Advances in IM Therapy

Douglas H. Hughes, MD

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

Transition to Oral Medication:Ziprasidone Drug Interactions

• Clearance mediated via reduction by aldehyde oxidase (2/3) and via P450 CYP3A4 (1/3)

• Inducers of CYP3A4 decrease the AUC; inhibitors increase the AUC and Cmax

• Unlikely to interact significantly with drugs metabolized by CYP450

• Should not be used with any agent that significantly prolongs the QT interval

Geodon [package insert]. New York, NY: Pfizer Inc, 2003.

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

*

QT Interval

• QT interval = time from beginning of ventricular depolarization through repolarization as seen on the ECG

• QT interval shortens as heart rate increases

• QT interval lengthens as heart rate decreases

Q S

R

P

T

Tortora G, Grabowski S. Principles of Anatomy and Physiology. Sydney, Australia: Harper Collins; 1995. Conover MB. Understanding Electrocardiography. St. Louis, Mo: Mosby; 1995.

Atrialdepolarization

Ventriculardepolarization

Ventricularrepolarization

QT Interval

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.