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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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

-8

-7

-6

-5

-4

-3

-2

-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

-7

-6

-5

-4

-3

-2

-1

0

% c

ha

ng

e f

rom

bas

elin

e

0 4 8 12 16 20 24 28 32 36 40 44 48 52

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)

-8

-7

-6

-5

-4

-3

-2

-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


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


% 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



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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Actual Use Trial (AUT)Actual Use Trial (AUT) 20032003 Self-selectionSelf-selectionUsageUsage



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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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


Weight surveyWeight survey 20052005 Self-recognitionSelf-recognition

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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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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

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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

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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%

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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%

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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


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




Do people self-select appropriately?Do people self-select appropriately?




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








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








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


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


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)

%%


%%


%%


%%

< 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

Documents

CC-1 Orlistat OTC Joint Endocrinologic and Metabolic Drugs – Nonprescription Drugs Advisory Committee Meeting January 23, 2006