Nonprescription Orlistat GlaxoSmithKline Consumer Healthcare, Ltd New Drug Application (21-887) Joint Nonprescription Drugs Advisory Committee and Endocrinologic.

Nonprescription OrlistatNonprescription OrlistatGlaxoSmithKline Consumer Healthcare, LtdGlaxoSmithKline Consumer Healthcare, Ltd

New Drug Application (21-887)New Drug Application (21-887)

Nonprescription OrlistatNonprescription OrlistatGlaxoSmithKline Consumer Healthcare, LtdGlaxoSmithKline Consumer Healthcare, Ltd

New Drug Application (21-887)New Drug Application (21-887)

Joint Nonprescription Drugs Advisory Committee and Joint Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee Endocrinologic and Metabolic Drugs Advisory Committee MeetingMeeting

Bethesda, MarylandBethesda, MarylandJanuary 23, 2006January 23, 2006

Julie Golden, M.D. Julie Golden, M.D. Division of Metabolic and Endocrine ProductsDivision of Metabolic and Endocrine Products

Joint Nonprescription Drugs Advisory Committee and Joint Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee Endocrinologic and Metabolic Drugs Advisory Committee MeetingMeeting

Bethesda, MarylandBethesda, MarylandJanuary 23, 2006January 23, 2006

Julie Golden, M.D. Julie Golden, M.D. Division of Metabolic and Endocrine ProductsDivision of Metabolic and Endocrine Products

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Joint Nonprescription Drugs and Endocrinologic and Joint Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee Meeting Metabolic Drugs Advisory Committee Meeting January 23, 2006

OutlineOutline

• Background• Studies reviewed• Efficacy considerations• Safety considerations • Conclusions

• Background• Studies reviewed• Efficacy considerations• Safety considerations • Conclusions


BackgroundBackgroundBackgroundBackground


Definitions: Overweight and ObesityDefinitions: Overweight and ObesityDefinitions: Overweight and ObesityDefinitions: Overweight and Obesity

• Normal weight: BMI 18.5 – 24.9 kg/m²• Overweight: BMI 25 – 29.9 kg/m² • Obese: BMI > 30 kg/m²• Morbidly obese: BMI > 40 kg/m²

• For this application:– Low overweight: BMI 25 – < 28 kg/m²– High overweight: BMI 28 – 29.9 kg/m²

• Normal weight: BMI 18.5 – 24.9 kg/m²• Overweight: BMI 25 – 29.9 kg/m² • Obese: BMI > 30 kg/m²• Morbidly obese: BMI > 40 kg/m²

• For this application:– Low overweight: BMI 25 – < 28 kg/m²– High overweight: BMI 28 – 29.9 kg/m²


Orlistat LabelOrlistat LabelNonprescription vs. PrescriptionNonprescription vs. Prescription

Orlistat LabelOrlistat LabelNonprescription vs. PrescriptionNonprescription vs. Prescription

NonprescriptionGSK

PrescriptionRoche

Indication Promotion of weight loss when used along with a reduced calorie and low fat diet

Obesity management including weight loss, weight maintenance, and prevention of weight regain when used in conjunction with a reduced-calorie diet

Population “Overweight” (defined by the consumer)≥ 18 yo

Obese (BMI ≥ 30 kg/m²) orBMI ≥ 27 kg/m² + other risk factors (e.g., HTN, DM, dyslipidemia)≥ 18 yo; 12-16 yo

Duration of use Up to 6 mos Chronic (clinical data up to 4 yrs)

Dose 60 mg; 1-2 capsules TID 120 mg TID


National Institutes of Health’s 2000 National Institutes of Health’s 2000 Practical Practical Guide: Identification, Evaluation, and Guide: Identification, Evaluation, and

Treatment of Overweight and Obesity in Treatment of Overweight and Obesity in AdultsAdults

National Institutes of Health’s 2000 National Institutes of Health’s 2000 Practical Practical Guide: Identification, Evaluation, and Guide: Identification, Evaluation, and

Treatment of Overweight and Obesity in Treatment of Overweight and Obesity in AdultsAdults

• Weight loss through diet and exercise– Obese – Overweight + comorbidities– High-risk waist circumference + comorbidities

• Pharmacotherapy– Only if lifestyle changes do not promote weight

loss after 6 months• Obese (≥ 30 kg/m²)• BMI ≥ 27 kg/m² + comorbidities

• Weight loss through diet and exercise– Obese – Overweight + comorbidities– High-risk waist circumference + comorbidities

• Pharmacotherapy– Only if lifestyle changes do not promote weight

loss after 6 months• Obese (≥ 30 kg/m²)• BMI ≥ 27 kg/m² + comorbidities


FDA’s Efficacy Criteria of FDA’s Efficacy Criteria of Prescription Weight-Loss DrugsPrescription Weight-Loss Drugs

FDA’s Efficacy Criteria of FDA’s Efficacy Criteria of Prescription Weight-Loss DrugsPrescription Weight-Loss Drugs

• Mean % weight loss (drug group) – mean % weight loss (placebo group) ≥ 5%, OR

• The proportion of subjects who reach and maintain a loss ≥ 5% of baseline body weight is statistically greater in drug group vs. placebo group

• Mean % weight loss (drug group) – mean % weight loss (placebo group) ≥ 5%, OR

• The proportion of subjects who reach and maintain a loss ≥ 5% of baseline body weight is statistically greater in drug group vs. placebo group

FDA 1996 Draft Guidance for the Clinical Evaluation of Weight-Control Drugs


How Orlistat WorksHow Orlistat WorksHow Orlistat WorksHow Orlistat Works• Pharmacodynamic Effect

– Orlistat 60 mg = ~25% fecal fat excretion– Orlistat 120 mg = ~30% fecal fat excretion

• Behavioral Modification Effect– Claim: patients favorably modify their diet due to

GI side effects– Patients may also decrease drug use because of

side effects

• The incidence of GI side effects is similar across different amounts of weight loss– Consume more fat: drug effect– Consume less fat: dietary/behavioral effect

• Pharmacodynamic Effect– Orlistat 60 mg = ~25% fecal fat excretion– Orlistat 120 mg = ~30% fecal fat excretion

• Behavioral Modification Effect– Claim: patients favorably modify their diet due to

GI side effects– Patients may also decrease drug use because of

side effects

• The incidence of GI side effects is similar across different amounts of weight loss– Consume more fat: drug effect– Consume less fat: dietary/behavioral effect


EfficacyEfficacyEfficacyEfficacy


Efficacy StudiesEfficacy StudiesEfficacy StudiesEfficacy Studies4

wee

ks

2 years

6 months1 year

Randomization Rx efficacy (weight maintenance)endpoint

Rx efficacy (weight loss) endpoint

NonRx efficacy endpoint

4 months

NonRx efficacy endpointRandomization

BM14149, NM14161 (BMI 28-43 kg/m²)

NM17247(BMI 25-28 kg/m²)

PlaceboOrlistat 60 mgOrlistat 120 mg

PlaceboOrlistat 60 mg


Efficacy StudiesEfficacy StudiesEfficacy StudiesEfficacy StudiesStudy BM14149 NM14161 NM17247N (ITT) PLA 236

60 mg 239120 mg 241

PLA 21260 mg 213120 mg 210

PLA 18460 mg 194

BMI 28-43 kg/m² 30-43 kg/m² 25-28 kg/m²

Population High overweight and obese

Obese Low overweight

Diet 30% fat

(BMR x 1.3) - 600 kcalMinimum allowable: 1200 kcal/d

30% fat

< 90 kg: 1200 kcal/d ≥ 90 kg: 1500 kcal/d

30% fat

< 90 kg: 1200 kcal/d (F), 1400 kcal/d (M)≥ 90 kg: 1400 kcal/d (F), 1600 kcal/d (M)

Educational Program

Regular counseling by dietician; food records returned monthly

No counseling; self-instructional; videos; food records returned every 2 mos

Self-instructional; dietary review; food records returned monthly


Completion RatesCompletion RatesCompletion RatesCompletion Rates

6 months 4 months

Study BM14149

Study NM14161

Study NM17247

Placebo 76% 73% 72%Orlistat 60 82% 79% 78%Orlistat 120 83% 80% NA


% of Subjects by BMI Group% of Subjects by BMI Group% of Subjects by BMI Group% of Subjects by BMI Group

< 28 kg/m² 28 - < 30 kg/m² ≥ 30 kg/m²

BM14149N = 729

2.5% 13.2% 84.4%

NM14161N = 642

0% 7.2% 92.8%

NM17247N = 391

89.3% 10.7% 0%


Categorical Weight Loss Results – LOCFCategorical Weight Loss Results – LOCFCategorical Weight Loss Results – LOCFCategorical Weight Loss Results – LOCFPercent of Subjects Achieving At Least 5%

Weight Loss

0102030405060708090

100

Pooled studies BMI 28-43

(6 mos)

Pooled studies BMI 28-43

(4 mos)

Study NM17247 BMI 25-28

(4 mos)

%Placebo

Orlistat 60

Orlistat 120* **

*

* p < 0.05 vs. placebo


Weight Change from Baseline – LOCFWeight Change from Baseline – LOCFWeight Change from Baseline – LOCFWeight Change from Baseline – LOCF

PLA 60 120-20

-15

-10

-5

0

5

10

Wt

chan

ge

fro

m b

asel

ine

(kg

)

PLA 60 120 PLA 60

BM14149 Mth 6BM14149 Mth 6 NM14161 Mth 6NM14161 Mth 6 NM17247 Mth 4NM17247 Mth 4


Placebo-Subtracted Difference in Placebo-Subtracted Difference in Weight Change from Baseline (kg) and Weight Change from Baseline (kg) and

95% CI – LOCF95% CI – LOCF

Placebo-Subtracted Difference in Placebo-Subtracted Difference in Weight Change from Baseline (kg) and Weight Change from Baseline (kg) and

95% CI – LOCF95% CI – LOCF

BM14149High overweight/obese Month 6

NM14161ObeseMonth 6

NM17247Low overweight Month 4

Pla vs 60 -1.8 (-2.6, -1.0) -2.4 (-3.2, -1.6) -1.1 (-1.7, -0.5)

Pla vs 120 -2.1 (-2.9, -1.3) -3.3 (-4.1, -2.5)


Weight Regain – 2 year dataWeight Regain – 2 year dataWeight Regain – 2 year dataWeight Regain – 2 year data

First year: hypocaloric diet; Second year: eucaloric diet

• Pooled studies: BM14149 and NM14161– Orlistat or placebo for 2 years

• Additional study from Rx NDA, published in JAMA 1999– Orlistat or placebo for 1 year– 2nd year:

First year: hypocaloric diet; Second year: eucaloric diet

• Pooled studies: BM14149 and NM14161– Orlistat or placebo for 2 years

• Additional study from Rx NDA, published in JAMA 1999– Orlistat or placebo for 1 year– 2nd year:

Placebo Placebo

OrlistatPlacebo

Orlistat


Pooled StudiesPooled StudiesWeight Change Over 2 Years – CompletersWeight Change Over 2 Years – Completers

Pooled StudiesPooled StudiesWeight Change Over 2 Years – CompletersWeight Change Over 2 Years – Completers

0 24 52 76 104WEEK

-10

-8

-6

-4

-2

0

2

4

We

igh

t c

ha

ng

e f

rom

ba

se

line

(k

g)

0 24 52 76 104WEEK

BM14149BM14149 NM14161NM14161TRT:

120 mg tid60 mg tidPlacebo


Weight Control and Risk Factor Reduction in Weight Control and Risk Factor Reduction in Obese Subjects Treated for 2 Years With Orlistat: Obese Subjects Treated for 2 Years With Orlistat:

A Randomized Controlled TrialA Randomized Controlled Trial

Weight Control and Risk Factor Reduction in Weight Control and Risk Factor Reduction in Obese Subjects Treated for 2 Years With Orlistat: Obese Subjects Treated for 2 Years With Orlistat:

A Randomized Controlled TrialA Randomized Controlled Trial

• Groups:– Placebo/placebo (n=133)– Orlistat 120/orlistat 120 (n=153)– Orlistat 120/orlistat 60 (n=152)– Orlistat 120/placebo (n=138)

• Behavior modification program: Dietitians, food diaries, counseling

Davidson MH, et al. JAMA 1999; 281:235-242

• Groups:– Placebo/placebo (n=133)– Orlistat 120/orlistat 120 (n=153)– Orlistat 120/orlistat 60 (n=152)– Orlistat 120/placebo (n=138)

• Behavior modification program: Dietitians, food diaries, counseling

Davidson MH, et al. JAMA 1999; 281:235-242


Mean Body Weight Change During 2 Years of Double-Blind Treatment –– Completers

Mean Body Weight Change During 2 Years of Double-Blind Treatment –– Completers

Adapted from: Davidson, MH, et al. JAMA 1999;281:235-242


Randomized Trial of Lifestyle Modification Randomized Trial of Lifestyle Modification and Pharmacotherapy for Obesityand Pharmacotherapy for Obesity

Randomized Trial of Lifestyle Modification Randomized Trial of Lifestyle Modification and Pharmacotherapy for Obesityand Pharmacotherapy for Obesity

224 obese adults, 1 year, sibutramine224 obese adults, 1 year, sibutramine

Type of Visit No. of visits/duration

Diet/activity record review

Drug + Intensive Therapy

Primary care provider + weekly group meetings w/trained psychologist

30 visits/90 min +8 visits/10-15 min

yes

Drug + Brief Therapy

Primary care provider 8 visits/10-15 min yes

Intensive Therapy

Weekly group meetings w/trained psychologist

30 visits/90 min yes

Drug Alone Primary care provider 8 visits/10-15 min no

Wadden TA, et al. N Engl J Med 2005; 353:2111-20


Results of Lifestyle Modification Study – LOCFResults of Lifestyle Modification Study – LOCFResults of Lifestyle Modification Study – LOCFResults of Lifestyle Modification Study – LOCF

Weight % SubjectsChange w/ 5% loss

Drug + Intensive Therapy -12.1 kg 73%Drug + Brief Therapy -7.5 kg 56%Intensive Therapy -6.7 kg 53%Drug -5.0 kg 42%


Weight % SubjectsChange w/ 5% loss

Drug + Intensive Therapy -12.1 kg 73%Drug + Brief Therapy -7.5 kg 56%Intensive Therapy -6.7 kg 53%Drug -5.0 kg 42%



SafetySafetySafetySafety


Safety DatabaseSafety DatabaseSafety DatabaseSafety Database

• Studies from original Rx NDA (pooled): BM14149, NM14161, NM14302

• New study: NM17247

• Supportive studies: BM14150, Actual Use Trial, Consumer Use Study

• Post-marketing data: FDA Adverse Event Reporting System (AERS)

• Published literature

• Review of original Rx orlistat NDA

• Studies from original Rx NDA (pooled): BM14149, NM14161, NM14302

• New study: NM17247

• Supportive studies: BM14150, Actual Use Trial, Consumer Use Study

• Post-marketing data: FDA Adverse Event Reporting System (AERS)

• Published literature

• Review of original Rx orlistat NDA


Pooled Safety StudiesPooled Safety StudiesPooled Safety StudiesPooled Safety Studies

Study BM14149 NM14161 NM14302N (ITT) PLA 237

60 mg 239120 mg 242

PLA 21260 mg 213120 mg 210

PLA 18530 mg 18660 mg 171120 mg 180

Design 4-week lead-in; 1-year weight loss; 1-year weight maintenance

4-week lead-in; 1-year weight loss; 1-year weight maintenance

6-month lead-in (dietary weight loss); 1-year weight maintenance

Multivitamin No No Yes


Safety Issues for DiscussionSafety Issues for DiscussionSafety Issues for DiscussionSafety Issues for Discussion

• Fat-soluble vitamins

• Drug interactions

• Pancreatitis

• Fat-soluble vitamins

• Drug interactions

• Pancreatitis


Study BM14149 (No MVI)Study BM14149 (No MVI)Mean Change in Vitamin Concentrations Over TimeMean Change in Vitamin Concentrations Over Time

Study BM14149 (No MVI)Study BM14149 (No MVI)Mean Change in Vitamin Concentrations Over TimeMean Change in Vitamin Concentrations Over Time

Vitamin A (retinol)

-0.05

0

0.05

0.1

0.15

0.2

0.25

Day 1 Week 24 Week 52

um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin A (retinol)

-0.05

0

0.05

0.1

0.15

0.2

0.25


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin D (25-OH vitamin D)

-5

0

5

10

15

20


nm

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin D (25-OH vitamin D)

-5

0

5

10

15

20


nm

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin E (alpha-tocopherol)

-2-1.5

-1-0.5

00.5

11.5

2


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin E (alpha-tocopherol)

-2-1.5

-1-0.5

00.5

11.5

2


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Beta-carotene

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Beta-carotene

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1


um

ol/

L Placebo

Orlistat 60

Orlistat 120

**

**

**

* p < 0.001 vs. placebo


Study NM14161 (No MVI)Study NM14161 (No MVI)Mean Change in Vitamin Concentrations Over TimeMean Change in Vitamin Concentrations Over Time

Study NM14161 (No MVI)Study NM14161 (No MVI)Mean Change in Vitamin Concentrations Over TimeMean Change in Vitamin Concentrations Over Time

Vitamin A

-0.1

0

0.1

0.2

0.3

0.4


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin A

-0.1

0

0.1

0.2

0.3

0.4


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin D

-15

-10

-5

0

5


nm

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin D

-15

-10

-5

0

5


nm

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin E

-1.5-1

-0.50

0.51

1.52

2.53


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin E

-1.5-1

-0.50

0.51

1.52

2.53


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Beta-carotene

-0.15

-0.1

-0.05

0

0.05


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Beta-carotene

-0.15

-0.1

-0.05

0

0.05


um

ol/

L Placebo

Orlistat 60

Orlistat 120

*

*

**

†

* p < 0.05 vs. placebo; † p < 0.10 vs. placebo


Study NM14302 (+ MVI)Study NM14302 (+ MVI)Mean Change in Vitamin Concentrations Over TimeMean Change in Vitamin Concentrations Over Time

Study NM14302 (+ MVI)Study NM14302 (+ MVI)Mean Change in Vitamin Concentrations Over TimeMean Change in Vitamin Concentrations Over Time

Vitamin A

-0.05

0

0.05

0.1

0.15

0.2

0.25


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin A

-0.05

0

0.05

0.1

0.15

0.2

0.25


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin D

-20

-15

-10

-5

0

5


nm

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin D

-20

-15

-10

-5

0

5


nm

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin E

-4

-3

-2

-1

0

1

2

3


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Vitamin E

-4

-3

-2

-1

0

1

2

3


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Beta-carotene

-0.4

-0.3

-0.2

-0.1

0

0.1


um

ol/

L Placebo

Orlistat 60

Orlistat 120

Beta-carotene

-0.4

-0.3

-0.2

-0.1

0

0.1


um

ol/

L Placebo

Orlistat 60

Orlistat 120

*

***

†

* p < 0.05 vs. placebo; † p < 0.10 vs. placebo

*


Frequency of 2 Consecutive Plasma Vitamin Frequency of 2 Consecutive Plasma Vitamin Concentrations Below the Limit of the Concentrations Below the Limit of the

Reference Range after 1 Year of TreatmentReference Range after 1 Year of Treatment

Frequency of 2 Consecutive Plasma Vitamin Frequency of 2 Consecutive Plasma Vitamin Concentrations Below the Limit of the Concentrations Below the Limit of the

Reference Range after 1 Year of TreatmentReference Range after 1 Year of Treatment

Placebo Orlistat 60 Orlistat 120

Vitamin A 0.5% 1.0% 1.8%

Vitamin D 3.6% 3.8% 7.7%

Vitamin E 0.5% 4.1% 3.9%

Beta-carotene 0.5% 1.9% 5.4%Rx NDA, 7 Phase 3 studies


Drug InteractionDrug InteractionWarfarinWarfarin

Drug InteractionDrug InteractionWarfarinWarfarin

• No significant alteration of pharmacokinetics of warfarin

• Post-marketing, literature reports of prolonged prothrombin time

• Post-marketing reports of bleeding• 7 of 14 patients on warfarin initially

failed to identify that orlistat was inappropriate for their use

• No significant alteration of pharmacokinetics of warfarin

• Post-marketing, literature reports of prolonged prothrombin time

• Post-marketing reports of bleeding• 7 of 14 patients on warfarin initially

failed to identify that orlistat was inappropriate for their use


Drug InteractionDrug InteractionCyclosporineCyclosporine

Drug InteractionDrug InteractionCyclosporineCyclosporine

• Weight gain is common after organ transplantation

• Orlistat-cyclosporine interaction study demonstrated decreased cyclosporine concentrations

• Post-marketing reports of decreased cyclosporine concentrations

• 2 cases of acute organ rejection: 1 mild, 1 moderate

• 1 of 2 patients on cyclosporine initially failed to identify that orlistat was inappropriate for use

• Weight gain is common after organ transplantation

• Orlistat-cyclosporine interaction study demonstrated decreased cyclosporine concentrations

• Post-marketing reports of decreased cyclosporine concentrations

• 2 cases of acute organ rejection: 1 mild, 1 moderate

• 1 of 2 patients on cyclosporine initially failed to identify that orlistat was inappropriate for use


PancreatitisPancreatitisPancreatitisPancreatitis

• FDA AERS Data– 99 raw reports of “pancreatitis” for

orlistat (30 US reports)– 8 raw reports of “pancreatitis” for

sibutramine (1 US report)• No increase in incidence of pancreatitis

in placebo-controlled trials of orlistat in patients treated for up to 4 years

• Review of issue is ongoing

• FDA AERS Data– 99 raw reports of “pancreatitis” for

orlistat (30 US reports)– 8 raw reports of “pancreatitis” for

sibutramine (1 US report)• No increase in incidence of pancreatitis

in placebo-controlled trials of orlistat in patients treated for up to 4 years

• Review of issue is ongoing


ConclusionsConclusionsConclusionsConclusions


Efficacy ConclusionsEfficacy ConclusionsDose and PopulationDose and Population

Efficacy ConclusionsEfficacy ConclusionsDose and PopulationDose and Population

• Low overweight population at 4 months, orlistat 60 mg TID (Study NM17247)– Mean weight loss 1.1 kg– Primary Rx weight loss drug

efficacy criterion (categorical weight loss) was not met

• Low overweight population at 4 months, orlistat 60 mg TID (Study NM17247)– Mean weight loss 1.1 kg– Primary Rx weight loss drug

efficacy criterion (categorical weight loss) was not met


Efficacy Conclusions Efficacy Conclusions Duration and LifestyleDuration and Lifestyle


• Pooled studies, obese and high overweight population (Study NM14161 and Study BM14149)– Greater overall weight loss was seen with

intensive lifestyle intervention (BM14149)– Smaller drug treatment and dose effect

was seen with intensive lifestyle intervention (BM14149)

– More weight regained over 2 years with less intensive lifestyle intervention (NM14161)

• Pooled studies, obese and high overweight population (Study NM14161 and Study BM14149)– Greater overall weight loss was seen with

intensive lifestyle intervention (BM14149)– Smaller drug treatment and dose effect

was seen with intensive lifestyle intervention (BM14149)

– More weight regained over 2 years with less intensive lifestyle intervention (NM14161)




• Weight regain after discontinuation of orlistat (JAMA paper)

• Weight-loss drug more effective with lifestyle intervention (NEJM paper)

• Weight regain after discontinuation of orlistat (JAMA paper)

• Weight-loss drug more effective with lifestyle intervention (NEJM paper)


Safety Conclusions Safety Conclusions Fat-Soluble Vitamin MalabsorptionFat-Soluble Vitamin Malabsorption

Safety Conclusions Safety Conclusions Fat-Soluble Vitamin MalabsorptionFat-Soluble Vitamin Malabsorption

• A higher percentage of orlistat-treated subjects had 2 consecutive plasma fat-soluble vitamin concentrations below the lower limit after 1 year of treatment than placebo-treated subjects

• Prolonged orlistat use without appropriate supplementation may lead to clinically significant fat-soluble vitamin malabsorption– Bone– Warfarin

• A higher percentage of orlistat-treated subjects had 2 consecutive plasma fat-soluble vitamin concentrations below the lower limit after 1 year of treatment than placebo-treated subjects

• Prolonged orlistat use without appropriate supplementation may lead to clinically significant fat-soluble vitamin malabsorption– Bone– Warfarin


Safety ConclusionsSafety ConclusionsImportant Drug InteractionsImportant Drug Interactions

Safety ConclusionsSafety ConclusionsImportant Drug InteractionsImportant Drug Interactions

• Warfarin– Reports of prolonged PT and bleeding likely

reflect vitamin K malabsorption and vitamin K insufficiency

• Cyclosporine– Reports of subtherapeutic cyclosporine

concentrations, organ rejection (2), reflect decreased cyclosporine absorption when taken with orlistat

• Actual use trial indicates that labeled warnings may not be adequately communicated

• Warfarin– Reports of prolonged PT and bleeding likely

reflect vitamin K malabsorption and vitamin K insufficiency

• Cyclosporine– Reports of subtherapeutic cyclosporine

concentrations, organ rejection (2), reflect decreased cyclosporine absorption when taken with orlistat

• Actual use trial indicates that labeled warnings may not be adequately communicated


Safety ConclusionsSafety ConclusionsPancreatitis: Unclear Association with Pancreatitis: Unclear Association with

OrlistatOrlistat

Safety ConclusionsSafety ConclusionsPancreatitis: Unclear Association with Pancreatitis: Unclear Association with

OrlistatOrlistat

• No evidence from clinical studies that orlistat increases the risk for pancreatitis

• Increased number of AERS reports of pancreatitis in users of orlistat

• Investigation ongoing

• No evidence from clinical studies that orlistat increases the risk for pancreatitis

• Increased number of AERS reports of pancreatitis in users of orlistat

• Investigation ongoing


Do you believe that the potential Do you believe that the potential benefits of nonprescription orlistat benefits of nonprescription orlistat

outweigh the risks?outweigh the risks?

Do you believe that the potential Do you believe that the potential benefits of nonprescription orlistat benefits of nonprescription orlistat

outweigh the risks?outweigh the risks?


AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements• DMEP Clinical Review Team

– Eric Colman, M.D.– Mary Parks, M.D.

• Statistical Review Team– Joy Mele, M.S.– Todd Sahlroot, Ph.D.

• Office of Drug Safety– Joslyn Swann, Pharm.D.– Lanh Green, Pharm.D., M.P.H.– Cynthia Kornegay, Ph.D.

• Project Management– Patricia Madara

• DMEP Clinical Review Team– Eric Colman, M.D.– Mary Parks, M.D.

• Statistical Review Team– Joy Mele, M.S.– Todd Sahlroot, Ph.D.

• Office of Drug Safety– Joslyn Swann, Pharm.D.– Lanh Green, Pharm.D., M.P.H.– Cynthia Kornegay, Ph.D.

• Project Management– Patricia Madara

Nonprescription Orlistat GlaxoSmithKline Consumer Healthcare, Ltd New Drug Application (21-887) Joint Nonprescription Drugs Advisory Committee and Endocrinologic.

Documents

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