subjects who lost 3% of their body 3% of their body weight at 4 months also lost weight at 4 months also lost 5% of their body 5% of their body weight at 6 months weight at 6 months
These data confirm that weight loss of These data confirm that weight loss of 3% at 3% at months is a strong predictor of achieving a months is a strong predictor of achieving a weight loss of weight loss of 5% at 6 months 5% at 6 months
EF-23
EF-127
Relative Weight Change at 4 Months Predicts Relative Relative Weight Change at 4 Months Predicts Relative Weight Change at 6 Months for Orlistat 60 mg tidWeight Change at 6 Months for Orlistat 60 mg tid
N = 385Radj
2 = 0.81ITT Population, observed dataStudies: BM14149, NM14161
EF-24
AT-128AT-81
PrevalencePrevalence of Exclusions on Actual Use Trial of Exclusions on Actual Use Trial Label & Current Proposed LabelLabel & Current Proposed Label
Actual Use Trial Label
N=681
68%Actual Use Trial label only
50%
Current Proposed Label
18% n % n %
More than 30 lbs to lose 346 51Allergic to ingredients 0
0
High blood pressure 166 24 Other weight loss drugs 33 5
High cholesterol/triglycerides 147 22
Gallbladder problems 25 4
On a doctor recommended diet 48 7 Problems absorbing food 12 2
Medicine for diabetes 46 7
Warfarin 14 2
Cyclosporine 2 <1
AT-129
Detailed Description of Level of Detailed Description of Level of Intervention in Controlled StudiesIntervention in Controlled Studies
Study #Written diary
guidanceInteractions
with dietitiansDiet diary provided
Review of diet diary with
patient
Informational material on
exercise
BM14149
NM14161
NM17247
AUT and OTC Material
EF-41
AT-130
Low Cyclosporine Level – Medical OutcomeLow Cyclosporine Level – Medical OutcomePost-marketing Experience from Roche WW Safety DatabasePost-marketing Experience from Roche WW Safety Database
29,333 Total Cases in Roche WW Database Through 11/05
44 reports with cyclosporine as co-suspect or concomitant
38 Low cyclosporine levels
2 Documented changein graft status
35 No changein graft status
1 Not in transplant patient (Nephrotic Syndrome)
NH-3
AT-131
Few Marketed Drugs with Log P Few Marketed Drugs with Log P 6.56.5
Drug Log P
Astemizole 6.4
Atovaquone 6.4
Isotretinoin 7.9
Phytonadione 11
Terfenadine 7.7
Halofantrine 8.5
Amiodarone 8.9
Probucol 10.9
Cyclosporine 14.4
JB-24
AT-132CL-5
Quick StartQuick Start
AT-133CL-11
Treatment EffectsTreatment Effects
AT-134
Variations from Typical Dosing Patterns – Variations from Typical Dosing Patterns – Users GroupUsers Group
Were there times when you took fewer/more capsules at a time?Were there periods when you did not use the medicine?
Users Group (N=237)Users Group (N=237)
Day 14 Day 14 InterviewInterview(N=217)(N=217)
%%
Day 30 Day 30 InterviewInterview(N=219)(N=219)
%%
Day 60 Day 60 InterviewInterview(N=197)(N=197)
%%
Day 90 Day 90 InterviewInterview(N=148)(N=148)
%%
< Average< Average 50.750.7 57.157.1 51.851.8 50.050.0
> Average> Average 24.424.4 26.926.9 30.530.5 28.428.4
Times not usedTimes not used 46.546.5 5353 68.568.5 67.667.6
MissingMissing 11 22 22 33
AT-128
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