Psychopharmacological Drugs

Advisory Committee Meeting

February 14, 2001

NDA 21-253

Intramuscular Olanzapine for the

Rapid Control of Agitation
Eli Lilly and Company
Indianapolis, IN
1
Agenda

The Agitated Patient John Kane, M.D.

Clinical Development of Alan Breier, M.D.

IM Olanzapine

2
 The Agitated Patient
John Kane, M.D.
Chairman
Department of Psychiatry
Hillside Hospital
Glen Oaks, NY
and
Professor of Psychiatry, Neurology, and Neuroscience
The Albert Einstein College of Medicine
Bronx, NY
3
Agitation
Common clinical challenge

When severe, may be the target for urgent

intervention

Cuts across the boundaries of diverse diagnostic

categories

Phenomenology relatively consistent across

disease states

4
Agitation: Definition
Agitation is excessive motor or verbal activity.

Common examples include:

hyperactivity
assaultiveness
verbal abuse
threatening gestures and language
physical destructiveness
vocal outbursts
excessive verbalizations of distress

5
Agitation: Clinical Implications
In more severe forms, agitation may cause:

A psychiatric emergency mandating rapid treatment

Violent, destructive behavior

Extreme personal distress

Harm to self, caregivers, and others

6
Agitation: A Major Clinical Challenge
Psychiatric Emergency
A mean of 400 patients per month are evaluated in
a typical Psychiatric Emergency Service (PES)
(Currier 1999)

135,000 psychiatric emergency visits per year in

New York State alone (Allen 2000)

7
Agitation: A Major Clinical Challenge
Mechanical Restraint
8.5% of all psychiatric emergency patients require
mechanical restraints for agitation (Currier 2000)
Mean duration of restraint is 6 hours (Currier 2000)
111 fatalities over 10 years in New York facilities due
to restraints (Sundram 1994)
Estimates of 50 - 150 deaths per year nationwide due
to restraints (Allen 2000)

8
Agitation: A Major Clinical Challenge
Assaults
A mean of 8 assaults per year occur in a typical
Psychiatric Emergency Service (Currier 2000)
56.5% of assaults resulted in lost time from work
(Currier 1999)
6 to 1 ratio of nurses being assaulted compared to
doctors, most likely related to nurses' role in
restraint application (Currier 2000)

9
Parenteral Pharmacotherapy
Indications for Use:

When very rapid control of agitation is required -

efficacy within minutes to hours

When compliance to oral treatment not feasible

In general, IM dosing used during first 24 hours,

switch to oral if longer term treatment is appropriate

Current Therapies include:

Benzodiazepines
Typical Antipsychotics

10
Limitations of
Parenteral Pharmacotherapy for Agitation
Benzodiazepines
respiratory depression
excessive sedation
disinhibition

Typical Antipsychotics
acute dystonia
akathisia
excessive sedation
Neuroleptic Malignant Syndrome

11
Acute Treatments for Agitation vs.
Sustained Therapies for Specific Diseases
Urgent Treatments for Agitation Sustained Therapies for Disease
Modality Duration Modality Duration
Schizo- Structured Environment Psychosocial
phrenia Min-Hrs Interventions Wks-
a
IM Antipsychotics / Oral / Depot Mos-Yrs
Benzodiazepines Antipsychotics

Bipolar Structured Environment Psychosocial

Disorder Min-Hrs Interventions Wks-
IM Benzodiazepines / Oral Mood Stabilizers / Mos-Yrs
Antipsychotics Antipsychotics

Dementia of Structured Environment Environmental Interventions

Alz. Type Min-Hrs Cholinesterase Inhibitors Wks-
IM Benzodiazepines / Oral Agents (e.g., depakote, Mos-Yrs
Antipsychotics carbamazepine, antipsychotics)
a When oral therapy is not feasible

12
Clinical Development of
IM Olanzapine
Alan Breier, M.D.
Leader, Zyprexa Product Team
Lilly Research Fellow
Lilly Research Laboratories
and
Professor of Psychiatry
Indiana University School of Medicine

13
Optimal Features of IM Pharmacotherapy
Rapid onset of action

Effective response to first dose

Calming effect without excessive sedation

Low incidence of acute dystonia and other

extrapyramidal side effects

Low incidence of ECG abnormalities

14
History of Regulatory Interactions
May 14, 1998 Meeting with FDA
FDA indicated IM antipsychotics are used for the
control of agitation in numerous disease states
FDA recommended studies of agitated patients in
multiple disease states based on anticipated use

November 12, 1998 Teleconference with FDA

Discussed the proposed clinical plan: 4 pivotal
clinical studies in 3 agitated patient populations
(schizophrenia, bipolar mania, dementia)
15
Proposed Label Indication

ZYPREXA IntraMuscular [IM olanzapine] is indicated

for the rapid control of agitation. The efficacy of
ZYPREXA IntraMuscular for the control of agitation
was established in 4 short-term (24 hours) placebo-
controlled trials in agitated inpatients with
schizophrenia, Bipolar I Disorder (manic or mixed
episodes), or dementia (see CLINICAL
PHARMACOLOGY)

16
Clinical Trial Challenges
No precedent
Placebo and active comparator designs
No "gold standard" agitation scale
Data capture frequency - over minutes to hours
Enrolling patients with appropriate levels of agitation
Ethical considerations

17
Efficacy and Safety of IM Olanzapine
Pharmacokinetics

Clinical methodology and rationale

Efficacy results

Safety

18
Mean Values of Olanzapine PK Variables:
One 10 mg Oral Dose vs. Two 5 mg IM Doses

PK units Oral IM
Parameter 10 mg 2x5 mg
Cmax (ng/mL) 15.1 23.7

AUC (nghr/mL) 499 522

CLp (L/hr) 22.1 20.2

T (hr) 31.0 30.4

Vd (L/kg) 12.2 11.1

N = 22 healthy subjects

19
Mean Olanzapine Plasma Concentrations:
One 10 mg Oral Dose vs. Two 5 mg IM Doses
20
Olanzapine Mean Plasma Conc. (ng/mL) 20

Plasma Conc.
15

(ng/mL)
10
15
5

10 0 2 4 6 8 10 12

Time (hr)
Mean Data, N=22

10 mg Oral Dose
5 2 x 5 mg IM Doses

0 24 48 72 96 120
Time (hr)

Mean olanzapine plasma concentrations following administration of one

10 mg oral dose or two 5 mg IM doses, 4 hours apart
N = 22 healthy subjects 20
Mean Olanzapine Plasma Concentrations:
Three 10 mg IM Doses
Olanzapine Mean Plasma
Concentration (ng/mL) 40

30

20

10

0
0 4 8 12 16 20 24
Time (hours)
Mean plasma concentration following three 10 mg doses of IM
olanzapine
N = 20 non-agitated patients 21
Comparison of Cmax after IM Doses vs. Oral
Olanzapine Steady-State Concentrations
Oral Olanzapine Olanzapine 10 mg IM
20 mg Dose Three Doses within 24 hours
Study HGAJ 120 Study HGJA
120
Concentration (ng/mL)
Average Steady-State

Olanzapine Cmax
100 100
Olanzapine

80 80

(ng/mL)
60 60

40 40

20 20

0 0
Daily Dose 1st 2nd 3rd
1 to 6 weeks Dose Dose Dose
n = 474 in 333 pts n=24 n=24 n=20
22
Pharmacokinetic Profile of IM Olanzapine
Fundamental PK characteristics similar to oral
Similar half-life, clearance, and volume of distribution
Follows linear pharmacokinetics

Key difference is a more rapid rate of absorption

Higher Cmax
Tmax earlier for IM (15 to 45 min vs. 3 to 6 hours)

Maximum IM plasma concentration comparable to

oral steady-state
Maximum IM plasma concentration after three 10 mg
injections is similar to steady-state plasma concentration
after oral 20 mg

Similar metabolite profile to oral

23
Efficacy and Safety of IM Olanzapine
Pharmacokinetics

Clinical methodology and rationale

Efficacy results

Safety

24
Selection of Efficacy Measures for the
Assessment of Agitation
January - November 1998:
Extensive literature search - review of studies in
agitation and efficacy scales
Consultation with regulatory agencies and experts
July 1998:
International Expert Advisory Panel on Agitation
Outcomes:
No single "gold standard" scale; however,
multiple clinically appropriate agitation scales
Core features common across agitation scales

25
Core Battery of Agitation Scales
Primary Efficacy Measure:

Positive And Negative Syndrome Scale Excited

Component (PANSS EC)

Secondary Efficacy Measures:

Agitation-Calmness Evaluation Scale (ACES)

Corrigan Agitated Behavior Scale (CABS)

or
Cohen-Mansfield Agitation Inventory (CMAI)

26
Selection of Primary Efficacy Measure:
PANSS Excited Component
Contains the common, core features identified in
extensive review of agitation scales

Established factor of the PANSS (Kay et al. 1987)

Validity established in agitated and non-agitated patients

Internal consistency, construct and discriminant validity,
responsiveness, reliability, reproducibility

Applicability across different patient populations

Rated by clinical observation not verbal response

Rapid completion allows for frequent administration

27
PANSS Excited Component:
Items and Anchor Descriptions
Poor Impulse Control - Disordered regulation and control of action on
inner urges, resulting in sudden, unmodulated, arbitrary, or misdirected
discharge of tension and emotions without concern about consequences.

Tension - Overt physical manifestations of fear, anxiety, and agitation, such

as stiffness, tremor, profuse sweating, and restlessness.

Hostility - Verbal and nonverbal expressions of anger and resentment,

including sarcasm, passive-aggressive behavior, verbal abuse, and
assaultiveness.

Uncooperativeness - Active refusal to comply with the will of significant

others, including the interviewer, hospital staff, or family, which may be
associated with distrust, defensiveness, stubbornness, negativism, rejection
of authority, hostility, or belligerence.

Excitement - Hyperactivity as reflected in accelerated motor behavior,

heightened responsivity to stimuli, hypervigilance, or excessive mood
liability.
Scoring: 1 = absent, 4 = moderate, 7 = extreme
28
Secondary Efficacy Measure:
Agitation-Calmness Evaluation Scale (ACES)
Developed by Lilly for use in these clinical trials
Designed to assess the clinical levels of calmness
and sedation
Allows for detection of excessive sedation

A 9-point scale that differentiates between agitation,

calm, and sleep states, with scores ranging from:
1: Marked Agitation
4: Normal
7: Marked Calmness
9: Unarousable

Reliability and validity established

29
Secondary Efficacy Measure:
Corrigan Agitated Behavior Scale (CABS)
14-item validated scale (Corrigan 1987)
Rates the degree to which specific behaviors are
observed
Degree ratings from 1 (absent) to 4 (extreme)
Total scores range from 14 to 56

Used in clinical trials of acute agitation across

multiple disease states
e.g. schizophrenia, mania, psychoactive substance abuse,
brain injury, Alzheimer's disease (Battaglia 1997, Corrigan
1988 & 1996)

30
Secondary Efficacy Measure:
Cohen-Mansfield Agitation Inventory (CMAI)
Validated instrument designed to assess agitated
behaviors in the elderly (Finkel 1992)

Used in numerous clinical trials of dementia patient

populations

Scoring adapted for use in shortened and more

frequent observation periods (Cohen-Mansfield
1989)
Behaviors assessed as absent or present (0 or 1)
Total scores range from 0 to 30

31
Criteria for Selected Patient Populations
Agitation is a common clinical challenge
IM medication is frequently used*
Diverse patient characteristics

Patient Populations Selected: Schizophrenia

Bipolar Mania
Dementia

* Based on IMS Data, 1999

32
Patient Populations Selected:
Diverse Clinical Characteristics
Schizophrenia, Bipolar Mania, and Dementia
encompass:
moderate to severely agitated states
psychotic and non-psychotic individuals
broad age range (young adult, middle age, elderly)
patients with and without concurrent medical conditions
psychiatric and neurological patients
differing underlying disease processes

33
Study Designs
Four Pivotal Studies

34
Agitation: 4 Pivotal Studies
Study Agitated Patient Duration Treatment Dose
Population IM Period Groups (mg)
SZ-d Schizophrenia, 24 hr IM olanzapine 2.5, 5,
Schizophreniform, or 7.5, 10
Schizoaffective IM haloperidol 7.5
IM placebo

SZ Schizophrenia, 24 hr IM olanzapine 10
Schizophreniform, or IM haloperidol 7.5
Schizoaffective IM placebo

BIP Bipolar, Manic, or 24 hr IM olanzapine 10

Mixed Episode IM lorazepam 2
IM placebo

DEM Dementia, Alzheimers, 24 hr IM olanzapine 2.5, 5

Vascular, or Mixed IM lorazepam 1
IM placebo

35
Comparator Dose Selection
IM Haloperidol 7.5 mg
5 to 10 mg doses most commonly used
Dose response analysis suggests that doses that exceed
7.5 10 mg do not appreciably increase immediate efficacy,
but may cause additional side effects (Baldessarini 1998)

IM Lorazepam
1 mg and 2 mg doses commonly used in geriatric and non-
geriatric patients, respectively

36
Study Design: 4 Pivotal Studies
24 Hour IM Dosing Period
Study Period I Study Period II

Screening Double-Blind Therapy Period

Period
IM olanzapine

Eligible IM comparator
Patients
IM placebo

24 hrs
Screening
> 2 hrs > 4 hrs (SZ-d, SZ)
> 1 hr (BIP, DEM)
Randomization
Inj. #2 Inj. #3
(if clinically (if clinically
Inj. #1 indicated) indicated)
37
Criteria for Inclusion in Agitation Study

Investigator judgment that the patient is

clinically agitated and a clinically appropriate
candidate for treatment with IM medication

and

PANSS Excited Component total score 14

plus a score of 4 (4 = moderate) on at least 1
item using the 1-7 scoring system

38
Other Entry Criteria
DSM-IV criteria (schizophrenia, bipolar); DSM-IV or
NINCDS-ADRDA criteria (dementia)

Age: 18 (schizophrenia, bipolar); 55 (dementia)

Agitation not caused by substance abuse

No benzodiazepines within 4 hrs prior to injection 1

No antipsychotics within 2 hrs (SZ-d, SZ) or 4 hrs

(BIP, DEM) prior to injection 1

No clinically significant ECG abnormalities that

would preclude participation
39
Patient Characteristics:
Demographics
SZ-d SZ BIP DEM
Demographica (N=270) (N=311) (N=201) (N=272)
Age:
Mean 36 38 39 77
Min 18 18 18 54
Max 73 72 79 97

Sex: %
Male 57.4 65.6 53.2 39.0
Female 42.6 34.4 46.8 61.0

Origin: %
Caucasian 65.9 72.7 72.6 92.3
African descent 24.1 19.0 15.9 5.9
Hispanic 0 5.5 6.0 1.5
Asian 1.5 1.0 4.0 0
Other 8.5 1.9 1.5 0.4

a No significant differences between treatment groups within each of the four studies
40
Clinical Characteristics at Baseline:
Four Pivotal Studies
SZ-d SZ BIP DEM
Study Study Study Study
(N=270) (N=311) (N=201) (N=272)

Psychosis (%) 100% 100% 52.3% 44.5%

Length of Current Admission:

- < 5 days (%) 44.2% 64.3% 84.9% 51.3%
- 6 30 days (%) 45.4% 33.3% 13.5% 20.1%
- > 30 days (%) 10.4% 2.5% 1.7% 28.6%
Psychiatric Scales: (Mean scores)
- BPRS Total 55.5 57.0 47.8 53.8
- Young Mania Rating Scale - - 26.0 -
- Mini Mental State Exam - - - 11.8

41
Baseline Level of Agitation:
Mean PANSS EC Scores of 4 Pivotal Studies

PANSS Schizophrenia Schizophrenia Bipolar Dementia

Excited Dosing Study Study Mania Study Study
Componenta (N=270) (N=311) (N=201) (N=272)

Mean 19.0 18.3 17.8 19.8

Baselineb

Upper Limit 32.0 29.0 30.0 34.0

a Total Score Range is 5 - 35; Minimum Criteria Score for inclusion: 14

b No significant differences between treatment groups for the 4 pivotal studies

42
PANSS Excited Component:
Distribution of Total Scores at Baseline
Schizophrenia Dose - all patients Schizophrenia - all patients
60 60

50 50

Frequency
Frequency

40 40

30 30

20 20

10 10

0 0
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Baseline PANSS Excited Score Baseline PANSS Excited Score

Bipolar - all patients Dementia - all patients

60 60

50 50
Frequency

40 40
Frequency

30 30
20 20
10 10
0 0
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Baseline PANSS Excited Score Baseline PANSS Excited Score

43
Baseline Agitation Across Disease States*
PANSS EC: Mean Scores of the 5 Items
SZ-d/SZ N=581
5 BIP N=199
DEM N=272

4
Mean Baseline

0
Excitement Hostility Poor Impulse Tension Uncooper-
Control ativeness

* All treatment groups 44

Efficacy and Safety of IM Olanzapine
Pharmacokinetics
Clinical methodology and rationale

Efficacy results
Analyses of Primary Scale: PANSS Excited Component
Primary Analysis
Response Rates; Efficacy at 24 hours; By-Item Analysis
Analyses of secondary scales
Onset of efficacy
Efficacy by severity analysis
Number of injections required in 24 hours
Psychosis and Non-Psychosis

Safety

45
Primary Analysis: Efficacy at 2 Hours
PANSS Excited Component
Mean change from baseline to 2 hrs post first IM inj (LOCF)
6
Mean Change from Baseline

Baseline Means:
4
2 19.0 18.3 17.8 19.8 Placebo
0 IMOlz 2.5
-2 IMOlz 5.0
-4
IMOlz 7.5
-6 *
-8 *
IMOlz 10
* * * * *
-10 * * * * IMHal 7.5
-12
IMLzp
-14
-16
SZ-d SZ BIP DEM
* p < 0.05 vs. placebo
p < 0.05 vs. lzp
46
Response Rates
PANSS Excited Component - 2 Hours After First Injection

90
* *
80
Percentage of Patients

* * *
70 *
* Placebo
*
* *
60 * IMOlz 2.5
* IMOlz 5
50
IMOlz 7.5
40
IMOlz 10
30 IMHal 7.5
20 IMLzp
10
0
SZ-d SZ BIP DEM
40% decrease in PANSS Excited Component
from Baseline to 2 hours post first IM injection
* p < 0.05 vs. placebo for all 47
Efficacy at 24 Hours:
PANSS Excited Component
Mean change from baseline to 24 hrs (LOCF)
Baseline Means: 19.0 18.3 17.8 19.8

0
Mean Change from Baseline

-1
Placebo
-2
IMOlz 2.5
-3 IMOlz 5
-4 IMOlz 7.5
-5 IMOlz 10
*
IMHal 7.5
-6 * *
* * IMLzp
* * *
-7 *

-8
SZ-d SZ BIP DEM

* p < 0.05 vs. placebo 48

PANSS EC By-Item Analysis: 2 Hours (LOCF)
Significant Contribution of All 5 Items: 5-10 mg Olz vs. Placebo

2 Schizophrenia Dose Schizophrenia

Mean Change from Baseline

Mean Change from Baseline

1 1
0 0
-1 *
Placebo -1
* Placebo
* ** **
* **
* IMOlz 2.5
-2 * * * * * * * *
* * * *
* * * * IMOlz 5.0 -2 * *
* * IMOlz 10
* * *
-3 IMOlz 7.5 -3
IMHal
-4 IMOlz 10 -4
-5 IMHal
-5
-6 -6
Poor Impulse Tension Hostility Uncooper- Excitement Poor Impulse Tension Hostility Uncooper- Excitement
Control ativeness Control ativeness

2 Bipolar 2 Dementia

Mean Change from Baseline

Mean Change from Baseline

1 1
0 0
-1 Placebo -1 Placebo
-2 * -2 * * * * * * *
IMOlz 2.5
* IMOlz 10 * * *
* * *
-3 * * -3 IMOlz 5.0
IMLzp IMLzp
-4 -4
-5 -5
-6 -6
Poor Impulse Tension Hostility Uncooper- Excitement Poor Impulse Tension Hostility Uncooper- Excitement
Control ativeness Control ativeness
* p<0.05 vs. placebo 49
 Efficacy at 2 Hours:
Agitation-Calmness Evaluation Scale
Mean Value at Endpoint - 2 hours (LOCF)
6
Mod. Calm
*
5 *
* Placebo
Mild Calm *
* *
* * IMOlz 2.5
* * *
4
Normal IMOlz 5
IMOlz 7.5
3 IMOlz 10
Mild Agit. IMHal 7.5
IMLzp
2
Mod. Agit.

1
Marked Agit.
SZ-d SZ BIP DEM
Baseline Mean: 2.3 2.5 2.3 2.2
* p < 0.05 vs placebo for mean change
4546.01 p < 0.05 vs hal (SZ-d) or lzp (BIP) for mean change 50
Efficacy in Agitation at 2 Hours:
Corrigan / Cohen-Mansfield
Mean change from baseline to 2 hours post first IM inj (LOCF)
Baseline Means:
4 30.5 27.5 28.3 7.0
Mean Change from Baseline

2
Placebo
0
IMOlz 2.5
-2 IMOlz 5.0
-4 IMOlz 7.5
* *
-6 *
IMOlz 10
-8 IMHal 7.5
* * * * IMLzp
-10 *
* *
-12
*
SZ-d SZ BIP DEM
CABS Range: 14-56 * p < 0.05 vs. placebo
CMAI Range: 0-30 p < 0.05 vs. hal (SZ-d) or lzp (BIP)
51
Onset of Efficacy: PANSS EC
Schizophrenia Study
Timepoint-wise change from baseline to 2 hrs post first IM inj (LOCF)
0 15 30 45 60 75 90 105 120
0
Time (mins)
-1
-2 Placebo
-3 IM Olz
Change

IM Hal
-4
Mean

* *
-5

-6
* *
-7
*
*
-8 * *
* *
-9 *
* p < 0.05 vs. Placebo
p < 0.05 vs. Haloperidol
52
Efficacy at 2 Hrs by Baseline Severity:
Schizophrenia Study
Efficacy comparison based on mean split of baseline PEC
Score < Average (18) Score Average (18)

0 0

-2

Mean Change in PEC

-2
Mean Change in PEC

-4 Placebo -4 Placebo
IM Olz 10
IMOlz 10
IM Hal 7.5
IMHal 7.5
-6 -6
* *
-8 -8

-10 -10 * *

* p < 0.05 vs. placebo

53
Number of IM Injections During 24 Hours:
Schizophrenia Dose Ranging Study

100% * * * * *
Percentage of Patients

80%

3 Inj
60%
2 Inj
40% 1 Inj

20%

0%
Placebo IMOlz IMOlz IMOlz IMOlz IMHal
2.5mg 5mg 7.5mg 10mg 7.5mg
Maximum of three injections allowed during 24 hours in each trial.
Investigator judgment determined the administration of a second or third injection.

* p < 0.05 vs. placebo

54
Efficacy Assessed by Presence of Psychosis
Comparison at 2 Hours: Bipolar Study
PANSS EC: Mean change from baseline (LOCF)
Psychotic Non-Psychotic
(N=104) (N=95)
0 0
-2 -2
Placebo n=24 Placebo n=26
-4 -4 IMOlz 10 n=46
IMOlz 10 n=52
IMLzp n=28 IMLzp n=23
-6 -6
-8 -8
-10 -10 *
*
-12 -12
Mean Change Mean Change

* p < 0.05 vs. placebo

55
Efficacy Assessed by Presence of Psychosis
Comparison at 2 Hrs: Dementia Study
PANSS EC: Mean change from baseline (LOCF)
Psychotic Non-Psychotic
(N=146) (N=117)

0 0
-2 -2
Placebo n=40
Placebo n=23
-4 IMOlz 2.5 n=35 -4 IMOlz 2.5 n=36
IMOlz 5.0 n=32 IMOlz 5.0 n=30
IMLzp n=28
-6 IMLzp n=39 -6

-8 -8
* *
*
-10 -10
Mean Change Mean Change

* p < 0.05 vs. placebo

56
Efficacy and Safety of IM Olanzapine
Pharmacokinetics

Clinical methodology and rationale

Efficacy results

Safety
Treatment-Emergent Adverse Events
Sedation
Laboratory Analyses
Vital Signs
Electrocardiograms
Extrapyramidal Symptoms
57
Summary of Safety Databases

Placebo-Controlled Geriatric Placebo-Controlled

(SZ-d, SZ, BIP) (DEM)
Olanzapine: N = 415 Olanzapine: N = 137
Placebo: N = 150 Placebo: N = 67

Overall Patient Database

(All agitated patients)
Haloperidol- Olanzapine: N = 722
Controlled (SZ-d, SZ)
Olanzapine: N = 316 Overall Subject Database
Haloperidol: N = 166 (All patients and healthy subjects)
Olanzapine: N = 850

58
Adverse Events

59
Adverse Events: Overall Patient Database
Discontinuations and Serious Adverse Events

Discontinuations:
Only 0.7% (5 / 722) of IM olanzapine-treated patients
discontinued due to an adverse event

Serious Adverse Events:

Only 0.4% (3 / 722) IM olanzapine-treated patients
experienced an adverse event that met criteria for
"serious" during the study
Anxiety (also led to study discontinuation)
Abnormal ECG and anemia (both present at baseline)
Tachycardia (discontinued due to agitation; received
lorazepam and haloperidol; developed tachycardia)

60
Adverse Events: 24 Hour IM Period
Placebo-Controlled Database
Treatment-emergent adverse events reported by at least 1% of
patients and with an incidence greater than placebo

Percentage of Patients With Event

Adverse Event Olanzapine Placebo
N=415 N=150
Somnolence 6 3
Dizziness 4 2
Asthenia 2 1
Hypotension 2 0
Postural Hypotension 1 0
Tremor 1 0

N.S.D. between olz and placebo for any event

61
Adverse Events: 24 Hour IM Period
Geriatric Placebo-Controlled Database
Treatment-emergent adverse events reported by at least 1% of
patients and with an incidence greater than placebo
Percentage of Patients With Event
Adverse Event Olanzapine Placebo
N=137 N=67
Somnolence 4 3
Headache 3 0
Accidental Injury 2 0
Dizziness 2 0
Tachycardia 1 0
Tremor 1 0
Vasodilation 1 0
Vomiting 1 0
N.S.D. between olz and placebo for any event
62
Adverse Events: Summary
Olanzapine vs. Haloperidol and Lorazepam
IM haloperidol > IM olanzapine (p<0.05) for:
acute dystonia dyspepsia
extrapyramidal syndrome amblyopia

IM lorazepam > IM olanzapine (p<0.05) for:

nausea
vomiting

No adverse event significantly more frequent for IM

olanzapine vs. IM haloperidol or IM lorazepam

No injection site reactions for IM olanzapine other than

pain, including allergic reactions
Pain only reported in 0.5% of IM olanzapine-treated patients
63
Sedation

64
Sedation Assessed Using:
Agitation-Calmness Evaluation Scale
ACES score of 8 (deep sleep) or 9 (unarousable) used
as indicators of excessive sedation

No IM olanzapine-treated patient scored a 9 at any time

Only 5.1% (28 / 551) of IM olanzapine-treated patients scored

an 8 at any time

No significant difference between IM olanzapine and either

comparator (haloperidol, lorazepam) in the incidence of 8
or 9

65
Sedation Assessed Using:
Treatment-Emergent Adverse Events
"Somnolence" was the only reported sedation-
related adverse event
No reports of "CNS depression," "stupor," or "coma"

Somnolence was reported in 5.1% (28 / 552) of

IM olanzapine-treated patients

No significant difference between IM olanzapine and

any other treatment group (including placebo) in the
incidence of somnolence.

66
Laboratory Analyses

67
Laboratory Results:
Schizophrenia, Bipolar, and Dementia Studies

Standard laboratory tests:

Clinical chemistry
Hematology
Urinalysis

Only one statistically significant difference between

olanzapine and placebo treatment groups:
mean cell hemoglobin (decreased in DEM placebo group)

68
Vital Signs

69
Vital Signs

Bradycardia observed with olanzapine

Greater incidence and magnitude in healthy subjects vs.
patients
Usually associated with hypotension
3 healthy subjects (2 IM and 1 oral) with sinus pauses
Proposed mechanism: vasovagal response

Vital Signs in IM Trials

Cardiology Consultants for Q&A

Arthur J. Moss, MD
William J. Groh, MD
70
Bradycardia
Bradycardia
Bradycardia w/ Hypotension
n % n %
Healthy Subjects
(N = 85) 28 32.9 19 22.4

Patients
(N = 765*) 36 4.7 21 2.7

Total
(N = 850) 64 7.5 40 4.7
*Includes agitated patients (N = 722) and non-agitated patients (N = 43)

Heart rate determined by palpation

21.0 (mean) times per subject
2.4 (mean) vital signs meeting criteria for bradycardia
71
Sinus Pauses
3 Healthy subjects:
26 yr old Male - 10 mg Oral Olz
55 yr old Male - 5 mg IM Olz
47 yr old Male - 5 mg IM Olz
Sinus pauses
up to 6 seconds
associated with hypotension
preceded by sinus bradycardia
self-terminating, followed by return to sinus rhythm

Sinus pauses in patients: 0/765 (0%)

minimum of three 12-lead ECGs with rhythm strips for all patients

Syncope in patients: 2/765 (0.3%)

72
Bradycardia Proposed Mechanism: Vasovagal
Response (i.e., Neurally Mediated Reflex Bradycardia)
Olanzapine associated with hypotension
1 antagonism (Ki=19 nM) decrease BP

Bradycardia associated with hypotension

Supported by clinical & animal data
~ 10% of general population will have bradycardia in response to decrements in
BP (Kapoor 1999)

Greater in healthy subjects: Possible Explanation

Increased vagal tone
No baseline agitation (agitation vagal tone)
Not taking 1 blocking agents at baseline (e.g., antipsychotics)

Outcome
Self-terminating
Transient; more marked early vs. later in treatment (rapid tachyphylaxis)
Management if symptomatic: recumbency
Usually benign

73
Vital Signs: Change to Value Outside
Reference Range - Any Time During 24 Hrs
Placebo-Controlled Database Placebo IMOlz

Basal / Resting Positional Challenge

12 *

10
Percentage of Patients

8
*
6 *

0
Low Low Low Low Low High Ortho
Supine Supine Supine Standing Standing Standing Drop
Systolic Diastolic Pulse Systolic Diastolic Pulse
* p < 0.05 vs. placebo
74
Vital Signs: Change to Value Outside
Reference Range - Any Time During 24 Hrs
Haloperidol-Controlled Database
IMOlz IMHal

12 Basal / Resting Positional Challenge

10
Percentage of Patients

4 *

0
Low Low Low Low Low High Ortho
Supine Supine Supine Standing Standing Standing Drop
Systolic Diastolic Pulse Systolic Diastolic Pulse
* p < 0.05 vs. Olz 75
 Vital Signs: Change to Value Outside
Reference Range Any Time During 24 Hrs
Geriatric Placebo-Controlled Database
Placebo IMOlz 2.5 IMOlz 5
Basal / Resting Positional Challenge
14
12
Percentage of Patients

10
8
6
4
2

0
Low Low Low Low Low High Ortho
Supine Supine Supine Standing Standing Standing Drop
Systolic Diastolic Pulse Systolic Diastolic Pulse
:n=0
N.S.D. between Olz and Pla on any measure 76
Incidence of Treatment-Emergent Dizziness
and Syncope: Data from IM and Oral Studies
Intramuscular Data
Olz Pla Olz Hal
Event N=415 N=150 N=316 N=166
Classification n % n % n % n %

Dizziness 17 4.1% 3 2.0% 8 2.5% 3 1.8%

Syncope 1 0.2% 0 0% 0 0% 0 0%
N.S.D. between treatment groups
Oral Dataa
Olz Pla Olz Hal
Event N=882 N=517 N=2213 N=1240
Classification n % n % n % n %

Dizziness 62 7.0%* 20 3.9% 140 6.3% 65 5.2%

Syncope 6 0.7% 3 0.6% 11 0.5% 3 0.2%
aOralolanzapine clinical trial database: Phase 2, 3, and 4 placebo-controlled /
haloperidol-controlled oral olanzapine studies
*p < 0.05 vs. placebo
77
Electrocardiograms

78
QTc Intervals: 2 Hours Post-Injection
Placebo-Controlled Database
Mean Change in QTc (msec) at 2 hrs
IM Pla IM Olz
10
(N = 148) (N = 408)
9 Mean change -0.7 -3.0
Percentage of Patients

8 SD 22.0 21.5
7 p-value vs. pla -- 0.199
6
5 : n=0
4
3 Placebo
2 IMOlz
1

0
97.5 Percentile 99 Percentile 500 msec

97.5 Percentile: 430 msec male 99 Percentile: 450 msec male

450 msec female 470 msec female

N.S.D. on any measure vs. placebo

79
QTc Intervals: 2 Hours Post-Injection
Haloperidol-Controlled Database
Mean Change in QTc (msec) at 2 hrs
10 IM Olz IM Hal
9 (N = 312) (N = 164)
Percentage of Patients

8 Mean change -3.3 1.8

7 SD 21.7 24.0
6
p-value vs. hal 0.006 --
5
IMOlz
4
IMHal
3
2 : n=0
1
0
97.5 Percentile 99 Percentile 500 msec

97.5 Percentile: 430 msec male 99 Percentile: 450 msec male

450 msec female 470 msec female
N.S.D. on any measure vs. placebo
80
Dementia Study:
Age and Co-Morbid Conditions
Advanced age of population:
45.2% of patients > 80 years; 8.8% > 90 years

Cardiac / Respiratory Conditions

Condition Percent of Patients
Coronary artery disorder 32.0
Cerebrovascular / Peripheral vascular dis. 12.9
Congestive heart failure 12.9
Diabetes 11.4
Electrocardiographic disorder 10.7
Hypercholesterolemia 6.3
Hypertension 41.2
Hypothyroidism 13.6
Respiratory disorder 13.2
Right / Left Bundle Branch Block 8.1 / 3.7
Pacemakers 2.2
81
Original QTc Data*: Dementia Study
Mean Change from Baseline to 2 Hours

Baseline Endpoint Change

Mean** Mean Mean p-value for
Treatment N (msec) (msec) (msec) change vs. pla

IM Olanzapine 2.5 mg 69 430.3 426.3 -4.0 0.171

IM Olanzapine 5.0 mg 61 419.0 428.0 9.0 0.214

IM Lorazepam 64 432.1 431.0 -1.2 0.493

IM Placebo 62 432.6 435.1 2.5 --

* Bazett formula used to calculate QTc

** Baseline QTc in IM Olz 5 mg treatment group significantly lower than all other
treatment groups (p < 0.05)

82
ECG Data from Dementia Study:
Decision for Re-Read
Consultation with external cardiologists
Random review of ECG tracings - discrepancies noted
Original guidelines required measurements of Lead II
These guidelines questioned because:
advanced age of patient population
significant medical co-morbidity at baseline
non-specific, low-amplitude T waves and baseline noise

Recommendation:
Blindly re-read all ECGs using 2 independent ECG Core Labs
Revised measurement guidelines:
Average of 3 leads: Leads II, avF, and V5
Hierarchical algorithm of alternative leads if primary leads
unsuitable
83
Re-Read QTc Data*: Dementia Study
Mean Change from Baseline to 2 Hours

Baseline Endpoint Change

Mean** Mean Mean p-value for
Treatment N (msec) (msec) (msec) change vs. pla

IM Olanzapine 2.5 mg 68 436.9 432.4 -4.5 0.044

IM Olanzapine 5.0 mg 61 430.5 433.5 3.1 0.936

IM Lorazepam 63 437.4 431.2 -6.2 0.019

IM Placebo 61 436.2 439.5 3.3 --

* Re-Read Data = all interval measurements from the 2 ECG Core Labs were
averaged for final reported values, Bazett formula used to calculate QTc

** No significant differences in mean QTc values at baseline

84
QTc Intervals: 2 Hours Post-Injection
Geriatric Placebo-Controlled Database
30 Mean Change in QTc (msec) at 2 hrs
IM Pla IM Olz2.5 IM Olz5
(N = 61) (N = 68) (N = 61)
25
Percentage of Patients

Mean change 3.3 -4.5 3.1

SD 21.1 22.0 24.6
20 p-value vs. pla -- 0.044 0.936

15
Placebo
10 IMOlz 2.5
IMOlz 5
5
* * p < 0.05 vs. placebo
0
97.5 Percentile 99 Percentile 500 msec

97.5 Percentile: 430 msec male 99 Percentile: 450 msec male

450 msec female 470 msec female
85
Comparison of Cmax after IM Doses vs. Oral
Olanzapine Steady-State Concentrations
Oral Olanzapine Olanzapine 10 mg IM
20 mg Dose Three Doses within 24 hours
Study HGAJ 120 Study HGJA
120
Concentration (ng/mL)
Average Steady-State

Olanzapine Cmax
100 100
Olanzapine

80 80

(ng/mL)
60 60

40 40

20 20

0 0
Daily Dose 1st 2nd 3rd
1 to 6 weeks Dose Dose Dose
n = 474 in 333 pts n=24 n=24 n=20
86
QTc Intervals: Normal to Prolonged
6-week Oral Study in Schizophrenia
Patients who were on the specified dose for at least 5 days prior to the ECG
Study HGAJ: Mean Change in QTc (msec)
1.4 Oral 5 mg Oral 10 mg Oral 15mg Oral 20 mg
(N=117) (N=150) (N=175) (N=309)
1.2
Percentage of Patients

Mean Change 1.632 -0.717 1.244 -0.074

SD 46.3 35.3 30.0 26.1
1

0.8 Oral 5 mg
: n=0
Oral 10 mg
0.6
Oral 15 mg
0.4
Oral 20 mg
0.2

0
97.5 Percentile 99 Percentile 500 msec

97.5 Percentile: 430 msec male 99 Percentile: 450 msec male

450 msec female 470 msec female
87
Summary of ECG Data:
Interval Data and Descriptive Findings
No clinically significant findings for any ECG
intervals
mean change from baseline to endpoint
categorical changes

No clinically significant changes for descriptive

findings
e.g. rhythm, morphology

88
Extrapyramidal Symptoms

89
Extrapyramidal Symptoms:
Schizophrenia Dose Ranging Study
Mean change from baseline to 24 hrs post first IM inj (LOCF)
0.8
*
Mean Change from Baseline

0.58
0.6
0.4
*
0.2 0.15 Placebo
IMOlz 2.5
0 IMOlz 5
-0.07 -0.06 -0.07
-0.2
-0.11 -0.11 IMOlz 7.5

IMOlz 10
-0.31
-0.4 IMHal 7.5
-0.46
-0.6

* p < 0.05 vs. pla

-0.8 -0.77

-0.89 -0.89
p < 0.05 vs. hal
-1

Barnes Global Score Simpson-Angus Total

90
Extrapyramidal Symptoms:
Schizophrenia Study
Mean change from baseline to 24 hrs post first IM inj (LOCF)
1 *
Mean Change from Baseline

0.7

0.5

0.01
0 Placebo
-0.08
IMOlz 10
-0.27
-0.5 IMHal 7.5
-0.61
* p < 0.05 vs. pla
-1
p < 0.05 vs. hal
-1.19
-1.5
Barnes Global Score Simpson-Angus Total

91
Extrapyramidal Symptoms:
Bipolar Mania Study
Mean change from baseline to 24 hrs post first IM inj (LOCF)
0
0.0
Mean Change from Baseline

-0.1

-0.2
-0.23
-0.3 -0.26 Placebo
IMOlz 10
-0.4 -0.39 IMLzp
-0.5 -0.49

-0.6
-0.61
-0.7
Barnes Global Score Simpson-Angus Total
N.S.D. between treatment groups at any measure 92
Extrapyramidal Symptoms:
Dementia Study
Mean change from baseline to 24 hrs post first inj (LOCF)
0
Mean Change from Baseline

-0.1

-0.2 -0.18
-0.20
Placebo
-0.25
-0.3 IMOlz 2.5
-0.4 -0.37 IMOlz 5
IMLzp
-0.5

-0.6

-0.7
Simpson-Angus Total
N.S.D. between any measure vs. placebo 93
Conclusions:
Efficacy of IM Olanzapine
The efficacy of IM olanzapine in the treatment of
agitation was established in all 4 pivotal studies:
IM olanzapine was superior to placebo in the primary
efficacy analysis for all doses studied (2.5 to 10 mg)
Secondary efficacy measures yielded similar results
The majority of IM olanzapine-treated patients required
only 1 injection in 24 hours
IM olanzapine, doses 5-10 mg, demonstrated efficacy
15 to 30 minutes after the first injection
IM olanzapine was effective in patients with and without
psychosis
94
Conclusions:
Safety of IM Olanzapine
IM olanzapine was safe and well tolerated:
Incidence of EPS similar to placebo; no cases of acute
dystonia
No clinically significant changes in laboratory analytes
or ECG data, including QTc intervals
Not associated with adverse effects on vital signs
except for mild and transient decrements in blood
pressure and heart rate
Not associated with excessive or undesirable sedation
Favorable adverse event profile

95
96