advances in im therapy douglas h. hughes, md. disclosure type of affiliation commercial entity...
TRANSCRIPT
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.
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
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-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.