Advances in IM Therapy

Douglas H. Hughes, MDVice Chair of Psychiatry

Boston University School of MedicineBoston, Massachusetts

Disclosure

Type of Affiliation Commercial Entity

Consultant, Honorarium Janssen Pharmaceutica, Pfizer, Inc.

Stock Shareholder Johnson & Johnson, Merck & Co., Inc.

Dr. Hughes intends to discuss off-label/unapproved uses of products or devices.

Learning Objectives

• Discuss current and future IM atypical neuroleptic drugs

• Discuss the benefits of medication over restraints in the acute crisis

Upon completion of this presentation, participants should be able to:

Onset of ActionMean ABS Scores

LorazepamHaloperidolCombination

50

40

30

20

10

0 2 4 6 8 10 12

Time (Hour)

Mea

n ±

Sta

ndar

d E

rror

*P < .014.ABS = Agitated Behavior Scale.Battaglia J et al. Am J Emerg Med. 1997;15:335-340.

*

Risperidone Liquid and Oral Lorazepam vs IM Haloperidol and IM Lorazepam

30

25

20

15

10

5

0Baseline 30 min 60 min

IM Haloperidol + IM Lorazepam

PO Risperidone + PO Lorazepam

Adapted from Currier GW, Simpson GM. J Clin Psychiatry. 2001;62:153-157.

Com

bine

d P

sych

oti c

Agi

tatio

n S

core

s

Clinical Studies of IM Ziprasidone:An Overview

• Two pivotal efficacy studies*: randomized, double-blind vs 2-mg control (no placebo arm)

• Three open-label, randomized, parallel-group (vs haloperidol), followed by switch to oral medication: 2 flexible dose, 1 fixed dose

• *Patient population in pivotal studies– Patient populations: schizophrenic, schizophreniform,

schizoaffective, delusional, bipolar, and other psychotic disorders

– Primary efficacy analyses: BARS, CGI-S in pivotal studies; BPRS Total, CGI-S, CGI-I vs haloperidol

BARS = Behavioral Activity Rating Scale; CGI-S = Clinical Global Impression-Severity; CGI-I = Clinical Global Impression-Improvement; BPRS = Brief Psychiatric Rating Scale.Briefing document for ziprasidone mesylate for intramuscular injection, 2001.

-20

-15

-10

-5

0

-20

-15

-10

-5

0

Ziprasidone Haloperidol

IM Ziprasidone vs IM Haloperidol: Efficacy

n = 83 n = 40 n = 83 n = 40

BPRS Total BPRS Agitation Items

% M

e an

Ch a

nge

f ro m

Bas

elin

e

P < .05

P < .01

Brook S et al. J Clin Psychiatry. 2000;61:933-941.

IM Ziprasidone vs IM Haloperidol:EPS and Akathisia

-2

-1

0

1

2

3

ZiprasidoneHaloperidol

Extrapyramidal Symptoms Rating Scale (ESRS) Barnes Akathisia Scale

Mea

n C

hang

e f r

om B

ase l

i ne

Brook S et al. 2001.Daniel DG et al. Poster presented at: 155th Annual Meeting of the AmericanPsychiatric Association; May 18-23, 2002; Philadelphia, Pa.

Last IMLast IM

P < .001 vs ziprasidonechange from baseline.

All patients, observed cases.*P < .05. †P .001. ‡P < .01.Lesem MD et al. J Clin Psychiatry. 2001;62:12-18.Daniel DG et al. Psychopharmacology (Berl). 2001;155:128-134.

0 15 min 1 2

10-mg StudyTime After First Injection (Hours)

Impr

ovem

ent

Cha

nge

in B

AR

S (

± S

E)

from

Bas

elin

e

20-mg StudyTime After First Injection (Hours)

0 30 min 1 2 3 40

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

2 mg Control (N = 54)

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

†

*

*

IM Ziprasidone 10 mg (N = 63)2 mg Control (N = 38)IM Ziprasidone 20 mg (N = 41)

IM Ziprasidone Study Dose vs 2-mg Control: Time to Symptom Control

††

†

†

††

†

‡

BARS Score

Swift RH et al. J Psychiatr Res. 2002;36:87-95.

• Validated as a reliable measure of activity levels in acute agitation, responsive to treatment differences

• When evaluated by 342 experienced raters, demonstrated inter- and intrarater reliability

• When correlated to scores in the CGI-S and PANSS negative scales, convergent and divergent validity were displayed

7 Violent, requires restraint

6 Extremely or continuously active

5 Signs of overt activity; can be calmed

4 Quiet and awake

3 Drowsy, appears sedated

2 Asleep, but responds normally

1 Difficult or unable to rouse

The BARS 7-Point Observational Scale

IM Ziprasidone vs IM Haloperidol: Adverse Events

Ziprasidone, No (%)n = 417

Haloperidol, No. (%)n = 133

Asthenia 32 (7.7) 4 (3.0)

Headache 36 (8.6) 2 (1.5)

Increased salvation 13 (3.1) 7 (5.3)

Agitation 22 (5.3) 9 (6.8)

Akathisia 34 (8.2) 31 (23.3)

Anxiety 45 (10.8) 13 (9.8)

Dizziness 36 (8.6) 6 (4.5)

Dystonia 13 (3.1) 14 (10.5)

EPS 22 (5.3) 30 (22.6)

Hypertonia 24 (5.8) 19 (14.3)

Insomnia 89 (12.9) 21 (15.8)

Somnolence 54 (12.9) 7 (5.3)

Tremor 21 (5.0) 14 (10.5)

Brook S et al. 2001.

15

10

5

0

-5

76543210

-1-2-3

OralIM

Ziprasidone vs Haloperidol Sequential IM to Oral Treatment: Efficacy

60

50

40

30

*P < .01 vs haloperidol.Daniel DG et al. Poster presented at: 155th Annual Meeting of the AmericanPsychiatric Association; May 18-23, 2002; Philadelphia, Pa.

Ziprasidone (n = 417)Haloperidol (n = 133)

0 14 28 42Study Day

BPRS Total Score

Mea

n B

PR

S T

otal

Sco

re

*

20

15

10

5

0

20

15

10

5

0

(4.6)(6.0)

Injection 1

Ziprasidone Haloperidol 20 mg 7.5 mg (n = 25) (n = 24)

IM Ziprasidone vs IM Haloperidol: QTc at Cmax

Ziprasidone Haloperidol 30 mg 10 mg (n = 25) (n = 24)

(12.8)

(14.7)

Mea

n (9

5% C

I) Q

Tc

Inte

rva l

Cha

nge

from

Bas

e lin

e (m

s ec)

Mea

n (9

5% C

I) Q

Tc

Inte

rva l

Cha

nge

from

Bas

e lin

e (m

s ec)

Injection 2(4 Hours After First Injection)

Baseline correction.Adapted from Miceli JJ et al. Poster presented at: 155th Annual Meeting of the AmericanPsychiatric Association; May 18-23, 2002; Philadelphia, Pa.

Prevalence Rates of HIVin the Seriously Mentally Ill

US Population Mentally Ill

HIV 0.3% to 0.4% 5.2% to 22.9%

Hepatitis B 4.9% 23.4%

Hepatitis C 1.8% 19.8%

Rosenberg SD et al. Psychiatric Services. 2003;54:854-859.

American Nurses Association. Needlestick injury. Available at: http://nursingworld.org/readroom/fsneedle.htm. Accessed September 25, 2003.

Needlestick Dataand Transmission Rates

• 600,000 to 1 million needle stick injuries occur per year to healthcare workers

• 16,000 of the above result in HIV exposure

• HIV transmission rate of 0.2%-0.4%, 35 per year

• Hepatitis B transmission is 2%-40%

• Hepatitis C transmission is 2.7%-10%

0

-1

-2

-3

-4

-5

-6

-7

-8

-9

15 30 45 60 90 120 30 60 90 1200

-2

-4

-6

-8

-10

-12

*

*

** *

****

*

*†

†

†

IM Olanzapine: Time to Symptom Control

Minutes Minutes*P < .05 vs placebo.†P < .05 vs haloperidol.

*P < .05 vs placebo.†P < .05 vs lorazepam.

Placebo

Olanzapine IM (10 mg)

Haloperidol IM (7.5 mg)

Placebo

Olanzapine IM (10 mg)

Lorazepam IM (2 mg)

Schizophrenia Bipolar Mania

Adapted from Briefing Document for ZYPREXA® IntraMuscular (orlanzapine for injection), 2001.

*†

*†

*† *

†Me

an

Ch

an

ge

in P

AN

SS

Exc

ited

Co

mp

on

en

t

Me

an

Ch

an

ge

in P

AN

SS

Exc

ited

Co

mp

on

en

t

IM Olanzapine vs IM Haloperidol: Movement Disorders

Placebo

Olanzapine 10 mg

Haloperidol 7.5 mg

Simpson-Angus Barnes Akathisia

††

*

2

1

0

-1

-2

Adapted from Briefing Document for ZYPREXA® IntraMuscular (olanzapine forinjection), 2001; Breier A et al. Arch Gen Psychiatry. 2002;59:441-448.

*P < .05 vs placebo. †P < .05 vs haloperidol.

Mea

n C

hang

e fr

om B

asel

ine

Physical Restraint Rates in the United States

Patients Favor Medication over Restraints by 2:1*

0

2

4

6

8

10

12

14

16

1983 1999

Allen MH. J Clin Psychiatry. 2000;61(suppl 14):11-20.*Currier GW et al. In: Allen MH, ed. Emergency Psychiatry. Washington, DC: American Psychiatric Publishing; 2002.

Per

cent

age

Combining IM Olanzapine with an IM Benzodiazepine

• Single-dose study of IM olanzapine 5 mg administered 1 hour before lorazepam 2 mg– Synergistic increase in somnolence

• Simultaneous IM administration not recommended

• If benzodiazepine needed, wait 1 hour

• If patient has received benzodiazepine– Evaluate clinical status before olanzapine

administration– Monitor for over sedation and cardiorespiratory

depression

Zyprexa United Kingdom Summary of Product Characteristics. Eli Lilly and Company.