# Presentation: 024467

##  Psychopharmacological Drugs Advisory Committee Meeting

**February 14, 2001****NDA 21-253****Intramuscular Olanzapine for the ****Rapid Control of Agitation****Eli Lilly and Company****Indianapolis, IN**

## The Agitated Patient

Clinical Development of  IM Olanzapine

**Clinical Development of  IM Olanzapine**

**Agenda**

**John Kane, M.D.**
**Alan Breier, M.D.**

##  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**

## 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**

## 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**

##  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 in a typical Psychiatric Emergency Service (PES)  (Currier 1999)**
**135,000 psychiatric emergency visits per year in New York State alone (Allen 2000)**

## 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)**

## 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)**

## 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

**a ****When oral therapy is not feasible**

##  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**

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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)**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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)**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Efficacy and Safety of IM Olanzapine

**Pharmacokinetics**
**Clinical methodology and rationale**
**Efficacy results**
**Safety**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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****	**
**T****1⁄2**** ****	****(hr)****	****31.0****	****30.4****	**
**Vd ****	****(L/kg)****	****12.2****	****11.1 **

**PK****	****units****	****Oral****	****IM****	**
**Parameter****	****	****10 mg****	****2x5 mg**

**N = 22 healthy subjects**

## Mean Olanzapine Plasma Concentrations: One 10 mg Oral Dose vs. Two 5 mg IM Doses

**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**

## Mean Olanzapine Plasma Concentrations: Three 10 mg IM Doses

**Mean plasma concentration following three 10 mg doses of IM olanzapine **
**N = 20 non-agitated patients**

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Efficacy and Safety of IM Olanzapine

**Pharmacokinetics**
**Clinical methodology and rationale**
**Efficacy results**
**Safety**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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)**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Secondary Efficacy Measure:Agitation-Calmness Evaluation Scale  (ACES)

**Developed by Lilly for use in these clinical trials**
**Designed to assess the clinical levels of calmness and sedation **
** ****Allows for detection of excessive sedation**
**A 9-point scale that differentiates between agitation, calm, and sleep states, with scores ranging from:**
**	****	****1 ****:  Marked Agitation**
**	****	****4**** :  Normal **
**	****	****7**** :  Marked Calmness**
**	****	****9**** :  Unarousable**
**Reliability and validity established**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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)**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Study Designs 

**Four Pivotal Studies**

## Agitation: 4 Pivotal Studies

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

## Study Design:  4 Pivotal Studies24 Hour IM Dosing Period 

**Study Period I**

**Study Period II**

- Screening

- Period

- Eligible

- Patients

- Double-Blind Therapy Period

- IM olanzapine

- IM placebo

- IM comparator

- _Screening_

- > 2

-  hrs

- _Inj. #1_

- _Inj. #2_

- (if clinically

- indicated)

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

- _Inj. #3_

- (if clinically

- indicated)

- 24

- hrs

- _Randomization_

**Notes:**
Study Characteristics:

In addition to the inclusion criteria* above, key exclusion criteria included the following:
  Pregnant or breastfeeding
  Serious suicidal risk
  Serious unstable medical illness
  Allergic to study drugs
  Treatment with benzodiazepines within the 4 hours prior to first injection of study drug
  Treatment with antipsychotics within the 2 hours prior to first injection of study drug

*Footnote:
Regarding the inclusion criteria for the PANSS-Excited Component:  The total score is based on a 1 to 7 scoring system, with possible scores ranging from 5 - 35.  Severity scores include:
	1 = absent 
	3 = mild severity
	4 = moderate severity
	7 = extreme severity
All patients must score  4 (moderate severity) on at least 1 item prior to randomization to treatment (the 5 items are poor impulse control, tension, hostility, uncooperativeness, and excitement)

## Criteria for Inclusion in Agitation Study 

**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**** **

**Notes:**
Study Characteristics:

In addition to the inclusion criteria* above, key exclusion criteria included the following:
  Pregnant or breastfeeding
  Serious suicidal risk
  Serious unstable medical illness
  Allergic to study drugs
  Treatment with benzodiazepines within the 4 hours prior to first injection of study drug
  Treatment with antipsychotics within the 2 hours prior to first injection of study drug

*Footnote:
Regarding the inclusion criteria for the PANSS-Excited Component:  The total score is based on a 1 to 7 scoring system, with possible scores ranging from 5 - 35.  Severity scores include:
	1 = absent 
	3 = mild severity
	4 = moderate severity
	7 = extreme severity
All patients must score  4 (moderate severity) on at least 1 item prior to randomization to treatment (the 5 items are poor impulse control, tension, hostility, uncooperativeness, and excitement)

##  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**

**Notes:**
Study Characteristics:

In addition to the inclusion criteria* above, key exclusion criteria included the following:
  Pregnant or breastfeeding
  Serious suicidal risk
  Serious unstable medical illness
  Allergic to study drugs
  Treatment with benzodiazepines within the 4 hours prior to first injection of study drug
  Treatment with antipsychotics within the 2 hours prior to first injection of study drug

*Footnote:
Regarding the inclusion criteria for the PANSS-Excited Component:  The total score is based on a 1 to 7 scoring system, with possible scores ranging from 5 - 35.  Severity scores include:
	1 = absent 
	3 = mild severity
	4 = moderate severity
	7 = extreme severity
All patients must score  4 (moderate severity) on at least 1 item prior to randomization to treatment (the 5 items are poor impulse control, tension, hostility, uncooperativeness, and excitement)

## Patient Characteristics:Demographics 

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

## Clinical Characteristics at Baseline:Four Pivotal Studies

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

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

**    ****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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## PANSS Excited Component: Distribution of Total Scores at Baseline

**Schizophrenia Dose - all patients**

**Dementia - all patients**

**Schizophrenia - all patients**

**Bipolar - all patients**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Baseline Agitation Across Disease States*PANSS EC:  Mean Scores of the 5 Items

*** All treatment groups**

** **

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Efficacy and Safety of IM Olanzapine

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

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**-2**

**0**

**2**

**4**

**6**

**SZ-d**

**SZ**

**BIP**

**DEM**

**Mean Change from Baseline**

**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 **

*****

*****

*****

*****

*****

*****

*****

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**†**

*****

**  ****Baseline Means:**
**     ****19.0                     18.3                  17.8                   19.8**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Percentage of Patients**

**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**

*****

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**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Mean Change from Baseline**

**Placebo**

**IMOlz 2.5**

**IMOlz 5**

**IMOlz 7.5**

**IMOlz 10**

**IMHal 7.5**

**IMLzp**

*** p < 0.05 vs. placebo**

*****

*****

*****

*****

*****

*****

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*****

**  ****Baseline Means:****	****19.0 ****	****18.3   ****	****17.8****	**** 19.8**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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 **

*****

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**Schizophrenia Dose**

**Bipolar**

*****

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**Schizophrenia**

**Dementia**

*****

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**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Efficacy at 2 Hours: Agitation-Calmness Evaluation ScaleMean Value at Endpoint - 2 hours (LOCF)

**1**
**  ****Marked Agit.**

**2**
**Mod. Agit****.**

**3**
** ****Mild Agit.**

**4**
**Normal**

**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 change**

**4546.01**

*****

*****

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**†**

**†**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Mean Change from Baseline**

**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)**

*****

*****
**†**

*****
**†**

*****

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**†**

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

**  ****Baseline Means:****	**
**	****30.5****	****27.5****	****28.3****	****7.0**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Onset of Efficacy:  PANSS ECSchizophrenia Study Timepoint-wise change from baseline to 2 hrs post first IM inj (LOCF)

**Mean Change**

**Time (mins)**

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

*****

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**†**

**†**

**†**

**Onset of Efficacy:  PANSS EC****Schizophrenia Study ****Timepoint-wise change from baseline to 2 hrs post first IM inj (LOCF)**

**Notes:**
The PANSS Excited Component; timepoints up to 2 hours:
The PANSS Excited Component was the first of the three core scales used to assess agitation.

  Although all treatment groups were effective in reducing agitation at 2 hours after the first IM injection, IM olanzapine also showed superior efficacy over IM haloperidol at the earliest timepoint (15 minutes) and at 30 and 45 minutes after the first IM injection

  This demonstrates the rapid onset of action of IM olanzapine, which may offer a significant clinical advantage for the treatment of acute agitation

   IM olanzapine was superior to IM placebo at all timepoints

## Efficacy at 2 Hrs by Baseline Severity: Schizophrenia Study

**Score  <  Average (18)**

**Score  ********  Average (18)**** **

*** p < 0.05 vs. placebo**** **

**    ****Efficacy comparison based on mean split of baseline PEC**

*****

*****

*****

*****

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

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

*** p < 0.05 vs. placebo**

*****

*****

*****

*****

*****

**Maximum of three injections allowed during 24 hours in each trial.**
**Investigator judgment determined the administration of a second or third injection.**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Efficacy Assessed by Presence of Psychosis Comparison at 2 Hours:  Bipolar Study PANSS EC:  Mean change from baseline  (LOCF) 

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

**Psychotic**
**(N=104)**** **

*** p < 0.05 vs. placebo**

- *

- *

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Efficacy Assessed by Presence of Psychosis Comparison at 2 Hrs:  Dementia Study

**Psychotic**
**(N=146)**

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

***  p < 0.05 vs. placebo**

*****

*****

*****

**PANSS EC:  Mean change from baseline  (LOCF)**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## 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**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

## Summary of Safety Databases

**Placebo-Controlled** (SZ-d, SZ, BIP)Olanzapine:  N = 415Placebo:       N = 150
**Haloperidol-Controlled** (SZ-d, SZ)Olanzapine:   N = 316Haloperidol:   N = 166

**Geriatric Placebo-Controlled**** **(DEM)Olanzapine:   N = 137Placebo:        N = 67
**Overall Patient Database**(All agitated patients)  		Olanzapine:   N = 722
**Overall Subject Database**(All patients and healthy subjects) Olanzapine:   N = 850**	**

**Notes:**
Key Points

Data/Protocol Reminders

Back-Up Slides

##  Adverse Events

## 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)**

**Notes:**
Adverse events:

  No patients were discontinued from the study due to an adverse event

Most Common Adverse Events:  
 Olanzapine (including all 4 treatment doses):   Hypotension was the most commonly reported adverse event across the olanzapine treatment groups.  The overall incidence was quite low in the olanzapine treatment groups (<4%), and there was no statistical difference (NSD) from the haloperidol and placebo treatment groups.

  Haloperidol:  Acute dystonia was only reported in the haloperidol treatment group.  With no dystonia reported in the olanzapine and placebo treatment groups , the incidence in the haloperidol treatment group (5%) was significantly different from olanzapine. The incidence of tremor  (5%) in the haloperidol treatment group was not significantly different from the olanzapine and placebo treatment groups. 

. Placebo:  Anxiety was the most commonly reported adverse event in the placebo treatment group (6.7%).  This incidence was significantly different from the olanzapine treatment group. 

## 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**

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

**Notes:**
Adverse events:

  No patients were discontinued from the study due to an adverse event

Most Common Adverse Events:  
 Olanzapine (including all 4 treatment doses):   Hypotension was the most commonly reported adverse event across the olanzapine treatment groups.  The overall incidence was quite low in the olanzapine treatment groups (<4%), and there was no statistical difference (NSD) from the haloperidol and placebo treatment groups.

  Haloperidol:  Acute dystonia was only reported in the haloperidol treatment group.  With no dystonia reported in the olanzapine and placebo treatment groups , the incidence in the haloperidol treatment group (5%) was significantly different from olanzapine. The incidence of tremor  (5%) in the haloperidol treatment group was not significantly different from the olanzapine and placebo treatment groups. 

. Placebo:  Anxiety was the most commonly reported adverse event in the placebo treatment group (6.7%).  This incidence was significantly different from the olanzapine treatment group. 

## 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**

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

**Notes:**
Adverse events:

  No patients were discontinued from the study due to an adverse event

Most Common Adverse Events:  
 Olanzapine (including all 4 treatment doses):   Hypotension was the most commonly reported adverse event across the olanzapine treatment groups.  The overall incidence was quite low in the olanzapine treatment groups (<4%), and there was no statistical difference (NSD) from the haloperidol and placebo treatment groups.

  Haloperidol:  Acute dystonia was only reported in the haloperidol treatment group.  With no dystonia reported in the olanzapine and placebo treatment groups , the incidence in the haloperidol treatment group (5%) was significantly different from olanzapine. The incidence of tremor  (5%) in the haloperidol treatment group was not significantly different from the olanzapine and placebo treatment groups. 

. Placebo:  Anxiety was the most commonly reported adverse event in the placebo treatment group (6.7%).  This incidence was significantly different from the olanzapine treatment group. 

## 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 **

**Notes:**
Key Points

Data/Protocol Reminders

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##  Sedation

## 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**

**Notes:**
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Data/Protocol Reminders

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## Sedation Assessed Using: Treatment-Emergent Adverse Events

**"Somnolence" was the only reported sedation-related adverse event **
**No reports of "CNS depression," "stupor," or "coma"**
**Somnolence was reported in 5.1% (28 / 552) of****IM olanzapine-treated patients**
**No significant difference between IM olanzapine and any other treatment group (including placebo) in the incidence of somnolence. **

**Notes:**
Key Points

Data/Protocol Reminders

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## Laboratory Analyses

## 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)**

**Notes:**
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Data/Protocol Reminders

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## Vital Signs

## 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**

**Notes:**
Key Points

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## 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****	**

**Notes:**
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Data/Protocol Reminders

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## 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%)**
** **

**Notes:**
Key Points

Data/Protocol Reminders

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## Bradycardia Proposed Mechanism:  Vasovagal Response  (i.e., Neurally Mediated Reflex Bradycardia) 

**Olanzapine associated with hypotension**
******1 ****antagonism (K****i****=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**

**Notes:**
Key Points

Data/Protocol Reminders

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

*** p < 0.05 vs. placebo**

*****

*****

*****

**Basal / Resting**

**Positional Challenge**

**Notes:**
Key Points

Data/Protocol Reminders

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## Vital Signs: Change to Value Outside Reference Range - Any Time During 24 HrsHaloperidol-Controlled Database

*** p < 0.05 vs. Olz**

*****

**Basal / Resting**

**Positional Challenge**

**Notes:**
Key Points

Data/Protocol Reminders

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

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

- 

- 

**Basal / Resting**

**Positional Challenge**

**Notes:**
Key Points

Data/Protocol Reminders

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## Incidence of Treatment-Emergent Dizziness and Syncope: Data from IM and Oral Studies

**Intramuscular Data**

**Oral Data****a**

**a****Oral 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**

**Notes:**
Key Points

Data/Protocol Reminders

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##  Electrocardiograms

## QTc Intervals:  2 Hours Post-InjectionPlacebo-Controlled Database

******     ******

****** ****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 Percentile**

****** ****97.5 Percentile**

****** ****99 Percentile: ****	******** 450 msec male**
**          ********               ****	******** ****470 msec female**

****** ****97.5 Percentile: ****	******** 430 msec male**
**          ********               ****	******** ****450 msec female**

****** ****:  n = 0**

**Notes:**
Key Points

Data/Protocol Reminders

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## QTc Intervals:  2 Hours Post-Injection Haloperidol-Controlled Database

****** ****500 msec**

****

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

-           **Mean Change in QTc (msec) at 2 hrs**
- 	IM Olz	IM Hal		_(N = 312)_	_(N = 164)_
- Mean change	-3.3	1.8SD	21.7	24.0
- p-value vs. hal	0.006	--

****** ****97.5 Percentile**

****** ****99 Percentile**

****** ****99 Percentile: ****	******** 450 msec male**
**          ********               ****	******** ****470 msec female**

****** ****97.5 Percentile: ****	******** 430 msec male**
**          ********               ****	******** ****450 msec female**

****** ****:  n = 0**

**Notes:**
Key Points

Data/Protocol Reminders

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## Dementia Study: Age and Co-Morbid Conditions 

**Advanced age of population: **
** ****45.2% of patients > 80 years;  8.8%  > 90 years**
**Cardiac / Respiratory Conditions**

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

**Notes:**
Study Characteristics:
In addition to the inclusion criteria above*, key exclusion criteria included the following:
  Pregnant or breastfeeding
  Serious suicidal risk
  Serious unstable medical illness
  Allergic to study drugs
  Treatment with benzodiazepines within the 4 hours prior to first injection of study drug
  Treatment with antipsychotics within the 2 hours prior to first injection of study drug

*Footnote:
Regarding the inclusion criteria for the PANSS-Excited Component:  The total score is based on a 1 to 7 scoring system, with a possible score ranging from 5 - 35.  Severity scores include:
	1 = absent 
	3 = mild severity
	4 = moderate severity
	7 = extreme severity
All patients must score 4 (moderate severity) on at least 1 item prior to randomization to study drug (the 5 items are poor impulse control, tension, hostility, uncooperativeness, and excitement)

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

** ***** 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)  **

**Notes:**
Key Points

Data/Protocol Reminders

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## 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

**Notes:**
Key Points

Data/Protocol Reminders

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

** ***** 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**

**Notes:**
Key Points

Data/Protocol Reminders

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## QTc Intervals:  2 Hours Post-Injection Geriatric Placebo-Controlled Database

****** ****500 msec**

*** p < 0.05 vs. placebo**

-                  **Mean Change in QTc (msec) at 2 hrs**
- 	IM Pla	IM Olz2.5	   IM Olz5              	_(N = 61)_	_(N = 68)_	_(N = 61)_
- Mean change	3.3	-4.5 	3.1SD	21.1	22.0	24.6
- p-value vs. pla	--	0.044	0.936

****** ****99 Percentile**

****** ****97.5 Percentile**

- *

****** ****99 Percentile: ****	******** 450 msec male**
**          ********               ****	******** ****470 msec female**

****** ****97.5 Percentile: ****	******** 430 msec male**
**          ********               ****	******** ****450 msec female**

**QTc Intervals:  2 Hours Post-Injection ****Geriatric Placebo-Controlled Database**

**Notes:**
Key Points

Data/Protocol Reminders

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## 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**

**Notes:**
Key Points

Data/Protocol Reminders

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## QTc Intervals:  Normal to Prolonged 6-week Oral Study in Schizophrenia

****** ****500 msec**

-         

****** ****97.5 Percentile**

****** ****99 Percentile**

****** ****99 Percentile: ****	******** 450 msec male**
**          ********               ****	******** ****470 msec female**

****** ****97.5 Percentile: ****	******** 430 msec male**
**          ********               ****	******** ****450 msec female**

**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****	**** -0.074**
**SD   ****	****           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**

**Notes:**
Key Points

Data/Protocol Reminders

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## 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**

**Notes:**
Key Points

Data/Protocol Reminders

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##  Extrapyramidal Symptoms 

## Extrapyramidal Symptoms: Schizophrenia Dose Ranging StudyMean change from baseline to 24 hrs post first IM inj (LOCF)

*** p < 0.05 vs. pla      **
**†**** ****p < 0.05 vs. hal**

- *

*****

**†**

**†**

**†**

**†**

**†**

**†**

**†**

**†**

**Notes:**
Key Points

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## Extrapyramidal Symptoms:  Schizophrenia StudyMean change from baseline to 24 hrs post first IM inj (LOCF)

**†**

*****

**†**

**  ***** p < 0.05 vs. pla**
** †**** ****p < 0.05 vs. hal**

**Notes:**
Key Points

Data/Protocol Reminders

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## Extrapyramidal Symptoms: Bipolar Mania StudyMean change from baseline to 24 hrs post first IM inj (LOCF)

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

**Notes:**
Key Points

Data/Protocol Reminders

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## Extrapyramidal Symptoms:  Dementia StudyMean change from baseline to 24 hrs post first inj (LOCF)

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

**Notes:**
Key Points

Data/Protocol Reminders

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## 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**

**Notes:**
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Data/Protocol Reminders

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## 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**

**Notes:**
Key Points

Data/Protocol Reminders

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## Slide 96