[PPT] - - ,-- patients (olanzapine incidence at least twice that for PowerPoint Presentation

SLIDE 1

Dr. William Wirshing: State of Alaska's Expert
"They are among the most powerful

disease modifiers in all of medicine••••

They are a godsend to most people:'

Tr.170,Ln.15-21

SLIDE 2

1996 Label- Zyprexa Prescribing Information

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El 2954

SLIDE 3

1996 Zyprexa Label:

Weight Gain Information

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Weight gain: olanzapine = 6%

placebo = 1%

Adverse Reactions:

Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials-

The most commonly observed adverse

events associated with the use of

lanzapine (incidence of 5% or greater)

and not observed at an equivalent

incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were:

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(emphasis ildded)

SLIDE 4

1996 Zyprexa Label: Weight Gain Information

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..... Adverse Reactions:

During long-term continuation therapy

with olanzapine...56% of olanzapine patients met the criterion for having gained greater than 7% of their baseline

weight.

(emphasis added)

SLIDE 5

'996 Zyprexa Label:

Hyperglycemia and Diabetes Information

Other Adverse Events Observed During the

Premarkering Evaluation ofOlanzapine

Frequent adverse events are those occurring

in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing)

.... Infrequent adverse events are those

ccurring in 1/100 to 1/1000 patients

...

Endocrine System -Infrequent: diabetes

mellitus.._

• •

Metabolic and Nutritional Disorders-

...Infrequent:...hypergIycemia....

SLIDE 6

Medical Letter: Zyprexa - Body Weight Changes

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EL 2991

SLIDE 7

Zyprexa Medical Letter:

Blood Glucose Changes

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EL 2986

SLIDE 8

Medical Letter: Zyprexa - Weight Reduction and Management

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SLIDE 9

Hyperglycemia/Diabetes Data on Demand Resource Guide (September 2001)

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even those customers who have not voiced concerns in the past. Remember, many physicians do

not proactively bring up the

diabetes issue....

EL 3387

SLIDE 10

Additional Weight Gain Information

Provided by Lilly (2000)

70% of patients on ZYPREXA either

lost weight. remained stable, or gained up to 10 kg (22Ibs) over 3 years

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Mean weight change plateaued after the first

39 weeks of treatment

Mean long-term LOCF weight change with

IYPREXA plateaued at 6.26 kg (13.8Ibs)

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SLIDE 11

Hyperglycemia/Diabetes Information Provided by Lilly (February 2001)

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EL33S1

SLIDE 12

Lilly Market Research

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El3387

SLIDE 13

G.

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May 2000 FDA Letter
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To assist us in fully evaluating

the possibility that atypical antipsychotics may produce disturbances in glucose metabolism, we are requesting that sponsors of these agents provide us with more extensive safety information.

PX 0775

SLIDE 14

July 31,2000

First major submission on hyperglycemia and

diabetes after more than 4 million exposures

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EL2043

SLIDE 15

(J _._.._-

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October 2000 FDA Letter

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The descriptive data that is provided

expresses a certain level of implied safety

with respect to treatment emergent

hyperglycemia. This reassuring language

is not appropriate for submission under

21 CFR 314.70(c) as a"Special Supplement

Changes Being Effected" (CBE). A more

complete submission of glucose data, and

additional discussion of pooling and analysis of this data is necessary before an appropriate review of treatment emergent hyperglycemia and diabetes can take place.

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PXOO195

SLIDE 16

May 21, 2001

Clinical trial analysis and two epidemiological studies regarding diabetes

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El 2038

SLIDE 17

October 2, 2002

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H 2129

SLIDE 18

March 28, 2003

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Review of severe adverse

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SLIDE 19

June 20, 2003

Submission of new data

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SLIDE 20

2003 Label: Class Warning

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Increased risk of diabetes mellitus in

schizophrenia

Epidemiological studies suggest an

increased risk of hyperglycemia-related adverse events in patients treated with the

atypical antipsychotics

Data is insufficient to provide reliable

estimates of differences in risk

Monitoring recommendations
"The relationship between atypical

antipsychotic use and

hyperglycemia-related adverse events is

not completely understood"

EL 2953A

SLIDE 21

September 2003 Letter From FDA

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Although we believe that the labeling changes

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information about antipsychotic use and

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diabetes mellitus, we acknowledge that

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events, exploration of the relative risk for

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diabetes mellitus adverse events among the

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El2014

SLIDE 22

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2007 Label
Abnormal or borderline glucose levels at

baseline: important risk factor for further

glucose increase.

While risk estimates are inconsistent, the

association between atypical antipsychotics

and increases in glucose levels appears to fall on a continuum; olanzapine appears to have a greater association than some other

atypical antipsychotics.

Significantly greater mean increases in total

cholesterol, LOL, and triglycerides were

bserved in Zyprexa-treated patients

compared with placebo-treated patients.

Labeling provides information on

magnitude and distribution of weight gain

ver 2 years.
Labeling provides information on glucose.

weight gain. and lipids from studies of Zyprexa for adolescent patients.

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SLIDE 23

Note to File re Japan Label Change

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On Friday, April 12, 2002, Drs. Breier and Brophy contacted Dr. Laughren to inform the Division of Neuropharmacological Drug Products that the olanzapine label in Japan was being revised to include information

regarding hyperglycemia and diabetes in the

Warnings and (ontraindications sections.

El2044

SLIDE 24

Submission to FDA re Japan

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SLIDE 25

FDA Response to Consensus Statement

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Gerard Boehm, MD, MPH

Judith A. Racoosin, MD, MPH Thomas P. Laughren, MD Russell Katz, MD From the Division of Neuropharmacological Drug Products, Center for Drug Evaluation and Research, u.s. Food and Drug Administration, Rockville, Maryland

...DNDP is not aware of evidence proving

that the treatment-emergent diabetes risk for these drugs is wholly or in part due to treatment-emergent weight gain. Although weight gain is widely recognized as a risk factor for diabetes in the general population, the clinical trial and epidemiological evidence has not shown a direct link between these treatment-emergent side effects.

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SLIDE 26

David Campana,

Alaska Medicaid Pharmacy Program Manager

September 19, 2007

Q. Has Eli Lilly ever made misrepresentations

about the safety, efficacy, effectiveness of

Zyprexa to the State of Alaska?

A. Not that I know of.
Tr. 298. In. 12-1 5

SLIDE 27

David Campana,

Alaska Medicaid Pharmacy Program Manager

September 19, 2007

Q. As of March 2006. did you have anything that

you would base your contention that the package insert was a misrepresentation of-- misrepresentation to the State of Alaska that Zyprexa was safe and effective?

A. No.
Tr. 300, In. 3-7

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