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1

Psychopharmacological DrugsAdvisory Committee Meeting

February 14, 2001

NDA 21-253

Intramuscular Olanzapine for the

Rapid Control of Agitation

Eli Lill and Com an



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 HospitalGlen Oaks, NY

andProfessor of Psychiatry, Neurology, and Neuroscience

The Albert Einstein College of MedicineBronx, NY



4

Agitation

• Common clinical challenge

• When severe, may be the target for urgentintervention

• Cuts across the boundaries of diverse diagnosticcategories

• 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



Agitation: A Major Clinical Challenge

Psychiatric Emergency

• A mean of 400 patients per month are evaluated ina typical Psychiatric Emergency Service (PES)(Currier 1999)

• 135,000 psychiatric emergency visits per year inNew York State alone (Allen 2000)




Mechanical Restraint

• 8.5% of all psychiatric emergency patients requiremechanical restraints for agitation (Currier 2000)

• Mean duration of restraint is 6 hours (Currier 2000)

• 111 fatalities over 10 years in New York facilities dueto restraints (Sundram 1994)

• Estimates of 50 - 150 deaths per year nationwide dueto restraints (Allen 2000)




Assaults

• A mean of 8 assaults per year occur in a typicalPsychiatric 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 todoctors, most likely related to nurses' role inrestraint application (Currier 2000)



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



Limitations of

Parenteral Pharmacotherapy for Agitation

Benzodiazepines – respiratory depression

– excessive sedation

– disinhibition

Typical Antipsychotics – acute dystonia

– akathisia

– excessive sedation – Neuroleptic Malignant Syndrome



Acute Treatments for Agitation vs.

Sustained Therapies for Specific Diseases

Urgent Treatments for Agitation Sustained Therapies for DiseaseModality Duration Modality Duration

Schizo-phrenia

Structured Environment PsychosocialInterventions

IMa Antipsychotics /Benzodiazepines

Min-Hrs

Oral / DepotAntipsychotics

Wks-Mos-Yrs

Bipolar Disorder

Structured Environment PsychosocialInterventions

IM Benzodiazepines /Antipsychotics

Min-Hrs

Oral Mood Stabilizers /Antipsychotics

Wks-Mos-Yrs

Dementia of Alz. Type

Structured Environment Environmental InterventionsCholinesterase Inhibitors

IM Benzodiazepines /Antipsychotics

Min-Hrs

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

Wks-Mos-Yrs

a When oral therapy is not feasible



Clinical Development of IM Olanzapine

Alan Breier, M.D.

Leader, Zyprexa Product TeamLilly Research Fellow

Lilly Research Laboratoriesand

Professor of PsychiatryIndiana University School of Medicine



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



History of Regulatory Interactions

May 14, 1998 Meeting with FDA

• FDA indicated IM antipsychotics are used for thecontrol of agitation in numerous disease states

• FDA recommended studies of agitated patients inmultiple 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)



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 CLINICALPHARMACOLOGY)



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



Efficacy and Safety of IM Olanzapine

• Pharmacokinetics

• Clinical methodology and rationale

• Efficacy results

• Safety



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 (ng×hr/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

a n z a p n e

e a n

a s m a

o n c . n g m

0

5

10

15

20

10 mg Oral Dose

2 x 5 mg IM Doses

Time (hr)0 2 4 6 8 10 12

P l a s m a C o n c .

( n g / m L )

0

5

10

15

20

Mean olanzapine plasma concentrations following administration of one10 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

C o n c e n t r a t i o

n ( n g / m L )

0

10

20

30

40

Mean plasma concentration following three 10 mg doses of IMolanzapine

N = 20 non-agitated patients



22

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



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 mginjections is similar to steady-state plasma concentrationafter 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 inagitation 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 ExcitedComponent (PANSS EC)

Secondary Efficacy Measures:

• Agitation-Calmness Evaluation Scale (ACES)

• Corrigan Agitated Behavior Scale (CABS)or

Cohen-Mansfield Agitation Inventory (CMAI)

S l ti f P i Effi M



27

Selection of Primary Efficacy Measure:

PANSS Excited Component

• Contains the common, core features identified inextensive 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

PANSS E it d C t



28

PANSS Excited Component:

Items and Anchor Descriptions

Poor Impulse Control - Disordered regulation and control of action oninner urges, resulting in sudden, unmodulated, arbitrary, or misdirecteddischarge 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, andassaultiveness.

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 moodliability.

Scoring: 1 = absent, 4 = moderate, 7 = extreme

S d Effi M



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 calmnessand 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 : Normal7 : Marked Calmness

9 : Unarousable

• Reliability and validity established

S d Effi M



30


Corrigan Agitated Behavior Scale (CABS)

• 14-item validated scale (Corrigan 1987)

• Rates the degree to which specific behaviors areobserved

– Degree ratings from 1 (absent) to 4 (extreme)

– Total scores range from 14 to 56

• Used in clinical trials of acute agitation acrossmultiple disease states

– e.g. schizophrenia, mania, psychoactive substance abuse,brain injury, Alzheimer's disease (Battaglia 1997, Corrigan1988 & 1996)

S d Effi M



31


Cohen-Mansfield Agitation Inventory (CMAI)

• Validated instrument designed to assess agitatedbehaviors 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-Mansfield1989)

– 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

P ti t P l ti S l t d



33

Patient Populations Selected:

Diverse Clinical Characteristics

• Schizophrenia, Bipolar Mania, and Dementiaencompass:

– 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 Studies

Study Agitated PatientPopulation DurationIM Period TreatmentGroups Dose(mg)

SZ-d Schizophrenia,Schizophreniform, or Schizoaffective

24 hr IM olanzapine

IM haloperidolIM placebo

2.5, 5,7.5, 10

7.5

SZ Schizophrenia,Schizophreniform, or Schizoaffective

24 hr IM olanzapineIM haloperidolIM placebo

107.5

BIP Bipolar, Manic, or

Mixed Episode

24 hr IM olanzapine

IM lorazepamIM placebo

10

2

DEM Dementia, Alzheimer’s,Vascular, or Mixed

24 hr IM olanzapineIM lorazepamIM placebo

2.5, 51



36

Comparator Dose Selection

IM Haloperidol 7.5 mg• 5 to 10 mg doses most commonly used

• Dose response analysis suggests that doses that exceed7.5 – 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

Study Design: 4 Pivotal Studies



37

Study Design: 4 Pivotal Studies

24 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 least1 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 thatwould preclude participation

Patient Characteristics:



40

Patient Characteristics:

Demographics

Demographica

SZ-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

65.924.10

1.58.5

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

Clinical Characteristics at Baseline:



41

Clinical Characteristics at Baseline:

Four Pivotal Studies

SZ-dStudy

(N=270)

SZStudy

(N=311)

BIPStudy

(N=201)

DEMStudy

(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--

47.826.0

-

53.8-

11.8

Baseline Level of Agitation:



42

Baseline Level of Agitation:

Mean PANSS EC Scores of 4 Pivotal Studies

PANSSExcitedComponent

a

SchizophreniaDosing Study

(N=270)

SchizophreniaStudy

(N=311)

Bipolar Mania Study

(N=201)

DementiaStudy

(N=272)

MeanBaselineb 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


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

F r e q u e n c y

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


F r e q u e n c y

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


F r e q u e n c y

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


F r e q u e n c y

Schizophrenia Dose - all patients

Dementia - all patients

Schizophrenia - all patients

Bipolar - all patients

Baseline Agitation Across Disease States*



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 Impulse

Control

Tension Uncooper-

ativeness

M e a n B a s e l i n e

SZ-d/SZ N=581BIP 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

Primary Analysis: Efficacy at 2 Hours



46

Primary Analysis: Efficacy at 2 Hours


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

-16

-14-12

-10

-8

-6-4-2

0

2

4

6

SZ-d SZ BIP DEM

M e a

n C h a n g e f r o m B

a s e l i n e

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

Response Rates



47

Response Rates

PANSS Excited Component - 2 Hours After First Injection

0

10

20

30

40

50

60

70

80

90

SZ-d SZ BIP DEM

P e r c e n t a g e o f

P a t i e n t s

Placebo

IMOlz 2.5

IMOlz 5IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp

≥ 40% decrease in PANSS Excited Componentfrom Baseline to 2 hours post first IM injection

* p < 0.05 vs. placebo for all

*

*

*

*

*

**

*

**

**

Efficacy at 24 Hours:



48



Mean change from baseline to 24 hrs (LOCF)

-8

-7

-6

-5

-4

-3-2

-1

0

SZ-d SZ BIP DEM

M e a n C h a n g e f r o m B

a s e l i n e

Placebo

IMOlz 2.5

IMOlz 5

IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp


* *

*

* **

**

*

Baseline Means: 19.0 18.3 17.8 19.8

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



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 Impulse

Control

Tension Hosti li ty Uncooper -

ativeness

Excitement


a s e l i n e

Placebo

IMOlz 10

IMLzp

**

*

*

**

-6

-5

-4

-3

-2

-1

0

1

2

Poor Impulse

Control

Tension Hosti lity Uncooper-

ativeness

Excitement

M e a n C

h a n g e f r o m B

a s e l i n e

Placebo

IMOlz 2.5

IMOlz 5.0

IMOlz 7.5

IMOlz 10

IMHal

**

*

*

* * **

*

***

*

***

*

**

** *

*

*

Schizophrenia Dose

Bipolar

-6

-5

-4

-3

-2

-1

0

12

Poor Impulse

Control

Tension Hosti lity Uncooper-

ativeness

Excitement

M e a n C h

a n g e f r o m B

a s e l i n e

Placebo

IMOlz 10

IMHal

-6

-5

-4

-3

-2

-1

0

1

2

Poor Impulse

Control

Tension Hostility Uncooper -

ativeness

Excitement


a s e l i n

e

Placebo

IMOlz 2.5

IMOlz 5.0

IMLzp

****

*** * ** *

Schizophrenia

Dementia

* ** *

* * * ** *




50


Agitation-Calmness Evaluation Scale

Mean Value at Endpoint - 2 hours (LOCF)

1Marked Agit.

2Mod. Agit.

3Mild Agit.

4Normal

5Mild 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

**

**

*

**

*

*

* *

††

Efficacy in Agitation at 2 Hours:



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

M e a n

C h a n g e f r o m B

a s e l i n e

Placebo

IMOlz 2.5

IMOlz 5.0

IMOlz 7.5

IMOlz 10

IMHal 7.5

IMLzp

*


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

*

*†

*†

* *

*

*

* *

*

†

CABS Range: 14-56

CMAI Range: 0-30

Baseline Means:

30.5 27.5 28.3 7.0



Efficacy at 2 Hrs by Baseline Severity:



53

Efficacy at 2 Hrs by Baseline Severity:

Schizophrenia Study

-10

-8

-6

-4

-2

0

M e a n C h a n g e i n

P E C

Placebo

IMOlz 10

IMHal 7.5

Score < Average (18) Score ≥ Average (18)

-10

-8

-6

-4

-2

0

M e a n C h a n g e i n P

E C

Placebo

IMOlz 10

IMHal 7.5


Efficacy comparison based on mean split of baseline PEC

* *

* *

Number of IM Injections During 24 Hours:



54

Number of IM Injections During 24 Hours:

Schizophrenia Dose Ranging Study

0%

20%

40%

60%

80%

100%

Placebo IMOlz

2.5mg

IMOlz

5mg

IMOlz

7.5mg

IMOlz

10mg

IMHal

7.5mg

P e r c e n t a g e o f

P a t i e n t s

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.

Efficacy Assessed by Presence of



55


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=26IMOlz 10 n=46

IMLzp n=23

Non-Psychotic

(N=95) Psychotic

(N=104)


*

*




56


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

Adverse Events: Overall Patient Database



60

O

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; receivedlorazepam and haloperidol; developed tachycardia)

Adverse Events: 24 Hour IM Period



61

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

N=415

Placebo

N=150Somnolence 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

Adverse Events: 24 Hour IM Period



62

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 OlanzapineN=137

PlaceboN=67

Somnolence 4 3

Headache 3 0

Accidental Injury 2 0

Dizziness 2 0

Tachycardia 1 0Tremor 1 0Vasodilation 1 0

Vomiting 1 0

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

Adverse Events: Summary



63

y

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

Sedation Assessed Using:



65

g

Agitation-Calmness Evaluation Scale

ACES score of 8 (deep sleep) or 9 (unarousable) usedas 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 scoredan 8 at any time

– No significant difference between IM olanzapine and either comparator (haloperidol, lorazepam) in the incidence of 8

or 9

Sedation Assessed Using:



66

g

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 andany other treatment group (including placebo) in the

incidence of somnolence.



67

Laboratory Analyses

Laboratory Results:



68

y

Schizophrenia, Bipolar, and Dementia Studies

• Standard laboratory tests: – Clinical chemistry

– Hematology

– Urinalysis

• Only one statistically significant difference betweenolanzapine 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%)

Bradycardia Proposed Mechanism: Vasovagal



73

Response (i.e., Neurally Mediated Reflex Bradycardia) • Olanzapine associated with hypotension

α1 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 inBP (Kapoor 1999)

• Greater in healthy subjects: Possible Explanation – Increased vagal tone

– No baseline agitation (agitation →↓vagal tone)

– Not taking α1 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

Vital Signs: Change to Value Outside



74

Reference Range - Any Time During 24 Hrs


0

2

4

6

8

10

12

Low

Supine

Systolic

Low

Supine

Diastolic

Low

Supine

Pulse

Low

Standing

Systolic

Low

Standing

Diastolic

High

Standing

Pulse

Ortho

Drop

P e r c e n t a g e o f P

a t i e n t s

Placebo IMOlz


*

*

*

Basal / Resting Positional Challenge

Vital Signs: Change to Value Outside



75

Reference Range - Any Time During 24 Hrs

Haloperidol-Controlled Database

0

2

4

6

8

10

12

Low

Supine

Systolic

Low

Supine

Diastolic

Low

Supine

Pulse

Low

Standing

Systolic

Low

Standing

Diastolic

High

Standing

Pulse

Ortho

Drop

P e r c e n t a g e o f P a

t i e n t s

IMOlz IMHal

* p < 0.05 vs. Olz

*

Basal / Resting Positional Challenge



Incidence of Treatment-Emergent Dizziness



77

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

OlzN=882

PlaN=517

OlzN=2213

HalN=1240Event

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

QTc Intervals: 2 Hours Post-Injection



79


0

1

2

3

4

5

6

7

8

9

10

P e r c e n t a g e o f P a t i e n t s

Placebo

IMOlz

♦ ♦

≥ 500 msec

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

Mean Change in QTc (msec) at 2 hrs

IM Pla IM Olz

(N = 148) (N = 408)

Mean change -0.7 -3.0

SD 22.0 21.5

p-value vs. pla -- 0.199

≥ 99 Percentile97.5 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

45

6

7

8

910

P e r c e n t a g e

o f P a t i e n t s

IMOlz

IMHal

≥ 500 msec

♦

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


IM Olz IM Hal(N = 312) (N = 164)

Mean change -3.3 1.8

SD 21.7 24.0

p-value vs. hal 0.006 --

≥ 97.5 Percentile ≥ 99 Percentile



♦ : n = 0

Dementia Study:



81

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 32.0

Cerebrovascular / Peripheral vascular dis. 12.9Congestive heart failure 12.9

Diabetes 11.4

Electrocardiographic disorder 10.7

Hypercholesterolemia 6.3

Hypertension 41.2Hypothyroidism 13.6

Respiratory disorder 13.2

Right / Left Bundle Branch Block 8.1 / 3.7

Pacemakers 2.2

Original QTc Data*: Dementia Study



82

Mean Change from Baseline to 2 Hours

Baseline Endpoint Change

Treatment NMean**

(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)



Re-Read QTc Data*: Dementia Study



84

Mean Change from Baseline to 2 Hours

Baseline Endpoint Change

Treatment NMean**

(msec)

Mean(msec)

Mean(msec)

p-value for 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 wereaveraged 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

P e r c e n t a g e o

f P a t i e n t s

Placebo

IMOlz 2.5

IMOlz 5

≥ 500 msec



IM Pla IM Olz2.5 IM Olz5

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

Mean change 3.3 -4.5 3.1

SD 21.1 22.0 24.6

p-value vs. pla -- 0.044 0.936

≥ 99 Percentile97.5 Percentile

*



Geriatric Placebo-Controlled Database

Comparison of Cmax after IM Doses vs. Oral



86

Olanzapine Steady-State Concentrations

Study HGAJ Study HGJA

Daily Dose

1 to 6 weeks

n = 474 in 333 pts

QTc Intervals: Normal to Prolonged



87

6-week Oral Study in Schizophrenia

0

0.2

0.4

0.6

0.8

1

1.2

1.4

P e r c e n

t a g e o

f P a

t i e n

t s

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

Summary of ECG Data:



88

Interval Data and Descriptive Findings

• No clinically significant findings for any ECGintervals

– mean change from baseline to endpoint

– categorical changes

• No clinically significant changes for descriptivefindings

– e.g. rhythm, morphology



89

Extrapyramidal Symptoms

Extrapyramidal Symptoms:



90

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

M e a n

C h a n g e f r o m

B a s e l i n e

Placebo

IMOlz 2.5IMOlz 5

IMOlz 7.5

IMOlz 10

IMHal 7.5

*

*

† † † †

†

†

†

†




91

Schizophrenia Study


-0.08

-1.19

-0.27

-0.61

0.01

0.7

-1.5

-1

-0.5

0

0.5

1


M e a n

C h a n g e f r o m B

a s e l i n e

Placebo

IMOlz 10

IMHal 7.5

†

*

†

* p < 0.05 vs. pla

† p < 0.05 vs. hal


Bi l M i S d



92

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


M e a n

C h a n g e f r o m B a s e l i n e

Placebo

IMOlz 10

IMLzp

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


D ti St d



93

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

M e a n

C h a n g e f r o m B a s e l i n e

PlaceboIMOlz 2.5

IMOlz 5

IMLzp

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

Conclusions:Effi f IM Ol i



94

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 primaryefficacy analysis for all doses studied (2.5 to 10 mg)

• Secondary efficacy measures yielded similar results

• The majority of IM olanzapine-treated patients requiredonly 1 injection in 24 hours

• IM olanzapine, doses 5-10 mg, demonstrated efficacy15 to 30 minutes after the first injection

• IM olanzapine was effective in patients with and withoutpsychosis

Conclusions:S f t f IM Ol i



95

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 analytesor ECG data, including QTc intervals

• Not associated with adverse effects on vital signsexcept for mild and transient decrements in bloodpressure and heart rate

• Not associated with excessive or undesirable sedation

• Favorable adverse event profile

us food and drug administration: 3685s1 1 elililly

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