1 Psychopharmacological Drugs Advisory Committee Meeting February 14, 2001 NDA 21-253 Intramuscular Olanzapine for the Rapid Control of Agitation Eli Lilly

1

Psychopharmacological Drugs Advisory Committee Meeting

February 14, 2001

NDA 21-253

Intramuscular Olanzapine for the

Rapid Control of Agitation

Eli Lilly and CompanyIndianapolis, IN

2

• The Agitated Patient

• Clinical Development of IM Olanzapine

Agenda

John Kane, M.D.

Alan Breier, M.D.

3

The Agitated Patient

John Kane, M.D.

ChairmanDepartment of Psychiatry

Hillside Hospital Glen Oaks, NY

and Professor of Psychiatry, Neurology, and Neuroscience

The Albert Einstein College of MedicineBronx, NY

4

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

5

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

6

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

7

Agitation: A Major Clinical ChallengePsychiatric 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)

8

Agitation: A Major Clinical ChallengeMechanical 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)

9

Agitation: A Major Clinical ChallengeAssaults

• 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)

10

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

11

Limitations of

Parenteral Pharmacotherapy for Agitation

Benzodiazepines– respiratory depression– excessive sedation– disinhibition

Typical Antipsychotics– acute dystonia– akathisia– excessive sedation – Neuroleptic Malignant Syndrome

12

Acute Treatments for Agitation vs.

Sustained Therapies for Specific Diseases Urgent Treatments for Agitation Sustained Therapies for Disease

Modality Duration Modality Duration

Schizo-phrenia

Structured Environment Psychosocial Interventions

IMa Antipsychotics / Benzodiazepines

Min-Hrs

Oral / Depot Antipsychotics

Wks-

Mos-Yrs

Bipolar Disorder

Structured Environment Psychosocial Interventions

IM Benzodiazepines / Antipsychotics

Min-Hrs

Oral Mood Stabilizers / Antipsychotics

Wks-

Mos-Yrs

Dementia of Alz. Type

Structured Environment Environmental Interventions Cholinesterase Inhibitors

IM Benzodiazepines / Antipsychotics

Min-Hrs

Oral Agents (e.g., depakote, carbamazepine, antipsychotics)

Wks-

Mos-Yrs

a When oral therapy is not feasible

13

Clinical Development of IM Olanzapine

Alan Breier, M.D.

Leader, Zyprexa Product Team Lilly Research Fellow

Lilly Research Laboratories and

Professor of PsychiatryIndiana University School of Medicine

14

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

15

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)

16

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)

17

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

18

Efficacy and Safety of IM Olanzapine

• Pharmacokinetics

• Clinical methodology and rationale

• Efficacy results

• Safety

19

Mean Values of Olanzapine PK Variables:

One 10 mg Oral Dose vs. Two 5 mg IM Doses

Cmax (ng/mL) 15.1 23.7

AUC (nghr/mL) 499 522

CLp (L/hr) 22.1 20.2

T½ (hr) 31.0 30.4

Vd (L/kg) 12.2 11.1

PK units Oral IMParameter 10 mg 2x5 mg

N = 22 healthy subjects

20

Mean Olanzapine Plasma Concentrations:

One 10 mg Oral Dose vs. Two 5 mg IM Doses

Mean Data, N=22

Time (hr)

0 24 48 72 96 120

Olanza

pine Mea

n Plasm

a Conc. (ng/m

L)

0

5

10

15

20

10 mg Oral Dose2 x 5 mg IM Doses

Time (hr)

0 2 4 6 8 10 12Plasm

a Conc.

(ng/m

L)

0

5

10

15

20

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

21

Mean Olanzapine Plasma Concentrations:

Three 10 mg IM Doses

Time (hours)0 4 8 12 16 20 24

Ola

nza

pin

e M

ean

Pla

sma

Co

nce

ntr

atio

n (

ng

/mL

)

0

10

20

30

40

Mean plasma concentration following three 10 mg doses of IM olanzapine

N = 20 non-agitated patients

22

Comparison of Cmax after IM Doses vs. Oral

Olanzapine Steady-State Concentrations

Study HGAJ Study HGJA

Daily Dose1 to 6 weeks

n = 474 in 333 pts

23

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

24





• Safety

25

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

26

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)

27

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

28

PANSS Excited Component: Items and Anchor DescriptionsPoor 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

29

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 Agitation4 : Normal 7 : Marked Calmness9 : Unarousable

• Reliability and validity established

30


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)

31


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

32

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

33

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

34

Study Designs

Four Pivotal Studies

35

Agitation: 4 Pivotal StudiesStudy Agitated Patient

Population Duration IM Period

Treatment Groups

Dose (mg)

SZ-d Schizophrenia, Schizophreniform, or Schizoaffective

24 hr IM olanzapine IM haloperidol IM placebo

2.5, 5, 7.5, 10

7.5

SZ Schizophrenia, Schizophreniform, or Schizoaffective

24 hr IM olanzapine IM haloperidol IM placebo

10 7.5

BIP Bipolar, Manic, or Mixed Episode

24 hr IM olanzapine IM lorazepam IM placebo

10 2

DEM Dementia, Alzheimer’s, Vascular, or Mixed

24 hr IM olanzapine IM lorazepam IM placebo

2.5, 5 1

36

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

37

Study Design: 4 Pivotal Studies24 Hour IM Dosing Period

Study Period I Study Period II

ScreeningPeriod

Eligible

Patients

Double-Blind Therapy Period

IM olanzapine

IM placebo

IM comparator

Screening> 2 hrs

Inj. #1

Inj. #2(if clinicallyindicated)

> 4 hrs (SZ-d, SZ)> 1 hr (BIP, DEM)

Inj. #3(if clinicallyindicated)

24 hrs

Randomization

38

• 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

Criteria for Inclusion in Agitation Study

39

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

40

Patient Characteristics:Demographics

DemographicaSZ-d

(N=270)SZ

(N=311)BIP

(N=201)DEM

(N=272)

Age:MeanMinMax

361873

381872

391879

775497

Sex: %MaleFemale

57.442.6

65.634.4

53.246.8

39.061.0

Origin: %CaucasianAfrican descentHispanicAsianOther

65.924.1

01.58.5

72.719.05.51.01.9

72.615.96.04.01.5

92.35.91.50

0.4

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

41

Clinical Characteristics at Baseline:Four Pivotal Studies

SZ-d Study

(N=270)

SZ Study

(N=311)

BIP Study

(N=201)

DEM Study

(N=272)

Psychosis (%)

100%

100%

52.3%

44.5%

Length of Current Admission: - < 5 days (%) - 6 – 30 days (%) - > 30 days (%)

44.2% 45.4% 10.4%

64.3% 33.3% 2.5%

84.9% 13.5% 1.7%

51.3% 20.1% 28.6%

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

42

Baseline Level of Agitation:

Mean PANSS EC Scores of 4 Pivotal Studies

PANSS Excited Componenta

Schizophrenia Dosing Study

(N=270)

Schizophrenia Study

(N=311)

Bipolar Mania Study

(N=201)

Dementia Study

(N=272)

Mean Baselineb

19.0

18.3

17.8

19.8

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

43

PANSS Excited Component:

Distribution of Total Scores at Baseline

0

10

20

30

40

50

60

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

Fre

qu

ency

0

10

20

30

40

50

60

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


Fre

qu

ency

0

10

20

30

40

50

60

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


Fre

qu

ency

0

10

20

30

40

50

60

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


Fre

quen

cy

Schizophrenia Dose - all patients

Dementia - all patients

Schizophrenia - all patients

Bipolar - all patients

44

Baseline Agitation Across Disease States*

PANSS EC: Mean Scores of the 5 Items

* All treatment groups

0

1

2

3

4

5

Excitement Hostility Poor ImpulseControl

Tension Uncooper-ativeness

Mea

n B

asel

ine

SZ-d/SZ N=581

BIP N=199

DEM N=272

45

Efficacy and Safety of IM Olanzapine• Pharmacokinetics


• 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

46

Primary Analysis: Efficacy at 2 Hours

PANSS Excited Component

Mean change from baseline to 2 hrs post first IM inj (LOCF)

-16-14-12-10-8-6-4-20246

SZ-d SZ BIP DEM

Me

an

Ch

an

ge

fro

m B

ase

line

Placebo

IMOlz 2.5

IMOlz 5.0

IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp

* p < 0.05 vs. placebo† p < 0.05 vs. lzp

*

* **

* **

** *

†

*

Baseline Means:

19.0 18.3 17.8 19.8

47

Response RatesPANSS Excited Component - 2 Hours After First Injection

0

10

20

30

40

50

60

70

80

90

SZ-d SZ BIP DEM

Per

cen

tag

e o

f P

atie

nts

Placebo

IMOlz 2.5

IMOlz 5

IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp

40% decrease in PANSS Excited Component from Baseline to 2 hours post first IM injection

* p < 0.05 vs. placebo for all

*

*

*

*

*

**

*

**

**

48

Efficacy at 24 Hours:PANSS Excited Component

Mean change from baseline to 24 hrs (LOCF)

-8

-7

-6

-5

-4

-3

-2

-1

0

SZ-d SZ BIP DEM

Mea

n C

han

ge

fro

m B

asel

ine

Placebo

IMOlz 2.5

IMOlz 5

IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp

* p < 0.05 vs. placebo

* *

*

* **

**

*

Baseline Means: 19.0 18.3 17.8 19.8

49

PANSS EC By-Item Analysis: 2 Hours (LOCF)

Significant Contribution of All 5 Items: 5-10 mg Olz vs. Placebo

* p<0.05 vs. placebo

-6

-5

-4

-3

-2

-1

0

1

2

Poor ImpulseControl

Tension Hostility Uncooper-ativeness

Excitement

Mea

n Ch

ange

from

Bas

elin

e

Placebo

IMOlz 10

IMLzp

**

**

**

-6

-5

-4

-3

-2

-1

0

1

2

Poor ImpulseControl


Excitement

Mea

n Ch

ange

from

Bas

elin

e

PlaceboIMOlz 2.5IMOlz 5.0IMOlz 7.5IMOlz 10IMHal

* **

** * **

*

***

*

***

*

**

** *

*

*

Schizophrenia Dose

Bipolar

-6

-5

-4

-3

-2

-1

0

1

2

Poor ImpulseControl


Excitement

Mea

n Ch

ange

from

Bas

elin

e

Placebo

IMOlz 10

IMHal

-6

-5

-4

-3

-2

-1

0

1

2

Poor ImpulseControl


Excitement

Mea

n Ch

ange

from

Bas

elin

ePlacebo

IMOlz 2.5

IMOlz 5.0

IMLzp

******* * ** *

Schizophrenia

Dementia

* ** *

* * * ** *

50

Efficacy at 2 Hours:

Agitation-Calmness Evaluation Scale

Mean Value at Endpoint - 2 hours (LOCF)

1 Marked Agit.

2Mod. Agit.

3 Mild Agit.

4Normal

5 Mild Calm

6 Mod. Calm

SZ-d SZ BIP DEM

Placebo

IMOlz 2.5

IMOlz 5

IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp

Baseline Mean: 2.3 2.5 2.3 2.2* p < 0.05 vs placebo for mean change† p < 0.05 vs hal (SZ-d) or lzp (BIP) for mean change4546.01

** *

*

*

**

*

** *

††

51

Efficacy in Agitation at 2 Hours:

Corrigan / Cohen-Mansfield

Mean change from baseline to 2 hours post first IM inj (LOCF)

-12

-10

-8

-6

-4

-2

0

2

4

SZ-d SZ BIP DEM

Me

an

Ch

an

ge

fro

m B

ase

line

Placebo

IMOlz 2.5

IMOlz 5.0

IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp

*

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

*

*†

*†

* *

*

*

* *

*

†

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

Baseline Means:

30.5 27.5 28.3 7.0

52

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 15 30 45 60 75 90 105 120

Placebo

IM Olz

IM Hal

Me

an

C

ha

ng

e

Time (mins)

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

*

*

** * *

*

**

*

*†

†

†

Onset of Efficacy: PANSS ECSchizophrenia Study

Timepoint-wise change from baseline to 2 hrs post first IM inj (LOCF)

53

Efficacy at 2 Hrs by Baseline Severity:

Schizophrenia Study

-10

-8

-6

-4

-2

0

Me

an

Ch

an

ge

in

PE

C

Placebo

IMOlz 10

IMHal 7.5

Score < Average (18) Score Average (18)

-10

-8

-6

-4

-2

0

Me

an

Ch

an

ge

in

PE

C

Placebo

IMOlz 10

IMHal 7.5


Efficacy comparison based on mean split of baseline PEC

* *

* *

54

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

0%

20%

40%

60%

80%

100%

Placebo IMOlz2.5mg

IMOlz5mg

IMOlz7.5mg

IMOlz 10mg

IMHal7.5mg

Per

cen

tag

e o

f P

atie

nts

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.

55

Efficacy Assessed by Presence of

Psychosis Comparison at 2 Hours: Bipolar Study

PANSS EC: Mean change from baseline (LOCF)

-12

-10

-8

-6

-4

-2

0

Mean Change

Placebo n=24

IMOlz 10 n=52

IMLzp n=28

-12

-10

-8

-6

-4

-2

0

Mean Change

Placebo n=26

IMOlz 10 n=46

IMLzp n=23

Non-Psychotic(N=95)

Psychotic(N=104)


*

*

56

Efficacy Assessed by Presence of

Psychosis Comparison at 2 Hrs: Dementia Study

-10

-8

-6

-4

-2

0

Mean Change

Placebo n=23

IMOlz 2.5 n=36

IMOlz 5.0 n=30

IMLzp n=28

Psychotic(N=146)

Non-Psychotic (N=117)

-10

-8

-6

-4

-2

0

Mean Change

Placebo n=40

IMOlz 2.5 n=35

IMOlz 5.0 n=32

IMLzp n=39


**

*

PANSS EC: Mean change from baseline (LOCF)

57





• Safety– Treatment-Emergent Adverse Events

– Sedation

– Laboratory Analyses

– Vital Signs

– Electrocardiograms

– Extrapyramidal Symptoms

58

Summary of Safety Databases

• Placebo-Controlled

(SZ-d, SZ, BIP)

Olanzapine: N = 415

Placebo: N = 150

• Haloperidol-Controlled

(SZ-d, SZ)

Olanzapine: N = 316

Haloperidol: N = 166

• Geriatric Placebo-Controlled

(DEM)

Olanzapine: N = 137

Placebo: N = 67

• Overall Patient Database

(All agitated patients)

Olanzapine: N = 722

• Overall Subject Database

(All patients and healthy subjects)

Olanzapine: N = 850

59

Adverse Events

60

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)

61

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 OlanzapineN=415

PlaceboN=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

62

Adverse Events: 24 Hour IM Period

Geriatric Placebo-Controlled DatabaseTreatment-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 N=137

Placebo 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

63

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

64

Sedation

65

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

66

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) ofIM olanzapine-treated patients

• No significant difference between IM olanzapine and any other treatment group (including placebo) in the incidence of somnolence.

67

Laboratory Analyses

68

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)

69

Vital Signs

70

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

71

Bradycardia Bradycardia Bradycardia w/ Hypotension

n % n %

• Heart rate determined by palpation – 21.0 (mean) times per subject– 2.4 (mean) vital signs meeting criteria for bradycardia

*Includes agitated patients (N = 722) and non-agitated patients (N = 43)

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

72

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%)

73

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

74

Vital Signs: Change to Value Outside

Reference Range - Any Time During 24 Hrs


0

2

4

6

8

10

12

LowSupineSystolic

LowSupine

Diastolic

LowSupinePulse

LowStandingSystolic

LowStandingDiastolic

HighStanding

Pulse

OrthoDrop

Perc

en

tag

e o

f P

ati

en

ts

Placebo IMOlz


*

*

*

Basal / Resting Positional Challenge

75


Reference Range - Any Time During 24 Hrs

Haloperidol-Controlled Database

0

2

4

6

8

10

12

LowSupineSystolic

LowSupine

Diastolic

LowSupinePulse

LowStandingSystolic


HighStanding

Pulse

OrthoDrop

Pe

rce

nta

ge

of

Pa

tie

nts

IMOlz IMHal

* p < 0.05 vs. Olz

*


76


Reference Range – Any Time During 24 Hrs

Geriatric Placebo-Controlled Database

0

2

4

6

8

10

12

14

LowSupineSystolic

LowSupine

Diastolic

LowSupinePulse

LowStandingSystolic


HighStanding

Pulse

OrthoDrop

Pe

rce

nta

ge

of

Pa

tie

nts

Placebo IMOlz 2.5 IMOlz 5

: n = 0N.S.D. between Olz and Pla on any measure


77

Incidence of Treatment-Emergent Dizziness

and Syncope: Data from IM and Oral Studies

OlzN=415

PlaN=150

OlzN=316

HalN=166Event

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%

Intramuscular Data

Olz N=882

Pla N=517

Olz N=2213

Hal N=1240

Event 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%

Oral Dataa

aOral olanzapine clinical trial database: Phase 2, 3, and 4 placebo-controlled / haloperidol-controlled oral olanzapine studies

N.S.D. between treatment groups

*p < 0.05 vs. placebo

78

Electrocardiograms

79

QTc Intervals: 2 Hours Post-Injection


0

1

2

3

4

5

6

7

8

9

10

Per

cen

tag

e o

f P

atie

nts

Placebo

IMOlz

500 msec

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

Mean Change in QTc (msec) at 2 hrsIM Pla IM Olz

(N = 148) (N = 408)Mean change -0.7 -3.0SD 22.0 21.5p-value vs. pla -- 0.199

99 Percentile 97.5 Percentile

99 Percentile: 450 msec male 470 msec female

97.5 Percentile: 430 msec male 450 msec female

: n = 0

80


Haloperidol-Controlled Database

0

1

2

3

4

5

6

7

8

9

10

Per

cen

tag

e o

f P

atie

nts

IMOlz

IMHal

500 msec

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

Mean Change in QTc (msec) at 2 hrsIM Olz IM Hal

(N = 312) (N = 164)Mean change -3.3 1.8SD 21.7 24.0p-value vs. hal 0.006 --

97.5 Percentile 99 Percentile



: n = 0

81

Dementia Study: Age and Co-Morbid Conditions • Advanced age of population:

• 45.2% of patients > 80 years; 8.8% > 90 years

• Cardiac / Respiratory ConditionsCondition Percent of Patients

Coronary artery disorder 32.0Cerebrovascular / Peripheral vascular dis. 12.9Congestive heart failure 12.9Diabetes 11.4Electrocardiographic disorder 10.7Hypercholesterolemia 6.3Hypertension 41.2Hypothyroidism 13.6Respiratory disorder 13.2Right / Left Bundle Branch Block 8.1 / 3.7Pacemakers 2.2

82

Original QTc Data*: Dementia Study Mean Change from Baseline to 2 Hours

Baseline Endpoint Change

Treatment

N Mean**

(msec) Mean (msec)

Mean (msec)

p-value for 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)

83

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

84

Re-Read QTc Data*: Dementia Study Mean Change from Baseline to 2 Hours

Baseline Endpoint Change

Treatment NMean**

(msec)Mean(msec)

Mean(msec)

p-value forchange 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

85

0

5

10

15

20

25

30

Per

cen

tag

e o

f P

atie

nts

Placebo

IMOlz 2.5

IMOlz 5

500 msec


Mean Change in QTc (msec) at 2 hrsIM Pla IM Olz2.5 IM Olz5

(N = 61) (N = 68) (N = 61)

Mean change 3.3 -4.5 3.1SD 21.1 22.0 24.6p-value vs. pla -- 0.044 0.936

99 Percentile 97.5 Percentile

*




Geriatric Placebo-Controlled Database

86

Comparison of Cmax after IM Doses vs. Oral

Olanzapine Steady-State Concentrations

Study HGAJ Study HGJA

Daily Dose1 to 6 weeks

n = 474 in 333 pts

87

QTc Intervals: Normal to Prolonged

6-week Oral Study in Schizophrenia

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Per

cen

tag

e o

f P

atie

nts

Oral 5 mg

Oral 10 mg

Oral 15 mg

Oral 20 mg

500 msec

97.5 Percentile 99 Percentile



Study HGAJ: Mean Change in QTc (msec)

Oral 5 mg Oral 10 mg Oral 15mg Oral 20 mg (N=117) (N=150) (N=175) (N=309)

Mean Change 1.632 -0.717 1.244 -0.074SD 46.3 35.3 30.0 26.1

Patients who were on the specified dose for at least 5 days prior to the ECG

: n = 0

88

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

89

Extrapyramidal Symptoms

90

Extrapyramidal Symptoms: Schizophrenia Dose Ranging Study


* p < 0.05 vs. pla

† p < 0.05 vs. hal

-0.07

-0.31

-0.06

-0.77

-0.07

-0.89

-0.11

-0.46

-0.11

-0.89

0.15

0.58

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

Barnes Global Score Simpson-Angus Total

Mea

n C

han

ge

fro

m B

asel

ine

Placebo

IMOlz 2.5

IMOlz 5

IMOlz 7.5

IMOlz 10

IMHal 7.5

*

*

† † † †

†

†

†

†

91

Extrapyramidal Symptoms: Schizophrenia Study


-0.08

-1.19

-0.27

-0.61

0.01

0.7

-1.5

-1

-0.5

0

0.5

1


Mea

n C

hang

e fr

om B

asel

ine

Placebo

IMOlz 10

IMHal 7.5

†

*

†

* p < 0.05 vs. pla

† p < 0.05 vs. hal

92

Extrapyramidal Symptoms: Bipolar Mania Study


-0.26-0.23

-0.49

-0.61

-0.39

0.0

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0


Mea

n C

han

ge

fro

m B

asel

ine

Placebo

IMOlz 10

IMLzp

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

93

Extrapyramidal Symptoms: Dementia Study

Mean change from baseline to 24 hrs post first inj (LOCF)

-0.18

-0.37

-0.25

-0.20

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Simpson-Angus Total

Mea

n C

han

ge

fro

m B

asel

ine

Placebo

IMOlz 2.5

IMOlz 5

IMLzp

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

94

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

95

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

96

Documents

1 Psychopharmacological Drugs Advisory Committee Meeting February 14, 2001 NDA 21-253 Intramuscular Olanzapine for the Rapid Control of Agitation Eli Lilly