Psychopharmacological Drugs Advisory Committee Meeting

February 14, 2001

NDA 21-253 Intramuscular Olanzapine for the Rapid Control of Agitation
Eli Lilly and Company
1

Agenda
• The Agitated Patient
John Kane, M.D.

• Clinical Development of IM Olanzapine

Alan Breier, M.D.

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 Modality Duration
Schizophrenia
Structured Environment Min-Hrs IM Antipsychotics / Benzodiazepines
a

Sustained Therapies for Disease Modality
Psychosocial Interventions Oral / Depot Antipsychotics

Duration
WksMos-Yrs

Bipolar Disorder

Structured Environment Min-Hrs IM Benzodiazepines / Antipsychotics

Psychosocial Interventions Oral Mood Stabilizers / Antipsychotics

WksMos-Yrs

Dementia of Structured Environment Alz. Type
IM Benzodiazepines / Antipsychotics
a

Min-Hrs

Environmental Interventions Cholinesterase Inhibitors WksMos-Yrs Oral Agents (e.g., depakote,
carbamazepine, antipsychotics)

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) placebocontrolled 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 Parameter Cmax AUC CLp T½ Vd
N = 22 healthy subjects
19

units (ng/mL) (ng×hr/mL) (L/hr) (hr) (L/kg)

Oral 10 mg 15.1 499 22.1 31.0 12.2

IM 2x5 mg 23.7 522 20.2 30.4 11.1

Mean Olanzapine Plasma Concentrations:
One 10 mg Oral Dose vs. Two 5 mg IM Doses
20 Plasma Conc. (ng/mL) Olanzapine Mean Plasma Conc. (ng/mL)
20 15 10 5 0

15

10

0

2

4

6

8

10

12 Mean Data, N=22
10 mg Oral Dose 2 x 5 mg IM Doses

Time (hr) 5

0 0 24 48 Time (hr) 72 96 120

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
Study HGAJ Study HGJA

Daily Dose 1 to 6 weeks n = 474 in 333 pts
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: 4: 7: 9: Marked Agitation Normal Marked Calmness 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 Population
SZ-d
Schizophrenia, Schizophreniform, or Schizoaffective Schizophrenia, Schizophreniform, or Schizoaffective Bipolar, Manic, or Mixed Episode Dementia, Alzheimer’s, Vascular, or Mixed

Duration IM Period
24 hr

Treatment Groups
IM olanzapine IM haloperidol IM placebo

Dose (mg)
2.5, 5, 7.5, 10 7.5 10 7.5 10 2 2.5, 5 1

SZ

24 hr

IM olanzapine IM haloperidol IM placebo IM olanzapine IM lorazepam IM placebo IM olanzapine IM lorazepam IM placebo

BIP

24 hr

DEM

24 hr

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 nongeriatric patients, respectively

36

Study Design: 4 Pivotal Studies 24 Hour IM Dosing Period
Study Period I Screening Period Study Period II Double-Blind Therapy Period IM olanzapine Eligible Patients IM comparator IM placebo

24 hrs Screening > 2 hrs > 4 hrs (SZ-d, SZ) > 1 hr (BIP, DEM) Inj. #2 (if clinically indicated) Inj. #3 (if clinically indicated)
37

Randomization Inj. #1

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
Demographica
Age: Mean Min Max Sex: % Male Female Origin: % Caucasian African descent Hispanic Asian Other
a

SZ-d
(N=270) 36 18 73 57.4 42.6 65.9 24.1 0 1.5 8.5

SZ
(N=311) 38 18 72 65.6 34.4 72.7 19.0 5.5 1.0 1.9

BIP
(N=201) 39 18 79 53.2 46.8 72.6 15.9 6.0 4.0 1.5

DEM
(N=272) 77 54 97 39.0 61.0 92.3 5.9 1.5 0 0.4
40

No significant differences between treatment groups within each of the four studies

Clinical Characteristics at Baseline: Four Pivotal Studies
SZ-d Study (N=270) Psychosis (%) Length of Current Admission: - < 5 days (%) - 6 – 30 days (%) - > 30 days (%) Psychiatric Scales: (Mean scores) - BPRS Total - Young Mania Rating Scale - Mini Mental State Exam 55.5 57.0 47.8 26.0 53.8 11.8 100% SZ Study (N=311) 100% BIP Study (N=201) 52.3% DEM Study (N=272) 44.5%

44.2% 45.4% 10.4%

64.3% 33.3% 2.5%

84.9% 13.5% 1.7%

51.3% 20.1% 28.6%

41

Baseline Level of Agitation: Mean PANSS EC Scores of 4 Pivotal Studies
PANSS Excited Componenta Mean Baselineb Upper Limit Schizophrenia Schizophrenia Bipolar Dosing Study Study Mania Study (N=270) (N=311) (N=201) 19.0 32.0 18.3 29.0 17.8 30.0 Dementia Study (N=272) 19.8 34.0

a b

Total Score Range is 5 - 35; Minimum Criteria Score for inclusion: ≥ 14 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
60 50 Frequency
Frequency
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

Schizophrenia - all patients
60 50 40 30 20 10 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

40 30 20 10 0 Baseline PANSS Excited Score

Baseline PANSS Excited Score

60 50 Frequency

Bipolar - all patients

60 50
Frequency

Dementia - all patients

40 30 20 10 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

40 30 20 10 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

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 4 Mean Baseline 3 2 1 0
Excitement Hostility Poor Impulse Control Tension

BIP DEM

N=199 N=272

Uncooperativeness
44

* All treatment groups

Efficacy and Safety of IM Olanzapine
• Pharmacokinetics • Clinical methodology and rationale

• Efficacy results

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

• Safety
45

Primary Analysis: Efficacy at 2 Hours
PANSS Excited Component
Mean change from baseline to 2 hrs post first IM inj (LOCF)
6 4 2 0 -2 -4 -6 -8 -10 -12 -14 -16 Mean Change from Baseline
Baseline Means: 19.0 18.3 17.8 19.8

* * * * * * * * * † * *

Placebo IMOlz 2.5 IMOlz 5.0 IMOlz 7.5 IMOlz 10 IMHal 7.5 IMLzp

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 Percentage of Patients 80 70 60 50 40 30 20 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
* * * * * * * * * * * *

Placebo IMOlz 2.5 IMOlz 5 IMOlz 7.5 IMOlz 10 IMHal 7.5 IMLzp

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 -2 -3 -4 -5 -6 -7 -8 SZ-d SZ BIP DEM
* p < 0.05 vs. placebo
48
* * * * * * * * *

Placebo IMOlz 2.5 IMOlz 5 IMOlz 7.5 IMOlz 10 IMHal 7.5 IMLzp

PANSS EC By-Item Analysis: 2 Hours (LOCF)
Significant Contribution of All 5 Items: 5-10 mg Olz vs. Placebo
2 1 0 Mean Change from Baseline Mean Change from Baseline -1 -2 -3 -4 -5 -6
Poor Impulse Control Tension Hostility Uncooperativeness Excitement
* * * * * * * * * * ** * * ** * ** * * * * *

Schizophrenia Dose

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

Schizophrenia

Placebo
* * * * * * * *

IMOlz 10 IMHal

Hostility

Uncooperativeness

Excitement

2 1 Mean Change from Baseline 0 -1 -2 -3 -4 -5 -6
Poor Impulse Control

Bipolar
Mean Change from Baseline

2 1 0
Placebo
*

Dementia

-1 -2 -3 -4 -5 -6
Poor Impulse Control Tension Hostility Uncooperativeness Excitement
* * * * * * * * * * *

*

*

*

*

*

IMOlz 10 IMLzp

Placebo IMOlz 2.5 IMOlz 5.0 IMLzp

Tension

Hostility

Uncooperativeness

Excitement

* 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
Mild Calm

*

*

*

4
Normal

3
Mild Agit.

2
Mod. Agit.

Placebo IMOlz 2.5 IMOlz 5 IMOlz 7.5 IMOlz 10 IMHal 7.5 IMLzp

1
Marked Agit.

SZ-d
2.3

SZ
2.5

BIP
2.3

DEM
2.2
50

Baseline Mean:
4546.01

* p < 0.05 vs placebo for mean change † p < 0.05 vs hal (SZ-d) or lzp (BIP) for mean change

Efficacy in Agitation at 2 Hours: Corrigan / Cohen-Mansfield
Mean change from baseline to 2 hours post first IM inj (LOCF)
Baseline Means:

Mean Change from Baseline

4 2 0 -2 -4 -6 -8 -10 -12
*

30.5

27.5

28.3

7.0

* * * * * *
† †

* * *

*

Placebo IMOlz 2.5 IMOlz 5.0 IMOlz 7.5 IMOlz 10 IMHal 7.5 IMLzp

SZ-d
CABS Range: 14-56 CMAI Range: 0-30

SZ

BIP

DEM
51

* p < 0.05 vs. placebo † p < 0.05 vs. hal (SZ-d) or lzp (BIP)

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 -1 -2 -3
Mean Change

Time (mins)

-4 -5 -6 -7 -8 -9

Placebo IM Olz IM Hal
*

*

*

* * * * * * * *
52

† * p < 0.05 vs. Placebo † p < 0.05 vs. Haloperidol

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
Mean Change in PEC
Mean Change in PEC

0 -2 -4 -6 -8 -10
* *
Placebo IMOlz 10 IMHal 7.5

-2 -4 -6
* *
Placebo IMOlz 10 IMHal 7.5

-8 -10

* p < 0.05 vs. placebo
53

Number of IM Injections During 24 Hours:
Schizophrenia Dose Ranging Study
100% Percentage of Patients 80% 60% 40% 20% 0% Placebo IMOlz 2.5mg IMOlz 5mg IMOlz 7.5mg IMOlz 10mg IMHal 7.5mg 3 Inj 2 Inj 1 Inj
* * * * *

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 (N=104) Non-Psychotic (N=95)

0 -2 -4 -6 -8 -10 -12
*
Mean Change
Placebo n=24 IM Olz 10 n=52 IM Lzp n=28

0 -2 -4 -6 -8 -10 -12
Mean Change
Placebo n=26 IMOlz 10 n=46 IMLzp n=23

*

* 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 (N=146) Non-Psychotic (N=117)

0 -2 -4 -6 -8 -10
Mean Change
Placebo IMOlz 2.5 IMOlz 5.0 IMLzp n=40 n=35 n=32 n=39

0 -2 -4 -6 -8 -10
* p < 0.05 vs. placebo
56
Placebo IMOlz 2.5 IMOlz 5.0 IMLzp n=23 n=36 n=30 n=28

*

*

*

Mean Change

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

• Geriatric Placebo-Controlled
(DEM) Olanzapine: N = 137 Placebo: N = 67

• Overall Patient Database
(All agitated patients)

• Haloperidol-Controlled
(SZ-d, SZ) Olanzapine: N = 316 Haloperidol: N = 166

Olanzapine: N = 722

• Overall Subject Database
(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 Somnolence Dizziness Asthenia Hypotension Postural Hypotension Tremor Olanzapine
N=415

Placebo
N=150

6 4 2 2 1 1

3 2 1 0 0 0
61

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

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
Adverse Event Somnolence Headache Accidental Injury Dizziness Tachycardia Tremor Vasodilation Vomiting Percentage of Patients With Event Olanzapine Placebo N=137 N=67 4 3 3 0 2 0 2 0 1 0 1 0 1 0 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 – extrapyramidal syndrome – dyspepsia – 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 sedationrelated 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 n % Bradycardia w/ Hypotension n %

Healthy Subjects (N = 85) Patients (N = 765*) Total (N = 850)

28 36 64

32.9 4.7 7.5

19 21 40

22.4 2.7 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
α antagonism (Ki=19 nM) 1 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 α blocking agents at baseline (e.g., antipsychotics) 1

• 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
12
Percentage of Patients
Basal / Resting
*

Placebo

IMOlz

Positional Challenge

10 8 6 4 2 0
Low Supine Systolic Low Supine Diastolic Low Supine Pulse Low Standing Systolic Low Standing Diastolic High Standing Pulse Ortho Drop
* *

* p < 0.05 vs. placebo

74

Vital Signs: Change to Value Outside Reference Range - Any Time During 24 Hrs
Haloperidol-Controlled Database
12
Percentage of Patients
Basal / Resting
IMOlz IMHal

Positional Challenge

10 8 6 4 2 0
Low Supine Systolic Low Supine Diastolic Low Supine Pulse Low Standing Systolic Low High Standing Standing Diastolic Pulse Ortho Drop
75
*

* p < 0.05 vs. Olz

Vital Signs: Change to Value Outside Reference Range – Any Time During 24 Hrs
Geriatric Placebo-Controlled Database
Placebo IMOlz 2.5 IMOlz 5

14
Percentage of Patients

Basal / Resting

Positional Challenge

12 10 8 6 4 2 0
Low Supine Systolic Low Supine Diastolic
♦ ♦

Low Supine Pulse

Low Standing Systolic

Low Standing Diastolic

High Standing Pulse

Ortho Drop
♦: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
Event Classification Dizziness Syncope Olz N=415 n % 17 1 4.1% 0.2% Pla N=150 n % 3 0 2.0% 0% Olz N=316 n % 8 0 2.5% 0% Hal N=166 n % 3 0 1.8% 0%

Oral Dataa
Event Classification Dizziness Syncope
a

N.S.D. between treatment groups

Olz N=882 n % 62 6 7.0%* 0.7%

Pla N=517 n % 20 3 3.9% 0.6%

Olz N=2213 n % 140 11 6.3% 0.5%

Hal N=1240 n % 65 3 5.2% 0.2%

Oral olanzapine 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
10 9 8 7 6 5 4 3 2 1 0
≥ 97.5 Percentile

Mean Change in QTc (msec) at 2 hrs IM Pla IM Olz
(N = 148) (N = 408)

Percentage of Patients

Mean change SD p-value vs. pla

-0.7 22.0 --

-3.0 21.5 0.199
♦ : n=0

Placebo IMOlz
♦ ♦

≥ 99 Percentile

≥ 500 msec ≥ 99 Percentile: ≥ 450 msec male ≥ 470 msec female N.S.D. on any measure vs. placebo
79

≥ 97.5 Percentile: ≥ 430 msec male ≥ 450 msec female

QTc Intervals: 2 Hours Post-Injection Haloperidol-Controlled Database
Percentage of Patients 10 9 8 7 6 5 4 3 2 1 0
≥ 97.5 Percentile ≥ 99 Percentile

Mean Change in QTc (msec) at 2 hrs IM Olz IM Hal
(N = 312) (N = 164)

Mean change SD p-value vs. hal

-3.3 21.7 0.006

1.8 24.0 -IMOlz IMHal
♦ : n=0

≥ 500 msec ≥ 99 Percentile: ≥ 450 msec male ≥ 470 msec female

≥ 97.5 Percentile: ≥ 430 msec male ≥ 450 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 Coronary artery disorder Cerebrovascular / Peripheral vascular dis. Congestive heart failure Diabetes Electrocardiographic disorder Hypercholesterolemia Hypertension Hypothyroidism Respiratory disorder Right / Left Bundle Branch Block Pacemakers Percent of Patients 32.0 12.9 12.9 11.4 10.7 6.3 41.2 13.6 13.2 8.1 / 3.7 2.2
81

Original QTc Data*: Dementia Study
Mean Change from Baseline to 2 Hours
Treatment IM Olanzapine 2.5 mg IM Olanzapine 5.0 mg IM Lorazepam IM Placebo N 69 61 64 62 Baseline Mean**
(msec)

Endpoint Mean
(msec)

Change Mean
(msec)

p-value for change vs. pla 0.171 0.214 0.493 --

430.3 419.0 432.1 432.6

426.3 428.0 431.0 435.1

-4.0 9.0 -1.2 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
Treatment IM Olanzapine 2.5 mg IM Olanzapine 5.0 mg IM Lorazepam IM Placebo N 68 61 63 61 Baseline Mean**
(msec)

Endpoint Mean
(msec)

Change Mean
(msec)

p-value for change vs. pla 0.044 0.936 0.019 --

436.9 430.5 437.4 436.2

432.4 433.5 431.2 439.5

-4.5 3.1 -6.2 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 Percentage of Patients 25 20 15 10 5
*

Mean Change in QTc (msec) at 2 hrs IM Pla IM Olz2.5 IM Olz5
(N = 61) (N = 68) (N = 61)

Mean change SD p-value vs. pla

3.3 21.1 --

-4.5 22.0 0.044

3.1 24.6 0.936
Placebo IMOlz 2.5 IMOlz 5

* p < 0.05 vs. placebo

0
≥ 97.5 Percentile ≥ 99 Percentile ≥ 500 msec ≥ 97.5 Percentile: ≥ 430 msec male ≥ 450 msec female ≥ 99 Percentile: ≥ 450 msec male ≥ 470 msec female
85

Comparison of Cmax after IM Doses vs. Oral Olanzapine Steady-State Concentrations
Study HGAJ Study HGJA

Daily Dose 1 to 6 weeks n = 474 in 333 pts
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
1.4 Percentage of Patients 1.2 1 0.8 0.6 0.4 0.2 0
≥ 97.5 Percentile
♦ ♦ ♦ ♦ ♦

Study HGAJ:

Mean Change in QTc (msec)
Oral 15mg (N=175) 1.244 30.0 Oral 20 mg (N=309) -0.074 26.1

Oral 5 mg Oral 10 mg (N=117) (N=150) Mean Change 1.632 -0.717 SD 46.3 35.3

♦ : n=0

Oral 5 mg Oral 10 mg Oral 15 mg Oral 20 mg

≥ 99 Percentile

≥ 500 msec

≥ 97.5 Percentile: ≥ 430 msec male ≥ 450 msec female

≥ 99 Percentile: ≥ 450 msec male ≥ 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 0.6 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 -1 Barnes Global Score
-0.77

0.58

*

Mean Change from Baseline

0.15

*

-0.07 -0.06 -0.07
† †

-0.11 -0.11
† †

-0.31 -0.46

Placebo IMOlz 2.5 IMOlz 5 IMOlz 7.5 IMOlz 10 IMHal 7.5 * p < 0.05 vs. pla

-0.89

-0.89

† p < 0.05 vs. hal

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 0.5 0
-0.08 0.01 0.7

*

-0.5 -1

-0.27


-0.61

Placebo IMOlz 10 IMHal 7.5

-1.19

* p < 0.05 vs. pla † p < 0.05 vs. hal

-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 -0.3 -0.4 -0.5 -0.6 -0.7 Barnes Global Score Simpson-Angus Total
92

-0.26

-0.23

-0.39 -0.49 -0.61

Placebo IMOlz 10 IMLzp

N.S.D. between treatment groups at any measure

Extrapyramidal Symptoms:
Dementia Study
Mean change from baseline to 24 hrs post first inj (LOCF)
0 Mean Change from Baseline -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 Simpson-Angus Total
N.S.D. between any measure vs. placebo
93
-0.37 -0.18 -0.20 -0.25

Placebo IMOlz 2.5 IMOlz 5 IMLzp

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