1 Psychopharmacological Drugs Advisory Committee Meeting February 14, 2001 NDA Intramuscular Olanzapine for the Rapid Control of Agitation Eli Lilly and Company Indianapolis, 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. Chairman Department of Psychiatry Hillside Hospital Glen Oaks, NY and Professor of Psychiatry, Neurology, and Neuroscience The Albert Einstein College of Medicine Bronx, 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 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)

8 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 deaths per year nationwide due to restraints (Allen 2000)

9 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)

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 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 Psychiatry Indiana 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) AUC(ng  hr/mL) CLp (L/hr) T ½ (hr) Vd (L/kg) PKunitsOralIM Parameter10 mg2x5 mg N = 22 healthy subjects

20 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

21 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

22 Comparison of Cmax after IM Doses vs. Oral Olanzapine Steady-State Concentrations Study HGAJStudy 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 mg injections is similar to steady-state plasma concentration after oral 20 mg Similar metabolite profile to oral

24 Efficacy and Safety of IM Olanzapine Pharmacokinetics Clinical methodology and rationale Efficacy results 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 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

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 Agitation 4 : Normal 7 : Marked Calmness 9 : Unarousable Reliability and validity established

30 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)

31 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

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 Studies

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 Studies 24 Hour IM Dosing Period Study Period IStudy 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) 24hrs 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 a No significant differences between treatment groups within each of the four studies

41 Clinical Characteristics at Baseline: Four Pivotal Studies

42 Baseline Level of Agitation: Mean PANSS EC Scores of 4 Pivotal Studies a Total Score Range is ; 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 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

45 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

46 Primary Analysis: Efficacy at 2 Hours PANSS Excited Component Mean change from baseline to 2 hrs post first IM inj (LOCF) SZ-dSZBIPDEM 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 * * * * * * * * * * † * Baseline Means:

47 Response Rates PANSS Excited Component - 2 Hours After First Injection SZ-dSZBIPDEM 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 * * * * * * * * * * * *

48 Efficacy at 24 Hours: PANSS Excited Component Mean change from baseline to 24 hrs (LOCF) SZ-dSZBIPDEM Mean Change from Baseline Placebo IMOlz 2.5 IMOlz 5 IMOlz 7.5 IMOlz 10 IMHal 7.5 IMLzp * p < 0.05 vs. placebo * * * * * * * * * Baseline Means:

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 * * * * * * * * * * * ** * * * * * * * * * * * * * ** * * Schizophrenia Dose Bipolar * * * * * * * * * * * Schizophrenia Dementia * * * * * * * * * *

50 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 SZBIPDEM Placebo IMOlz 2.5 IMOlz 5 IMOlz 7.5 IMOlz 10 IMHal 7.5 IMLzp Baseline Mean: * p < 0.05 vs placebo for mean change † p < 0.05 vs hal (SZ-d) or lzp (BIP) for mean change * * * * * * * * * ** † †

51 Efficacy in Agitation at 2 Hours: Corrigan / Cohen-Mansfield Mean change from baseline to 2 hours post first IM inj (LOCF) SZ-dSZBIPDEM 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) * *†*† *†*† * * * * * * * † CABS Range: CMAI Range: 0-30 Baseline Means:

52 Mean Change Time (mins) *p < 0.05 vs. Placebo †p < 0.05 vs. Haloperidol * * * * * * * * * * * † † † Onset of Efficacy: PANSS EC Schizophrenia Study Timepoint-wise change from baseline to 2 hrs post first IM inj (LOCF)

53 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 * * * *

54 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.

55 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 * *

56 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)

57 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

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

62 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

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) of IM 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) Patients (N = 765*) Total (N = 850)

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 (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

74 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

75 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

76 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

77 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

78 Electrocardiograms

79 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 PlaIM Olz (N = 148)(N = 408) Mean change SD p-value vs. pla  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 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 OlzIM Hal (N = 312)(N = 164) Mean change SD p-value vs. hal  97.5 Percentile  99 Percentile  99 Percentile:  450 msec male   470 msec female  97.5 Percentile:  430 msec male   450 msec female  : n = 0

81 D ementia 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 disorder32.0 Cerebrovascular / Peripheral vascular dis.12.9 Congestive heart failure12.9 Diabetes11.4 Electrocardiographic disorder10.7 Hypercholesterolemia 6.3 Hypertension41.2 Hypothyroidism13.6 Respiratory disorder13.2 Right / Left Bundle Branch Block 8.1 / 3.7 Pacemakers 2.2

82 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)

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 * 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  500 msec * p < 0.05 vs. placebo Mean Change in QTc (msec) at 2 hrs IM PlaIM Olz2.5 IM Olz5 (N = 61)(N = 68)(N = 61) Mean change SD p-value vs. pla  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

86 Comparison of Cmax after IM Doses vs. Oral Olanzapine Steady-State Concentrations Study HGAJStudy HGJA Daily Dose 1 to 6 weeks n = 474 in 333 pts

87 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 SD  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 Mean change from baseline to 24 hrs post first IM inj (LOCF) * p < 0.05 vs. pla † p < 0.05 vs. hal * * † † †† † † † †

91 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

92 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

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