Clinical Information Monograph

FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE

Best Clinical Practice With Ziprasidone IM:

Update After 2 Years of Experience
AUTHORS
Dan L. Zimbroff, MD Daniel L. Herr, MS, MD, FCCM
Michael H. Allen, MD Douglas Hughes, MD
John Battaglia, MD Marc Martel, MD
Leslie Citrome, MD, MPH Horacio Preval, MD
Avrim Fishkind, MD Ruth Ross, MA
Andrew Francis, MD, PhD

Sponsored by

ABSTRACT
Acute agitation is a common psychiatric emergency often treated with intramuscular (IM) medication when rapid control is neces-
sary or the patient refuses to take an oral agent. Conventional IM antipsychotics are associated with side effects, particularly move-
ment disorders, that may alarm patients and render them unreceptive to taking these medications again. Ziprasidone (Geodon®)
is the first second-generation, or atypical, antipsychotic to become available in an IM formulation. Ziprasidone IM was approved
by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia. In October 2004, a
roundtable panel of physicians with extensive experience in the management of acutely agitated patients met to review the first 2
years of experience with this agent. This monograph, a product of that meeting, discusses clinical experience to date with ziprasi-
done IM and offers recommendations on its use in various settings.
In clinical trials, patients treated with ziprasidone IM demonstrated significant and rapid (within 15–30 minutes) reduction in
agitation and improvement in psychotic symptoms, agitation, and hostility to an extent greater than or equal to that attained with
haloperidol IM. Tolerability of ziprasidone IM was superior to that of haloperidol IM, with a lower burden of movement disor-
ders. Clinical trials have also shown that ziprasidone IM can be administered with benzodiazepines without adverse consequences.
Transition from IM to oral ziprasidone has been well tolerated, with maintenance of symptom control. The most common adverse
events associated with ziprasidone IM were insomnia, headache, and dizziness in fixed-dose trials and insomnia and hyperten-
sion in flexible-dose trials. No consistent pattern of escalating incidence of adverse events with escalating ziprasidone doses has
been observed. Changes in QTc interval associated with ziprasidone at peak serum concentrations are modest and comparable
to those seen with haloperidol IM. Results of randomized clinical trials of ziprasidone IM have been corroborated in studies in
real-world treatment settings involving patients with extreme agitation or a recent history of alcohol or substance abuse. In these
circumstances, clinically significant improvement was seen within 30 minutes of ziprasidone IM administration, without regard
to the suspected underlying etiology of agitation. Agents with a good safety/tolerability profile, such as ziprasidone IM, may be
more cost effective long term than older agents, due to reduced incidence of acute adverse effects (eg, acute dystonia) that often
require extended periods of observation. Additional trials of ziprasidone IM in agitated patients in a variety of clinical settings are
warranted to generate comparative risk/benefit data with conventional agents and other second-generation antipsychotics.

This clinical information monograph is sponsored by Pfizer Inc. Sponsorship of this review does not imply the sponsor’s agreement with the views expressed herein. Although
every effort has been made to ensure that the information is presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither
the publisher, the sponsor, nor the participants can be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are
strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.

Copyright ©2005, MBL Communications, Inc.

333 Hudson Street, 7th floor, New York, NY 10013. Printed in the USA.
All rights reserved, including the right of reproduction, in whole or in part, in any form.

CNS Spectrums, September 2005 1 Vol 10 – No 9 (Suppl 11)

 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
Best Clinical Practice With Ziprasidone IM:
Update After 2 Years of Experience
Focus Points
• Ziprasidone is the first second-generation antipsychotic to
become available in an intramuscular (IM) formulation.
• In clinical trials, ziprasidone IM rapidly reduced agita-
tion (within 15–30 minutes) in psychotic patients.
• Ziprasidone IM has demonstrated improvement in psy-
chotic symptoms, agitation, and hostility to an extent
greater than or equal to that attained with haloperidol
IM, with a lower burden of movement disorders.
• Transition from IM to oral ziprasidone is well tolerated,
with maintained symptom control.
• Clinical trial data on ziprasidone IM have been sup-
ported by experience with agitated patients in both
emergency care and intensive care settings.
Faculty Affiliations and Disclosures
Dr. Allen is director of psychiatric emergency services and
associate professor of psychiatry at the University of Colorado
Health Sciences Center in Denver. He has served as a consul-
tant to Abbot, Alexza, AstraZeneca, Bristol-Myers Squibb,
and Pfizer; has been a member of the speaker’s bureaus of
Abbot, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and
Pfizer; has received research/grant support from Abbot,
AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and
Pfizer; and has received honoraria from Pfizer.
Dr. Battaglia is medical director at the Program of
Assertive Community Treatment at the Mendota Mental
Health Institute in Madison, Wisconsin. He has served as
a consultant to and has received honoraria from Eli Lilly
and Pfizer.
Dr. Citrome is director of the Clinical Research and
Evaluation Facility at the Nathan S. Kline Institute for
Psychiatric Research in Orangeburg, New York, and pro-
fessor of psychiatry at the New York University School of
Medicine in New York City. He has received research sup-
port from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli
Lilly, Janssen, Novartis, Organon, Pfizer, Repligen; and has
received honoraria for serving on the advisory boards and
speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers
Squibb, Eli Lilly, GlaxoSmithKline, Novartis, and Pfizer.
CNS Spectrums, September 2005
Dr. Fishkind is medical director at the Neuropsychiatric
Center of Houston in Texas. He has received honoraria
from Pfizer.
Dr. Francis is professor of psychiatry at the State University
of New York at Stony Brook. He has received honoraria
from Pfizer.
Dr. Herr is medical director of the Surgical Intensive Care
Unit at Washington Hospital Center in Washington, DC.
He has received honoraria from Pfizer.
Dr. Hughes is associate professor at Boston University
School of Medicine in Boston, Massachusetts. He has
served as a consultant to Janssen and Pfizer; and has
received honoraria from Pfizer.
Dr. Martel is assistant professor in the Department of Emergency
Medicine at Hennepin County Medical Center in Minneapolis,
Minnesota. He has received honoraria from Pfizer.
Dr. Preval is medical director of the Comprehensive
Psychiatric Emergency Program and assistant clinical pro-
fessor of psychiatry and emergency medicine at the State
University of New York at Stony Brook. He is a consultant
speaker for and has received honoraria from Pfizer.
Ms. Ross is a medical writer/editor at Ross Editorial, in
Independence, Virginia. She has received honoraria or pay-
ments for consultancy work from Abbott, AstraZeneca,
Pfizer, and several medical communications firms with a
variety of clients.
Dr. Zimbroff is medical director at Pacific Clinical Research
Medical Group in Upland, California. He has served as a
consultant to Bristol-Myers Squibb and Pfizer; has been a
member of the speaker’s bureaus of Bristol-Myers Squibb,
Otsuka, and Pfizer; and has received grant/research con-
tracts and support from Bristol-Myers Squibb, Cephalon,
DOV, Forest, GlaxoSmithKline, Indevus, Merck, Novartis,
Organon, Pfizer, Sanofi-Synthelabo, and Solvay.
Please Direct All Correspondence To:
Dan L. Zimbroff, MD, Pacific Clinical Research Medical
Group, 1317 West Foothill Blvd, Ste. 200, Upland, CA
91786. E-mail: dan.zimbroff@pcrmg.com.
2 Vol 10 – No 9 (Suppl 11)
 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
Introduction
In recent years, increasing emphasis has been placed on the
importance of treating patients with behavioral emergen-
cies effectively and humanely, with the objective of fostering
more positive therapeutic relationships. In parallel with this
development, several new treatment options for managing agi-
tated patients in the emergency setting have become available.
Among these is intramuscular (IM) ziprasidone (Geodon®), the
first IM formulation of a second-generation (atypical) antipsy-
chotic. In October 2004, a roundtable panel of physicians with
extensive experience in the management of acutely agitated
patients met to review the first 2 years of experience with this
agent. Their purpose was to consolidate clinical experience and
make recommendations for the use of ziprasidone IM in acutely
agitated patients. This monograph, a product of that meeting,
summarizes clinical experience to date with ziprasidone IM and
offers recommendations on its use in various settings. It is not
intended as a comprehensive overview of the different medical
treatments, either with conventional (first-generation) antipsy-
chotics or with other second-generation agents, available for
acutely agitated patients. Nonetheless, the panelists did discuss
other treatments if there was a clinically relevant contrast with
ziprasidone IM regarding efficacy or safety.
To ensure the broadest applicability of the recommenda-
tions regarding ziprasidone IM, the assembled panelists
represented various treatment settings in which agitation
is frequently encountered—psychiatric emergency services
(PES), medical emergency departments (ED), acute inpa-
tient psychiatric units, and intensive care units (ICU)—as
well as various geographic areas (California, Colorado,
Massachusetts, Minnesota, New York, Texas, Washington
DC, and Wisconsin). The panel was co-chaired by Drs.
Zimbroff and Allen, and included Drs. Battaglia, Citrome,
Fishkind, Francis, Herr, Hughes, Martel, and Preval.
The following issues were discussed by the panelists:
Choice of agent. When is it appropriate to select ziprasidone IM
instead of a conventional IM antipsychotic? Are there clinical
situations in which use of a conventional IM agent is the bet-
ter therapeutic choice? What is known about the efficacy and
tolerability of ziprasidone IM in managing acute agitation?
Transition to oral medication. How soon after IM administra-
tion can oral ziprasidone be given, and what initial oral dose
should be used? What are the advantages, if any, to using
ziprasidone for both IM and oral treatment?
Use in nonpsychiatric settings. What is the potential role of
ziprasidone IM in managing agitation in the medical ED and
in the general hospital or ICU?
Safety issues. Now that global exposure to ziprasidone
exceeds 1 million patients and there have been no confirmed
or published cases of torsade de pointes or sudden cardiac
death clearly attributable to the agent, is there any basis for
concern over QTc prolongation? Should long-term toler-
ability and safety issues (eg, tardive dyskinesia, weight gain,
prolactin elevation) influence selection of an agent for the
initial management of acutely agitated patients?
Future research. What types of postmarketing studies of
ziprasidone IM are needed?
CNS Spectrums, September 2005
Clinically Significant Agitation
Definition and Scope of the Problem
Agitation is a common clinical challenge whose phe-
nomenology is similar across diverse diagnoses, including
psychosis, dementia, delirium, and substance withdrawal.
Similarity of presentation can make it difficult to quickly
determine underlying etiology. Agitation may lead to
violent, destructive behavior and cause extreme personal
distress, while posing a physical risk to patient, caregivers,
nursing staff, and others. As such, it constitutes a psychiatric
emergency in which the need for rapid treatment frequently
precludes a thorough evaluation of etiology. Clinicians there-
fore require rapidly acting treatments that are effective and
safe, regardless of the genesis of agitation.
Agitation requiring acute intervention is a significant
public health problem. A mean of 400.7 patients per month
(range 90–1,200) are evaluated in a typical PES; 8.5% of
these require mechanical restraints for agitation, with the
mean duration of restraint time being 3.3 hours/episode.1
The risks associated with misuse and overuse of restraints
in the PES have been highlighted both in scientific studies
and in the general media.2-5 In the United States, these risks
include an estimated 50–150 deaths/year7 and a mean annual
rate of 5.8 assaults (range 0–35), with 56.5% of the assaults
causing lost time from work.1 The fact that nurses are three
times as likely as physicians to be assaulted may be due to
their role in applying restraints.
Increasing emphasis on patient autonomy and involve-
ment in therapeutic decision making can be a challenge in
cases of acute agitation, where a patient’s decision-making
capacity may be impaired and safety is a primary concern.
Nonetheless, clinical experts in the management of psychi-
atric emergencies strongly endorse efforts to involve patients
in decisions about their treatment, eg, by encouraging
them to express treatment preferences and by asking them
which treatments have worked for them previously.7 When
surveyed about their experiences of and attitudes toward
psychiatric emergency care, patients repeatedly stress the
importance of staff treating them respectfully, talking and
listening to them, helping them calm down, reassuring
them, and involving them in treatment decisions. They
consider it highly important to be asked about medication
preferences and to receive the least restrictive care possible
as soon as possible.8 Nonetheless, despite wanting medica-
tion and acknowledging its benefits, many patients also
express strong concerns about drug side effects and have
rated haloperidol unfavorably among medications they have
received in this setting.8
The panel noted that when patients are heavily sedated to
ensure their own safety as well as that of caregivers and staff
members, it is virtually impossible to engage them in col-
laborative interactions or to elicit meaningful information
from them. The failure to achieve a therapeutic relationship
during an initial interaction may adversely affect subsequent
inpatient and outpatient care, as well as the individual’s
willingness to seek long-term care and adhere to prescribed
treatments. Medications that calm without excessive seda-
3 Vol 10 – No 9 (Suppl 11)
 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
tion have been identified by both US and European authori-
ties as crucial to the management of agitated patients.9
Indications for Parenteral Treatment
Parenteral medication is indicated when very rapid (ie,
within minutes) control of acute agitation is necessary
to prevent harm to the patient or staff or when treat-
ment is necessary but the patient is unable or unwilling
to take an oral agent. Available parenteral treatments
include IM and intravenous (IV) benzodiazepines; halo-
peridol IM and IV; droperidol IM; chlorpromazine IM,
perphenazine IM, and thiothixene IM (first-generation
antipsychotics); and ziprasidone IM and olanzapine IM (sec-
ond-generation antipsychotics). In general, IM formulations
are used during the first 24 hours of treatment to manage
acute agitation. The patient is then generally switched
to oral medication, provided he or she is willing to take
an oral agent and longer term treatment is needed.
Profile of the Ideal Parenteral Medication
Over the past several decades, management of acute agi-
tation requiring parenteral treatment has predominantly
entailed administration of a conventional short-acting IM
antipsychotic, a benzodiazepine, or (frequently) a combina-
tion of both. While all of these therapeutic options effective-
ly reduce acute agitation and have a long history of relatively
safe use, they also have limitations.
Compared to second-generation antipsychotics, conven-
tional IM antipsychotics have a greater association with
problematic side effects, specifically, movement disorders
(eg, tremor, dystonia, and akathisia),10 excessive sedation, and
dysphoria.11 These side effects may alarm patients and ren-
der them unwilling to take such medications in the future.
Use of concomitant anticholinergic agents (eg, benztropine)
to minimize the risk of EPS may contribute to cognitive
disturbances, further complicating patient assessment and
treatment. Other adverse effects commonly associated with
conventional antipsychotics include hypotension and, less
frequently, cardiovascular events (eg, torsade de pointes).12,13
Benzodiazepines reduce agitation without causing EPS
and are generally preferred by agitated patients,8 but
they fail to address underlying psychosis when present.
Moreover, agitation may recur once sedative effects wear
off. At generally prescribed parenteral doses, benzodiaz-
epines may also induce respiratory depression, particularly
in patients with compromised airways; excessive sedation
and ataxia, especially in geriatric patients; and in rare cases,
paradoxical disinhibition.14,15
Combining benzodiazepines with conventional antipsy-
chotics may only temporarily mask or mitigate EPS if the
benzodiazepine is eliminated more rapidly than the anti-
psychotic. Moreover, the combination may also result in
excessive sedation.16
The need for parenteral medications that effectively man-
age acute agitation while causing the fewest adverse effects
is obvious (Slide 1).
Agents that generally meet the criteria for an ideal antipsy-
CNS Spectrums, September 2005
chotic are thought to help in forging an effective therapeutic
alliance early in a patient’s treatment, thereby improving the
chances for adherence during maintenance therapy.17 IM for-
mulations of second-generation antipsychotics come closer
than other available agents to meeting these criteria insofar
as they allow for rapid management of acute agitation, con-
current treatment of underlying psychosis (if present), and
minimization of sedative effects, EPS, and dysphoria. By
lowering the risk of excessive sedation, the second-genera-
tion IM antipsychotics may facilitate clinical assessment and
allow patient participation in therapeutic decision making.
By reducing the incidence of EPS and dysphoria, they may
also engender a better subjective response and a more favor-
able attitude toward treatment on the part of patients.18
Ziprasidone IM, the focus of this monograph, was approved
by the Food and Drug Administration in 2002. The fol-
lowing sections summarize research findings and describe
clinical experience with ziprasidone IM after 2 years of use
in patients with acute agitation.
Slide 1
Attributes of the Ideal Parenteral Antipsychotic
• Offers rapid onset of therapeutic effect
• Calms without causing excessive or profound sedation
• Has a low risk of acute movement disorders
• Has a low risk of hypotension, with a resultant low risk of
cardiovascular events
• Is not associated with dysphoria
• Has a low risk of drug-drug interactions
• Initiates treatment of underlying psychosis, if present
• Provides for effective, well-tolerated transition from IM to oral
maintenance therapy
IM=intramuscular.
Efficacy Data From Clinical Trials
Ziprasidone IM is indicated for the treatment of acute agita-
tion in patients with schizophrenia and schizoaffective disorder.
It is available in a single-dose vial as ziprasidone mesylate (20
mg/mL when reconstituted). Peak serum concentrations are
achieved approximately 30–45 minutes after administration
of a single dose (versus 6–8 hours for the oral formulation),19
and the mean half-life is 2.2–3.4 hours.20 Clinical studies have
shown onset of action (as indicated by improvement in agita-
tion significantly greater than that observed with the control
dose) in 15−30 minutes after the first injection of ziprasidone
IM,21,22 and little accumulation after 3 days of dosing.23
24-Hour Pivotal Studies
The efficacy of ziprasidone IM in subjects with acute psy-
chotic agitation was evaluated in two 24-hour, randomized,
double-blind, fixed-dose multicenter trials that used similar
designs except for dosages. In the study by Lesem and col-
leagues,21 subjects were randomly assigned to receive up to
four injections (every 2 hours PRN) of 2 mg (n=54) or 10 mg
(n=63) ziprasidone IM. In a study by Daniel and colleagues,22
patients were randomly assigned to receive up to four injections
(every 4 hours PRN) of 2 mg (n=38) or 20 mg (n=41) ziprasi-
done IM. A subtherapeutic 2-mg dose was used as a “pseudo-
placebo” control in both studies. Agitation was assessed using
4 Vol 10 – No 9 (Suppl 11)
=110)
Clinical Information Monograph
n=9)
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
Simpson–Angus Scale Bames Akathisia Scale Simpson–Angus Scale Bames Akathisia Scale
1 hour Last 1 hour Last 1 hour Last 1 hour Last 7 Ziprasidone 20-mg IM (n=110)
postdose observation postdose observation postdose observation postdose observation
0 0 Conventional IM agents (n=9)
the Behavior Activity Rating Scale (BARS ), with a 2-point
–0.1 –0.1
TM
or haloperidol
6 IM (n=42), followed by oral medication until
Clinical trial of 20-mg IM
–0.2 –0.2
drop in score defining response. The BARS, a validated 7-point
Mean Change
day 7. Ziprasidone was given in an initial
Ziprasidone IM dose of 10
(n=41)‡

Mean Change
–0.3 –0.3
5 *
scale, assesses agitation and level of consciousness (Slide 2).24 mg, followed by 5−20 mg†IM every 4–6 hours (maximum
–0.4 –0.4
†

BARS Score
–0.5 –0.5
†

Improvement
–0.6
–0.7
–0.6
–0.7 of 80 mg/day),
4 and then in oral doses†of 80−200 mg/day.
* †
Slide
–0.9
2 –0.8 –0.8
–0.9 Haloperidol was initially *dosed at 2.5−10 mg †IM, fol-
Behavioral ActivityZiprasidone,
Rating10 mgScale
Ziprasidone, 2 mg (m=54)
24
Ziprasidone, 2 mg (m=38)
3 *
–1
(m=83)
–1
Ziprasidone, 20 mg (m=41) lowed by 2.5−10 mg IM every 4–6 hours (maximum of 40
*
1=Difficult or unable to rouse
mg/day), and
2 then in oral doses of 10−80 mg/day. * *Subjects
120
2=Asleep, but responds normally to verbal or physical contact given ziprasidone IM showed significantly greater improve-
1
3=Drowsy, appears sedated ment in Brief Psychiatric Rating Scale (BPRS) total score
4=Quiet and awake (normal level of activity) and agitation
0 items and in CGI-S at last assessment on IM
5=Signs of overt (physical or verbal) activity, calms down with instruction treatment26 Baseline 15
than those 30
given 45
haloperidol 60
IM90(Slide120
4). Both
6=Extremely or continuously active, not requiring restraint groups showed furtherMinutes After Injection
improvement after the transition to
7=Violent, requires restraint oral therapy, with ziprasidone subjects exhibiting signifi-
PSYCH (n=72) cantly greater mean improvement on the CGI-S scale than
ETOH (n=10)
7
SUBS (n=28)
haloperidol subjects at endpoint.
ay 7) Both 10-mg and 20-mg Clinical ziprasidone IM
trial of 20 mg IM produced sig-
6 * Ziprasidone (n=41)‡ Slide 4
nificant reductions in agitation as measured by scores on the
Mean Change From Baseline in BPRS Agitation Items* After
BARS compared
5 with the† 2-mg (pseudo-placebo) dose (Slide Ziprasidone IM: 7-Day Study25
Improvement

3), with the 20-mg dose producing the largest and most rapid
BARS Score

4
Improvement

response. A significantly higher percentage of subjects in the Last IM Dose Oral Endpoint (Day 7)
0

Mean Change From Baseline

20-mg group
3 (90%) responded to therapy than those in the
10-mg group (57%), while also showing a slightly † faster time –0.5
2

Improvement
)
to first response (ie, time after injection to reach a 2-point
drop in BARS
1 score). The calming effect of ziprasidone IM 20 –1

mg was also
0
evident in the significant reduction in scores on –1.5
agitation items
Baselineon15
the Positive
30 45 and60 Negative 90 Syndrome
120 Scale
(P<.05) and on theMinutes ClinicalAfter
GlobalInjection
Impression of Severity –2
*
(CGI-S) scale (P=.008) at 4 hours postdose.
–2.5 Ziprasidone (n=90) Haloperidol (n=42)

Slide 3 *BPRS items include 2, anxiety; 6, tension; 10, hostility; and 17, excitement.
Change in BARS Scores After Ziprasidone IM 10 mg and 20 mg: †P=.015 versus haloperidol.
24-Hour Pivotal Studies21,22 BPRS=Brief Psychiatric Rating Scale; IM=intramuscular.
Brook S, Lucey JV, Gunn KP. J Clin Psychiatry. 2000;61:933-941. Copyright 2000, Physicians Postgraduate
Tc Average Press. Reprinted by permission.
er 24 Hours All patients, observed cases
10 mg study (Study 125) 20 mg study (Study 126)
Zip Time after first injection (hours) Time after first injection (hour)
Hal 0 15
m
in
1 2 3 4 0 30
m
in
1 2 3 4
A randomized, flexible-dose, open-label, 6-week multi-
Change in BARS (+/–SE)

0 0
center trial compared the efficacy and tolerability of zipra-
–0.5 –0.5
sidone IM and haloperidol IM, along with the transition
from baseline

Improvement

age Over
Hours –1 –1

Hal –1.5 –1.5

† to oral treatment, in 567 subjects hospitalized within the
–2.0
‡
‡ † –2.0
‡
‡ preceding 7 days∆for QTcacute exacerbations of schizophrenia
at Cmax ∆ QTc Average or
‡
6.3 ms
–2 –2 ‡ ‡ ‡ schizoaffective
25 Injectiondisorder.
1 27
Inclusion
Injectioncriteria
2 wereOver 24 Hours
a minimum
‡ score of 40 on the BPRS(Second and Injection
the need
Cmax) for IM treatment
Mean QTc Change, ms (95% CI)

4 ms Zip
–3 –3
Ziprasidone IM 10 mg (n=65) Ziprasidone IM 20 mg (n=41) as20determined by investigator clinical judgment. Hal Subjects
Control Group (n=54) Control Group (n=38) Zip Hal
Minutes After Injection were randomly
20 mg 7.5 mg assigned to treatment with ziprasidone IM
*P<.05; †P<.01; ‡P≤.001 versus 2-mg control. 15
BARS=Behavior Activity Rating Scale; IM=intramuscular.
(n=429, 10 or 20 mg;
First Injection Cmax)
maximum 40 mg/day)
14.7 ms
or haloperidol
Average Over
~24 Hours
Panel 1: Lesem MD, Zajecka JM, Swift RH, et al. J Clin Psychiatry. 2001;62:12-18. Copyright 2001, IM (n=138, 2.5–5.0 mg; maximum 12.8 ms 10 mg/day) for up to
10 Zip Hal
Physicians Postgraduate Press. Reprinted by permission.
3 days and received a minimum of two IM doses before the
Panel 2: Daniel DG, Potkin SG, Reeves KR, et al. Psychopharmacology Berl. 2001;155:128-134. Copyright Zip Hal
2001, Springer-Verlag. Reprinted by permission. transition to oral treatment. Oral-phase 30 mg 10 mg dosing, which lasted
5 6.0 ms 6.3 ms
for up to 6 weeks,
4.6 ms was 40–80 mg BID with ziprasidone 3.4 ms
and
IM/Oral Transition Studies 5–20
0
mg/day with haloperidol. Ziprasidone showed numeri-
In a 7-day, randomized, open-label, multicenter study, cally superior efficacy to haloperidol at the end of both the
Brook and colleagues25 compared the efficacy and tolerability IM and oral treatment phases, and the difference in BPRS
of ziprasidone IM and haloperidol IM, and the transition scores was significant (P<.002) at the end of the 3-day IM
from IM to oral treatment, in hospitalized subjects with treatment period. Ziprasidone was associated with markedly
acute psychotic agitation associated with schizophrenia, fewer treatment-emergent adverse effects than haloperidol,
schizoaffective disorder, bipolar disorder, brief psychotic dis- with the exception of insomnia. Mean daily doses in the
order, or psychotic disorder not otherwise specified. Subjects combined IM/oral phases were 116 mg for ziprasidone and
received up to 3 days of flexible-dose ziprasidone IM (n=90) 11.5 mg for haloperidol.

CNS Spectrums, September 2005 5 Vol 10 – No 9 (Suppl 11)

 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE

A 7-day, randomized, open-label IM/oral transition study improvement in psychotic symptoms (such as hallucinations
compared the tolerability of ziprasidone IM and haloperi- or delusions) or of the development of akathisia.29 Primary
dol IM in subjects hospitalized with a psychotic disorder. outcome measures were the BPRS hostility item 10 and the
Subjects were randomly assigned to receive one of three fixed agitation factor (sum of items 2 [anxiety], 6 [tension], 10
doses of ziprasidone IM (5 mg QID [n=69], 10 mg QID [hostility], and 17 [excitement]). Results were analyzed by
[n=71], or 20 mg QID [n=66]) or flexible-dose haloperidol mixed-model repeated measures analysis.30 Treatment group
IM (up to 10 mg QID [n=100]) for 3 days. Following IM (between-subject factor) and time (within-subject factor)
treatment, oral therapy with the same medication was initi- served as independent variables, while repeated assessments of
ated for up to 4 days.28 Although mean BPRS scores showed a BPRS item or factor over time were dependent variables. The
small reductions from baseline across all treatment groups, interaction between independent variables was included in the
fixed-dose ziprasidone IM was associated with a lower model. Results were analyzed for change before the transition
burden of movement disorders than haloperidol IM (mean to oral medication, change at the end of the first week of treat-
dose=11 mg/day). No bradycardia, sinus pauses, disinhibi- ment, and outcome at day 42 in the 6-week study.
tion, confusion, excessive sedation, or respiratory depression In the first 1–3 days of treatment, ziprasidone showed
was observed with ziprasidone. Approximately half of all greater efficacy than haloperidol with respect to the agitation
subjects in the four treatment groups received concomitant factor (P<.05) and hostility item (P<.05). Efficacy measures
lorazepam at some point during the study without experi- for each of the two treatments converged after 3 days, sug-
encing adverse consequences. The transition from IM to oral gesting that further improvement was likely due to a time
ziprasidone was well tolerated, with continued maintenance effect. Statistically significant anti-hostility effects (P<.0001)
of symptom control. were seen for both drugs by the end of the study (pooled data
In summary, the results of these three IM/oral transition to day 7 and to day 42 in the 6-week study), with correction
studies show that ziprasidone IM was at least as efficacious for the confounds of BPRS positive symptoms (suspicious-
as haloperidol, and was associated with better tolerability, in ness, grandiosity, unusual thought content, conceptual disor-
acutely agitated subjects who required ongoing oral therapy, ganization, and hallucinatory behavior) and akathisia.
even when dosed at 20 mg QID (80 mg/day), which is a dosage As Dr. Citrome noted, one limitation of the analysis was
higher than the currently recommended maximum in the US. that the subjects were not specifically selected for a history
The rationale for the oral transition dosage used in these stud- of hostile, aggressive behavior (eg, physical assault). Second,
ies is shown in Slide 5, which compares serum concentrations hostility, rather than overt aggression, was rated. Overt hos-
of ziprasidone IM 10 mg and 20 mg with those of oral zipra- tility was mostly inferred from verbal cues, which makes it
sidone 80 mg BID. As the data suggest, patients who tolerate more difficult to find any effect. However, other studies have
ziprasidone IM 20 mg with good results have already achieved observed that reductions in verbal assaultiveness parallel
ziprasidone plasma levels higher than would be expected with those in physical assaultiveness.31 Definitive studies of the
an initial oral dose of 80 mg BID (160 mg/day). anti-aggression properties of drugs would require double-
blind selection for aggressive behavior and treatment ran-
Slide 5 domization, and would therefore be difficult to conduct.32
Serum Ziprasidone Concentrations: Single-Dose 10- or 20-mg
IM Versus 80-mg Oral BID Administration20 Safety Data From Clinical Trials
10 mg IM
Important safety issues in trials of currently available
Serum concentration,

400
350 20 mg IM second-generation antipsychotics include the potential for
80 mg BID PO drug interactions, cardiotoxicity, cerebrovascular effects, and
mg/mL (±SD)

300
250 hypotension, as well as safety in overdose.
200
150 Adverse Effects in Efficacy Trials
100
Adverse events with an incidence >5% from fixed-dose and
50
0
flexible-dose trials of ziprasidone IM are reported separately
0 2 4 6 8 10 12 in Slide 6 (non-motor effects) and Slide 7 (motor effects). The
Hours post-dose most common adverse events were insomnia, headache, and
dizziness (all >10%) in fixed-dose trials; and insomnia and
IM=intramuscular.
FDA Psychopharmacologic Drugs Advisory Committee. Briefing document for ziprasidone meylate for intra- hypertension (20 mmHg threshold; both <10%) in flexible-
muscular injection. Available at: http:/www.fda.gov/ohrms/dockets/ac/01/briefing/3685b2_01_pfizer.pdf. dose trials.
In the 24-hour studies by Lesem and colleagues21 and
Posthoc Analysis of Hostility in IM/Oral Daniel and colleagues22 10- and 20-mg doses of ziprasidone
Transition Studies IM were very well tolerated. The 20-mg dose was more
Dr. Citrome reported to the panel initial results of a effective and produced more rapid symptom abatement than
posthoc analysis of pooled data from the two trials by Brook the 10-mg dose but was not associated with EPS, dystonia,
and colleagues,25,27 designed to determine if ziprasidone or akathisia, respiratory depression, or excessive sedation. None
haloperidol
1 hour
had Bames
Simpson–Angus Scale
Last
a specific
1 hour Last
anti-hostility
Akathisia Scale
effect independent
Simpson–Angus Scale
1 hour Last
of
Bames Akathisia Scale
1 hour Last
of 63 subjects given 10 mg ziprasidone IM experienced
postdose observation postdose observation postdose observation postdose observation
0 0

CNS Spectrums, September 2005–0.1

–0.1
–0.2 –0.2
6 Vol 10 – No 9 (Suppl 11)
hange

hange

–0.3 –0.3
–0.4 –0.4
 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE

orthostatic hypotension, while 2 of 41 (5%) given 20 mg Dosing and Adverse Effects

did. Similarly, no patient given a 10-mg injection experi- Although the clinical trials evaluating the efficacy and
enced bradycardia, while 1 (2%) given a 20-mg injection safety of ziprasidone IM were not powered to detect dose-
did. Subjects treated with the 10-mg dose were calm but not dependent differences in side effects, the data suggest a
excessively sedated, with mean BARS scores decreasing from low likelihood of dose dependency. Double-blind studies
4.79 (overtly active) at baseline to 3.18 (drowsy and appears employing doses of 2 mg (a pseudo-placebo) or of 10, 20,
sedated) after 2 hours and 3.14 after 4 hours. The mean or 40 mg revealed few significant differences in most non-
BARS score of those treated with the 20-mg dose decreased motor side effects (Slide 6). These same studies showed
from 4.98 (overtly active) at baseline to 2.43 (asleep but mean reductions from baseline in Simpson-Angus Scale and
responds normally to verbal or physical contact) after 2 hours Barnes Akathisia Scale scores 1 hour after the10first
mg IMinjection
Agitated Patients20versus Time

Serum concentration,
400
and remained
60 at 2.80 after 4 hours. and at last 350
observation whether subjects had 20received
mg IM 2-mg
80 mg BID PO
In the 7-day flexible-dose study, postural hypotension

mg/mL (±SD)
Droperidol (pseudo-placebo),
300 10-mg, or 20-mg doses of ziprasidone IM
No. of Patients

was reported
40 in 1 of 90 (1%) subjects receiving Ziprasidone
ziprasidone 250
over 24 hours200
(Slide 7). Moreover, the incidence of certain
Midazolam
IM.25 The incidence of movement disorders in this open- side effects 150
(eg, dizziness, tachycardia, and dystonia) declined
label study20 was much lower with ziprasidone than with with higher100ziprasidone doses in both open-label and blind-
haloperidol during both IM treatment (1.1% and 2.4%, 50
ed studies. Importantly, no substantial changes were found
0
respectively,0 for0tremor;
15 0% 30 versus
45 21.4%,
60 respectively,
90 120 for in median heart 0 rate 2
or blood4 pressure
6 when
8 ziprasidone
10 12 IM
EPS) and oral treatment Time(2.2% versus(min)
After Drug 9.5%, respectively, was dosed at 20 mg QID Hours post-dose
(ie, twice the current maximum
for tremor; 1.1% versus 38.1%, respectively, for EPS). In recommended dosage of 10 mg QID) in open-label studies.
addition, 47.6% of subjects given haloperidol required In summary, the clinical trials database revealed no con-
anticholinergic medication versus only 14.4% of those sistent pattern of escalating incidence of side effects with
given ziprasidone. escalating ziprasidone doses.

Slide 6 Slide 7
Non-Motor Adverse Events in ≥10% of Subjects in Trials of Mean Change From Baseline in Movement Disorder Scale
Ziprasidone IM20-22,25,27,28
7 Ziprasidone 20-mg IM (n=110) Scores in 1-Day Fixed-Dose Trials21,22
Conventional IM agents (n=9)
1-Day Fixed-Dose, Double-Blind TrialsIM
Clinical trial of 20-mg 6 Simpson–Angus Scale
1 hour Last
Bames Akathisia Scale
1 hour Last
Simpson–Angus Scale
1 hour Last
Bames Akathisia Scale
1 hour Last
Ziprasidone (n=41)‡ postdose observation postdose observation postdose observation postdose observation
5 ZIP 2-mg* 0 0

Pseudo-pla- ZIP† 10 mg* ZIP 20 mg† –0.1 –0.1

BARS Score

†
Improvement

4cebo (n=92) † –0.2 –0.2

(n=63) (n=41)

Mean Change
Mean Change

–0.3 –0.3

* † –0.4 –0.4
Headache 3 3% 13% * 5% † –0.5 –0.5
–0.6 –0.6
Nausea 4% 8% * 12% –0.7 –0.7
2 * * –0.8 –0.8
Dizziness 3% 3% 10% –0.9
Ziprasidone, 2 mg (m=54)
–0.9
Ziprasidone, 2 mg (m=38)
–1 –1
Somnolence 1 8% 8% 20% Ziprasidone, 10 mg (m=83) Ziprasidone, 20 mg (m=41)

Injection 0 9% 6% 7%
site pain Baseline 15 30 45 60 90 120 Panel 1: Lesem MD, Zajecka JM, Swift RH, et al. J Clin Psychiatry. 2001;62:12-18. Copyright 2001,
Physicians Postgraduate Press. Reprinted by permission.
7-Day Fixed-Dose, Open-Label
Minutes Trial (with 3-day IM Phase)
After Injection
Panel 2: Daniel DG, Potkin SG, Reeves KR, et al. Psychopharmacology Berl. 2001;155:128-134. Copyright
ZIP 5 mg‡ ZIP 10 mg‡ ZIP 20 mg‡ Halo <10 mg§ 2001, Springer-Verlag. Reprinted by permission.
(n=69) (n=71) (n=66) (n=100)
Insomnia 10% 16% 21% 12% Drug–Drug Interactions
Headache 17% 14% 20% 8%
It is frequently impossible in emergency settings to
Injection 6% 10% 17% 2% PSYCH (n=72)

site pain determine7

which medications
ETOH (n=10) patients may have taken.
SUBS (n=28)
Anxiety 16%IM Dose
Last 14% Oral Endpoint
17% (Day 7) 13% Moreover, recent investigations 33
indicate that severely agi-
Clinical trial of 20 mg IM
0 *
Mean Change From Baseline

6
Dizziness 16% 20% 15% 0% tated patients requiring emergency
Ziprasidone (n=41)‡IM medication tend to
Vomiting –0.5 9% 11% 12% 5% have significantly
5 more laboratory abnormalities, including
†
Improvement

Tachycardia 3% 11% 8% 6% QTc prolongation, than nonagitated patients who present in

–1
BARS Score

4
Improvement

Somnolence 7% 10% 6% 8% the ED. Both of these factors underscore the need for agents
–1.5 Open-Label Flexible-Dose Trials (with 3-day IM Phase) with a low
3 likelihood of drug-drug interactions in the treat-
42-Day Trial 7-Day Trial †
–2
* mg/d Halo ≤10 mg ZIP ≤80 mg/d Halo ≤10 mg ment of2acutely agitated patients.
ZIP ≤40
–2.5 doseZiprasidone
(n=427) (n=90)
(n=138) Haloperidol
(n=90)(n=42) (n=42) Ziprasidone is metabolized predominantly via the liver,
1
Hypertension 7% 0% with the aldehyde oxidase system responsible for approxi-
Insomnia 7% 5% mately two-thirds
0
Baseline 15
of 30metabolism.
45 60
34
As
90
there
120
are no known
clinically relevantMinutes
inhibitors or inducers
After Injection
of aldehyde oxidase,
IM=intramuscular; ZIP=ziprasidone.
* Maximum of 4 IM doses within 24 hours, with successive doses given at least 2 hours apart. ziprasidone is associated with a low risk of drug-drug inter-
† Maximum of 4 IM doses within 24 hours, with successive doses given at least 4 hours apart. actions. The cytochrome p450 (CYP) isoenzyme CYP 3A4
‡ Dosed QID, with 5- and 10-mg IM doses given at least 2 hours apart and 20-mg IM doses given at is responsible for less than one third of the metabolism of
least 4 hours apart.
§ Dosed BID, TID, or QID.
ziprasidone; therefore, ziprasidone is unlikely to interfere
with the metabolism of drugs metabolized by CYP 3A4.35
∆ QTc at Cmax ∆ QTc Average
Over 24 Hours All patients, observed cases
Injection
CNS Spectrums,
25 1
September Injection 2
2005 7 Vol 10 – No 9 (Suppl 11)
10 mg study (Study 125) 20 mg study (Study 126)
% CI)

(Second Injection Cmax) Zip Time after first injection (hours) Time after first injection (hour)
in in
20 Hal 0 15 m 1 2 3 4 0 30
m 1 2 3 4
)
 Baseline 15 30 45 60 90 120

Minutes After Injection

Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE

Co-administration of carbamazepine, a CYP 3A4 inducer, IM 20 mg followed 4 hours later by ziprasidone IM 30 mg

lowers ziprasidone serum concentrations by ~35%, whereas (a higher-than-recommended dose; n=25) or haloperidol 7
co-administration of ketoconazole, a CYP 3A4 inhibitor, IM 7.5 mg followed by haloperidol
Last IM Dose IM 10
Oral Endpoint (Daymg7) (n=24). No
0 *

Mean Change From Baseline

6
increases ziprasidone concentrations by 35% to 40%.36,37 patient in either group experienced a change from baseline
Significantly, co-administration of ketoconazole produces no QTc ≥75–0.5 ms or had a QTc interval ≥500 ms. The mean 5

Improvement
further QTc prolongation in patients receiving ziprasidone.37 change –1in QTc interval from baseline after the first injection

BARS Score
4

Improvement
In psychiatric emergencies, clinicians commonly combine was 4.6 ms with ziprasidone IM and 6.0 ms with haloperidol
–1.5
an antipsychotic and a benzodiazepine. The panel therefore IM (Slide 8). After the second injection, the mean change 3

considered safety issues related to combining the two avail- was 12.8 –2 ms and 14.7 ms, respectively. Differences were not
* 2
able IM atypical antipsychotics with lorazepam. Limited evi- statistically
–2.5 significant. Overall,
Ziprasidone (n=90) findings
Haloperidol (n=42)from controlled
1
dence suggests that ziprasidone IM can be combined safely studies indicate that changes in QTc with ziprasidone IM
with benzodiazepines. Daniel and colleagues38 analyzed data may be smaller than those with haloperidol IM (a mean of 0
Baseline 15
from a 3-day trial comparing ziprasidone IM 10 or 20 mg 0.1 ms with all ziprasidone IM doses ≥5 mg versus 0.6 ms M
with haloperidol IM 2.5 or 5 mg, with or without concomi- with haloperidol IM).20
tant administration of a benzodiazepine.27 The incidence and
severity of adverse events in subjects treated with ziprasidone Slide 8
and a benzodiazepine (n=167) was found to be comparable Ziprasidone IM 20-mg Versus Haloperidol IM 7.5-mg:
Effect on QTc at Cmax40
to that which occurred in subjects given ziprasidone without
a benzodiazepine (n=262). In another study28 comparing ∆ QTc at Cmax ∆ QTc Average
Over 24 Hours
25 Injection 1 Injection 2
ziprasidone IM (maximum dosage 20 mg QID) and halo- Mean QTc Change, ms (95% CI)
10 mg stu
(Second Injection Cmax) Zip Time after f
peridol IM (maximum dosage 10 mg QID), co-administra- 20 Hal 0 15 m
in
1

Change in BARS (+/–SE)

0
Zip Hal
tion of lorazepam up to 12 mg/day was permitted, and 48% 20 mg 7.5 mg –0.5
15

from baseline
and 59% of subjects in the treatment groups received this First Injection Cmax) 14.7 ms
Average Over
~24 Hours –1
12.8 ms
medication. The researchers reported observing no adverse 10 Zip Hal –1.5
‡
events associated with concomitant benzodiazepines. The Zip Hal –2.0
5 30 mg 10 mg
US package insert for ziprasidone contains no information 4.6 ms
6.0 ms 6.3 ms
–2
3.4 ms
specifically about co-administration of benzodiazepines and 0
–3
Ziprasid
ziprasidone. However, the combination of a benzodiazepine Control

with an atypical IM antipsychotic may affect the safety pro-
file of the antipsychotic. The current US package insert for
olanzapine states the following:
Concomitant administration of intramuscular olanzapine and parenteral
benzodiazepine has not been studied and is therefore not recommended.
If use of intramuscular olanzapine in combination with parenteral benzo-
diazepines is considered, careful evaluation of clinical status for excessive
sedation and cardiorespiratory depression is recommended.39
However, several members of the panel felt that more high-
quality data were needed to fully know the safety profiles of the
combination of both ziprasidone IM with a benzodiazepine and
the combination of olanzapine IM with a benzodiazepine.
Use in Patients With Complicating Conditions
Age and sex exert no significant effect on the pharmacoki-
netics of ziprasidone, and dosage adjustment is not required
in patients with renal or hepatic impairment.23 Ziprasidone
IM has not been systematically evaluated in relation to these
conditions; however, since the cyclodextrin excipient is
cleared by renal filtration, caution should be used when giv-
ing the drug to patients with impaired renal function.19
Cardiovascular Effects
The cardiac safety of ziprasidone IM has been well docu-
mented in controlled clinical studies. Miceli and colleagues40
compared the QTc effects of ziprasidone IM and haloperidol
IM at peak drug concentrations in 59 subjects with psycho-
sis. Existing medication was tapered over a 10-day period,
and subjects were randomly assigned to receive ziprasidone
IM=intramuscular; Zip=ziprasidone; Hal=haloperidol.
Miceli JJ, Anziano MS, Swift RH, et al. Presented at: 156th Annual Meeting of the American Psychiatric
Association; May 17-22, 2003; San Francisco, CA.
These observations suggest that the effects of ziprasidone
IM and haloperidol IM on the QTc interval are comparably
small. The panel therefore observed that clinicians comfort-
able with the cardiac safety profile of haloperidol IM should
be equally comfortable with that of ziprasidone IM because
QTc prolongation with the two agents is statistically com-
parable (ie, their confidence intervals overlap) (Slide 8). It is
worth noting that while cases of torsade de pointes have been
reported with haloperidol, the incidence is small and has
largely been confined to the use of very high doses in ICU
patients with multiple medical comorbidities.13 Similarly,
although the FDA recently issued a “black box” warning
about the potential for fatal cardiac arrhythmias with dro-
peridol, a recent review of the literature spanning the years
1960–2002 concludes that clinical experience suggests little
prospect of cardiovascular events with the drug, as stated
by Shale and colleagues41:
While in theory droperidol may prolong the QT interval to an extent
similar to thioridazine, in clinical use there is no pattern of sudden
deaths analogous to those that provoked the FDA warning about
thioridazine.
The package insert for ziprasidone lacks any recommen-
dation for routine electrocardiograms (ECGs) prior to treat-
ment initiation. It does, however, caution against giving
ziprasidone with other drugs known to prolong the QTc
interval, and notes a contraindication to usage in patients

CNS Spectrums, September 2005 8 Vol 10 – No 9 (Suppl 11)

 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
with a known history of QT prolongation, recent acute
myocardial infarction, or uncompensated heart failure.19
There have now been over 1 million patient exposures to
ziprasidone worldwide. (In the US, exposures have totaled
nearly 700,000 to the oral agent and 110,000 to the IM
agent.) Until recently there have been no confirmed or
published cases of torsade de pointes or sudden cardiac
death (Data on file, Pfizer Inc). Heinrich and colleagues42
recently reported a case of QT prolongation and torsade
de pointes in a 28-year old woman receiving oral ziprasi-
done. The patient exhibited QT prolongation alone at an
initial admission, and at second admission, after ziprasi-
done had been resumed, exhibited QT prolongation and
torsade de pointes. The arrhythmia resolved following
discontinuation of ziprasidone and did not recur, although
QT prolongation continued, and other medications were
subsequently withdrawn. The authors reported that the
interpretation of these observations was complicated by
comorbidities and concomitant medications. On the initial
admission, the patient exhibited lithium toxicity and was
hypokalemic. On the second admission, the patient was
receiving other medications known to be associated with
QT interval prolongation, including ciprofloxacin and
fluconazole, although her lithium had been discontinued.
As of July 2005, there remain no published reports of sud-
den cardiac death, or death of any cause, associated with
ziprasidone. Findings from the clinical trials database
indicate that QTc increases with oral ziprasidone average
6–10 ms,43 which is considerably smaller than average
increases seen with commonly used medications (eg, 47
ms with erythromycin IM).44 Published studies also sup-
port the cardiac safety of oral ziprasidone,45 as does the
lack of serious cardiac events or deaths in instances of over-
dose (up to 12,800 mg in one confirmed case).19
Overdose
The few reported cases of overdose with oral ziprasidone
suggest relative safety,46-48 although transient hypotension47
and hypertension46—but no deaths—have been noted.
Coadministration of IM and Oral Ziprasidone
The package insert for ziprasidone states that, as there is no
experience regarding the safety of administering ziprasidone
IM to schizophrenic patients already taking oral ziprasidone,
the practice of co-administration is not recommended.19
Postmarketing Experience in the Psychiatric
Emergency Service
The randomized clinical trials described in this mono-
graph provide data demonstrating the safety and efficacy of
ziprasidone IM to support regulatory approval for market-
ing. However, subjects in randomized clinical trials are not
necessarily representative of patients in real-world clinical
practice,33 as these studies must exclude severely agitated
individuals unable or unwilling to consent to participation,
as well as others with a recent history of alcohol or substance
abuse. To address this issue, panelists from a large PES, a
CNS Spectrums, September 2005
medical ED, and an ICU, provided data from naturalistic
studies conducted in real-world treatment settings.
Naturalistic Study in a Comprehensive PES
Drs. Preval and Francis presented findings from a natu-
ralistic, observational study49 of ziprasidone IM in subjects
with severe agitation seen in the PES of the State University
of New York (SUNY) at Stony Brook. This PES handles
~6,500 patients a year, 44% of whom present with major
psychiatric illness and 16% with alcohol- or substance-
related disorders. The majority of patients (75%) arrive by
police escort.
The study received administrative approval from the
Quality Assurance (QA) committee to determine if zipra-
sidone IM, which had just become commercially available,
was sufficiently effective to justify use in place of haloperi-
dol. Informed consent, unobtainable from severely agitated
patients, was not employed. Following completion of the
QA study, the human subjects committee at SUNY Stony
Brook approved a retrospective analysis of the resulting data
for publication.
The study population included 110 agitated subjects—72
with psychotic agitation (PSYCH; ie, negative toxicology
screen), 10 with alcohol-induced agitation (ETOH), and 28
with substance-induced agitation (SUBS)—who received
ziprasidone IM 20 mg between October 2002 and July
2003. Only individuals with a known contraindication to
ziprasidone (eg, a history of active cardiac problems) were
excluded. Study subjects ranged in age from 13–87 years
(median 37 years) and included 64 males and 46 females.
Also included were 9 subjects who had been given other
sedatives: 7 given haloperidol with or without lorazepam,
1 given chlorpromazine, and 1 given lorazepam. Subjects
underwent routine clinical monitoring, and ECGs were
obtained 30–45 minutes postdose (ie, at peak blood level)
in 19 individuals.
Mean BARS scores were high at baseline (6.5 in the
PSYCH group, 6.9 in the ETOH group, and 6.6 in the
SUBS group), reflecting more severe levels of agitation
than seen in clinical trials of ziprasidone IM, where, for
example, mean baseline scores ranged from 4.7–5.0 in the
24-hour pivotal studies. Ziprasidone IM was associated with
rapid decrease from baseline in agitation, with significant
improvements in the PSYCH, ETOH, and SUBS subjects at
15 minutes (mean BARS scores of 5.6, 5.3, and 5.8, respec-
tively; P<.05 for all). Further significant improvements in
mean BARS scores were seen at 30 minutes (4.2, 4.1, and
4.1, respectively; P<.01 for all) and at 2 hours post-first dose
(2.6, 2.2, and 2.3, respectively; P<.01 for all).
Slide 9 shows changes in BARS scores from baseline
through 120 minutes postdose for the 110 ziprasidone sub-
jects and 9 recipients of other medications, along with results
for 41 subjects given ziprasidone IM 20 mg in the clinical
trial by Daniel and colleagues.21 As shown, the decreases in
agitation observed in this real-world setting were greater in
magnitude than those seen in clinical trials, with mean BARS
scores declining from 6.6 (violent, requires restraint) to
9 Vol 10 – No 9 (Suppl 11)
 0 0
0 15 30 45 60 90 120 0 2 4 6 8 10 12
Hours post-dose
Clinical
Time After Drug (min) Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE

slightly above 4.0 (quiet and awake, normal level of activity) mg and lorazepam 2 mg, droperidol 5 mg and lorazepam 2
within 30 minutes. This 2.5-point drop in BARS score from mg, and either chlorpromazine 50 mg or haloperidol 5 mg
baseline was statistically (P<.01) and clinically significant. plus benztropine 1 mg.
Overall, ziprasidone IM was well tolerated in the PES sub-
Slide 9
jects. Only one individual experienced a dystonic reaction,
BARS Scores in PES Patients After Ziprasidone IM 20 mg49
and there were no cases of QTc prolongation among the 19
7 Ziprasidone 20-mg IM (n=110) subjects who underwent ECG monitoring.
Conventional IM agents (n=9) There was a small sample of Bames
Simpson–Angus Scale
severely agitated adolescent
Akathisia Scale Simpson–Angus Scale Bames Akathisia Sc
6 Clinical trial of 20-mg IM
Ziprasidone (n=41)‡
and elderly subjects treated
1 hour Last with1 hour
IM ziprasidone
Last in the1 hour
PES. Last 1 hour Last
postdose observation postdose observation postdose observation postdose observat
5 * Overall responses0
in these groups, as well as those0
in five
† –0.1 –0.1
BARS Score

† agitated adults
–0.2 with mental retardation or autism,–0.2 were com-
Improvement

4 †

Mean Change

Mean Change
–0.3 –0.3

* † parable to findings
–0.4
in the 110 subjects described above,
–0.4
with
† mean BARS–0.5 scores dropping by more than 2 points within
3 * –0.6
–0.5
–0.6
me * 10 mg IM
30 minutes, –0.7
indicating a statistically (P<.05) and –0.7 clinically
Serum concentration,

400
2 350 * 20 mg IM
* –0.8 –0.8
80 mg BID PO rapid improvement in agitation. Furthermore, treatment had
mg/mL (±SD)

roperidol 300 –0.9

Ziprasidone, 2 mg (m=54)
–0.9
Ziprasidone, 2 mg (m=
prasidone 1 250 no effect on blood
–1
pressure or cardiac
Ziprasidone, status.
10 mg (m=83)
–1
Ziprasidone, 20 mg (m
idazolam 200
150
In summary, this naturalistic study demonstrated that
0
100
Baseline 15 30 45 60 90 120 ziprasidone IM produced a marked decrease in agitation
50
scores in a clinically meaningful time (ie, in 15–30 minutes)
0 Minutes After6 Injection
120 0 2 4 8 10 12 in highly agitated subjects treated in a real-world PES.
* P<.01 versus baseline for ziprasidone in PES patients.Hours post-dose
† P<.01 versus baseline for conventionals in PES patients.
Ziprasidone was also well tolerated. Of note, restraint time
‡ Daniel DG, Potkin SG, Reeves KR, et al. Psychopharmacology Berl. 2001;155:128-134. was reduced with ziprasidone IM versus conventional agents.
BARS=Barnes-Akathisia Rating Scale; PES=psychiatric emergency services; IM=intramuscular. These promising preliminary results warrant further system-
Preval H, Klotz SG, Southard R, Francis A. Gen Hosp Psychiatry. 2005;27:140-144. Reprinted with
permission from Elsevier.
atic study.
PSYCH (n=72)
Similar changes in BARS scores were seen when recipi- Preliminary Experience in Other ETOH
Clinical
(n=10)
ents of ziprasidone IM were defined by suspected etiology Settings 7
SUBS (n=28)
(n=110)
Last IMETOH,
of agitation (PSYCH, Dose or SUBS),
Oral Endpoint (Day 7)
with significant, Medical Emergency6Department Clinical trial of 20 mg IM
0 *
Mean Change From Baseline

ts (n=9)

Patients frequently arrive in the medicalZiprasidone ED with(n=41)‡

Simpson–Angus Scale Bames Akathisia Scale Simpson–Angus Scale Bames Akathisia Scale
M
rapid improvements again noted within 15–30 minutes of 1 hour Last 1 hour Last
postdose observation postdose observation
1 hour Last 1 hour Last
postdose observation postdose observation
“acute
injection
–0.5(Slide 10). As also noted by the investigators, 77 –0.1
0
–0.1
0
undifferentiated agitation,”
5 leaving the emergency physician
–0.2 –0.2
† is medical, traumatic,
Improvement

severely agitated subjects given ziprasidone IM within 5 to determine if the underlying etiology
Mean Change

Mean Change

–0.3 –0.3

minutes–1
–0.4 –0.4
†
of being restrained spent significantly less time in toxicologic, or psychiatric. It is necessary for the patient to
BARS Score

–0.5 –0.5
4
Improvement

–0.6 –0.6

restraints
–1.5(54±3 minutes; P<.01) than the 80 patients given be calm for the clinician to evaluate the etiology of the agi-
–0.7 –0.7

* –0.8 –0.8
–0.9 –0.9
3
conventional agents in the month before ziprasidone IM was –1
Ziprasidone, 2 mg (m=54)
Ziprasidone, 10 mg (m=83)
–1
Ziprasidone, 2 mg (m=38)
Ziprasidone, 20 mg (m=41) tation. It is also often required to reduce the risk of cardiac
introduced
–2 (91±4 minutes). Conventional therapy in the arrest in agitated patients who develop profound metabolic †
120 *
control period included IM combinations of haloperidol 5
2
acidosis secondary to the use of mechanical restraints.50 In
–2.5 Ziprasidone (n=90) Haloperidol (n=42)
these circumstances,1 the ideal calmative agent is a rapid-act-
Slide 10 ing parenteral agent with a relatively short (ie, 5–6 hours)
BARS Scores in PES Patients By Diagnosis After Ziprasidone IM duration of action and0 a low liability for 45
interaction with
20 mg49 Baseline 15 30 60 90 120
other agents (eg, benzodiazepines) that the patient may have
PSYCH (n=72)
taken prior to presentation in the Minutes
ED. After Injection
ETOH (n=10)
7
Day 7)
SUBS (n=28) Preliminary findings from two studies on the use of zipra-
Clinical trial of 20 mg IM
6 * Ziprasidone (n=41)‡ sidone IM in the medical ED was presented to the panel by
5 Dr. Martel. Both studies were undertaken because of concern
†
Improvement

about QTc prolongation (as seen with droperidol) and other

BARS Score

4
Improvement

side effects, including EPS (as seen with haloperidol).

3
†
The first trial used a nonconsecutive convenience sample
∆ QTc at Cmax ∆ QTc Average
Injection 1
2
Injection 2 Over 24 Hours of 144 subjects with acute undifferentiated All patients,agitation
observedwho cases
42) 25
1 received droperidol IM105 mg mgstudy
(n=50), (Studymidazolam
125) IMmg
20 5 mg
study (Study 126)
Mean QTc Change, ms (95% CI)

(Second Injection Cmax) Zip

0
(n=48), or ziprasidone IM 20 mg (n=46)
Time after first injection (hours)
i n in randomized,
Time after first injection (hour)
i n
20 Baseline 15 30 45 60 90 120
Hal 0 15 m 1 2 3 4 0 30 m 1 2 3 4
double-blind fashion. 0 (Although the Institutional Review
Change in BARS (+/–SE)

0
Zip Hal
20 mg 7.5 mg Minutes After Injection Board granted an–0.5exception for informed –0.5 consent, com-
15
from baseline

Improvement

Average Over
* P<.05 for all First
PES groups versus
Injection baseline at 15 minutes.
Cmax) 14.7 ms
~24 Hours munity consultation–1and notification were done.) –1 The main
† P<.01 for all PES groups versus baseline at 30 minutes12.8and
ms2 hours. †
‡ Daniel Zip
10 DG, Potkin SG, Reeves KR, et al. Psychopharmacology Berl. 2001;155:128-134. Hal outcome measure –1.5 was effectiveness of sedation, –1.5 which was
‡ 51,52 ‡
BARS=Barnes-Akathisia Rating Scale; PES=psychiatric emergency services; IM=intramuscular;
Zip Hal assessed using the –2.0
Altered Mental ‡ Status Scale. † –2.0 Data ‡ on
PSYCH=psychotic agitation; ETOH=alcohol-induced agitation; SUBS=substance-induced agitation. ‡
5 H, Klotz SG, Southard R, Francis
Preval
30 mg 10 mg 6.3 ms
6.0 msA. Gen Hosp Psychiatry. 2005;27:140-144. Reprinted with permis- respiratory depression,
–2
need for rescue sedation, –2
and other
‡ ‡
QTc Average ‡
Over 24 Hours sion from Elsevier. 4.6 ms All patients, observed cases
3.4 ms adverse events were collected. All three agents produced a‡
10 mg study (Study 125) 20 mg study (Study 126) –3 –3
Zip 0 Time after first injection (hours) Time after first injection (hour)
Ziprasidone IM 10 mg (n=65) Ziprasidone IM 20 mg (n=41)
CNS Spectrums, 0September
in
2005
in
Hal 0 1 2 3 4 15
m 0 30
m 1 2 3 4
10 Vol 10 – No 9 (Suppl 11)
S (+/–SE)

0 Control Group (n=54) Control Group (n=38)

–0.5 –0.5
Minutes After Injection
line

ent

erage Over
–1 –1
 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE

good response beginning at 15 minutes—ie, the number of
agitated subjects in all groups decreased by ≥50%—although
the onset of action of ziprasidone was delayed relative to that
of droperidol and midazolam, with 28 ziprasidone-treated
patients remaining agitated at 15 minutes versus 20 receiv-
ing droperidol and 15 receiving midazolam. At 30 minutes,
all three agents demonstrated comparable control of agita-
tion (Slide 11). Duration of effect was greater with ziprasi-
done and droperidol than with midazolam—ie, rescue seda-
tion was needed by only 9 subjects in the ziprasidone group
and 5 in the droperidol group versus 24 in the midazolam
group. Respiratory depression occurred in 10 subjects given
midazolam versus 7 given ziprasidone and 4 given droperi-
dol. No clinically significant adverse events were recorded.
There was no significant difference between agents in time
spent in the ED (droperidol 448 minutes, ziprasidone 440
minutes, and midazolam 390 minutes).
Slide 11
Effect of Ziprasidone Versus Droperidol and Midazolam on
Agitation in the Medical ED
Agitated Patients versus Time
Furthermore, its duration of action may be advantageous, as it
can be used to calm patients on either a short- or longer-term
basis. Ongoing studies are evaluating the utility of ziprasidone
with respect to arousal and disposition time in the medical ED.
Intensive Care Unit
Delirium in patients on mechanical ventilation in the ICU
predicts a higher 6-month mortality, longer hospital stay, and
higher costs (39% higher ICU costs and 31% higher hospital
costs).53,54 Recently published clinical practice guidelines
of the Society of Critical Care Medicine recommend moni-
toring for the presence of delirium in all mechanically
ventilated patients because of the potential for associated
adverse outcomes.55 However, a recent survey found that few
healthcare professionals monitor patients for delirium, and
most admit that it is underdiagnosed.56 In that survey, 66%
of respondents said that they treated delirium with haloperi-
dol, 12% with lorazepam, and <5% with second-generation
antipsychotics. More than 55% of respondents administered
haloperidol and lorazepam at daily doses of <10 mg, whereas
some used doses >50 mg/day.56
One of the panelists, Dr. Herr, reported on agitated
10 mg IM

Serum concentration,
400
60 delirium at his350
institution, a large tertiary care 20 surgical
mg IM
center where, 300
in 2003, 90% of patients in the 52-bed ICU
80 mg BID PO

mg/mL (±SD)
Droperidol
No. of Patients

40 Ziprasidone required ventilators,

250 ~80% developed delirium or agita-
Midazolam tion, and 1,600200doses of haloperidol were given. The large
150
doses of haloperidol required for ICU patients may cause
20 100 sedation, a cataleptic-like state upon awak-
prolonged heavy
50
ening, dysphoria, and dystonia. Additionally, such doses have
0 0
0 15 30 45 60 90 120 been associated with 0 ventricular
2 tachycardia
4 6 and8 neuroleptic
10 12
Time After Drug (min) malignant syndrome. Concern about Hoursthese
post-dose
problems led to
a trial of ziprasidone IM, especially after psychiatrists in
ED=emergency department; min=minutes.
the hospital’s ED reported that it worked quickly and left
A second trial comparing droperidol IM 5 mg, lorazepam patients sufficiently alert for clinical evaluation. Dr. Herr has
IM 2 mg, and ziprasidone IM 10 mg and 20 mg is underway. had positive preliminary experiences with ziprasidone IM in
Preliminary data indicate that all treatments are effective, with 90 patients in the ICU. In addition, in his practice setting,
no significant respiratory depression associated with any agent. oral ziprasidone is frequently administered through a small
bowel tube. The following cases are illustrative.
Case 1: Agitated Male with Head Trauma
A 45-year-old
7 man, smelling slightly
Ziprasidone 20-mg IMof(n=110)
alcohol, was Case 2: Agitated Female on a Ventilator
Conventional IM agents (n=9)
brought to6 the ED by the police after he was
Clinical trial of 20-mg IM
found scream- A 54-year-old woman
Simpson–Angus Scale withScale
Bames Akathisia schizophrenia wasScaleadmitted
Simpson–Angus Bames Akathisia Scale
1 hour Last 1 hour Last 1 hour Last 1 hour Last
ing obscenities and chasing cars down (n=41)‡
Ziprasidone a highway. No history to the postdose
hospital withpostdose
observation necrotizing
observation fasciitis of observation
postdose the face. Sheobservation
postdose
5 * 0 0

was available. After six security

† guards were called in for a was taking eight psychotropic medications at the time of
–0.1 –0.1
BARS Score

†
Improvement

† –0.2 –0.2
show of force
4 and concern, the patient was†given ziprasidone admission, all of which were withdrawn. After massive
Mean Change

Mean Change

–0.3 –0.3

* –0.4 –0.4
IM 20 mg3 and became calm in* 20 minutes. Evaluation † pro- facial surgery, the patient was placed on a ventilator and
–0.5 –0.5
–0.6 –0.6
duced no evidence of trauma. The patient’s * breathalyzer level sedated with propofol and fentanyl for 2 days. To facilitate
–0.7 –0.7
*
2
was .05. Urine toxicology proved negative, but*a computed weaning from the ventilator,
–0.8
–0.9
dexmedetomidine was Ziprasidone,
Ziprasidone, 2 mg (m=54)
–0.8
–0.9
started2 mg (m=38)
tomography1 scan of the head revealed a moderate-size, sub- along with approximately
–1
Ziprasidone, 10half of her preoperative psycho-
mg (m=83)
–1
Ziprasidone, 20 mg (m=41)

acute subdural
0
hematoma. After undergoing a craniotomy, tropic drugs. Despite increasing dosages of psychotropic
the patient Baseline
was discharged
15 30 neurologically
45 60 intact1205 days later.
90 medications, extreme agitation ensued at every attempt to
The ED staff later learned
Minutes After Injection in a minor car
that he had been complete the wean. After 5 days, all psychotropic medica-
accident 10 days earlier. tions were discontinued and the patient was given zipra-
As this case indicates, ziprasidone IM appears to be a viable sidone IM 20 mg QID. A ventilator wean the following
option in the medical ED. The panelists suggested that it day was proceeding uneventfully until the patient objected
may have a slightly slower onset of action than midazolam or to the injections and ziprasidone IM was discontinued.
droperidol but that it works at least as quickly as haloperidol. She was then switched to oral ziprasidone 20 mg BID
PSYCH (n=72)
ETOH (n=10)
7
SUBS (n=28)
LastSeptember
CNS Spectrums, IM Dose 2005
Oral Endpoint (Day 7) 11 Volof10
Clinical trial – No
20 mg IM 9 (Suppl 11)
0 *
seline

6 Ziprasidone (n=41)‡
 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
but became so agitated that the ventilator wean was again
stopped. At this point, the physician started the patient on
ziprasidone IM 20 mg plus 20 mg oral ziprasidone QID
via a nasogastric tube, and subsequently increased the dos-
age of the oral agent to 40 mg QID. The patient was suc-
cessfully weaned from the ventilator 5 days later.
Case 3: Female with a History of Substance Abuse in
Postoperative Care
A 39-year-old woman with a thoracic aneurysm and
an undisclosed history of substance abuse underwent
emergency surgery to replace her thoracic aorta. She was
treated with propofol and fentanyl for 4 days postopera-
tively, while norepinephrine and epinephrine were given to
enhance cardiac contractility and maintain blood pressure.
When a wean from propofol was attempted, she became
sweaty, tachycardic, and agitated. At this point, the family
revealed that the patient had been using illicit drugs until
admission for surgery. Addition of dexmedetomidine con-
trolled the withdrawal symptoms but she remained highly
agitated, uncooperative, and “out of touch.” To control
these problems, ziprasidone IM 20 mg was administered
and followed by a 20 mg BID dose of oral formulation
via a nasojejunal tube. Increasing the dosage to 40 mg
IM QID via nasojejunal tube produced a salutary response
without inducing an untoward level of sedation. Within
a day, the patient was following commands, communi-
cating by gesture, and cooperating with her care. She
was weaned from the ventilator shortly thereafter.
Case 4: Elderly Cardiac Bypass Patient
An 82-year-old woman who had undergone cardiac bypass
surgery woke up highly agitated and unable to follow instruc-
tions, which posed a serious risk to survival. She was started
on propofol and haloperidol IV 40 mg QID. Haloperidol was
gradually increased to 80 mg QID, but delirium returned
whenever a propofol wean was attempted. Consequently,
haloperidol was discontinued and ziprasidone IM 20 mg
QID was started. Within 2 hours of the first dose, the patient
became calmer and more cooperative. Following two more
doses, she slept through the night and was extubated the
next morning without need for additional ziprasidone.
Consensus Clinical Recommendations
Choice of Initial IM Agent: Atypical Versus Conventional
Currently, IM conventional antipsychotics, particularly
haloperidol, are more widely used in emergency settings
than second-generation IM agents. This preference for the
older agents is doubtless attributable, at least in part, to years
of safe and effective use, as well as to a large body of clini-
cal data supporting the safety and efficacy of these agents;
however, it may also be attributable to institutional culture
and longstanding practice, lack of experience with the newer
agents, lack of comparative risk/benefit data from a variety of
clinical settings, and the higher cost of the newer IM agents.
Although the (direct) acquisition costs of a medicine are
CNS Spectrums, September 2005
quite small compared with the (indirect) costs of prolonged
hospitalization and disabling side effects, justifying the
expense of a new medication is often difficult.
When asked which factors clinicians should consider in
choosing an IM agent for acute agitation and psychosis,
the panelists stressed the importance of selecting an agent
that comes as close as possible to meeting the criteria for
an ideal parenteral medication, as outlined in Slide 1. They
also emphasized the need to consider an agent’s overall
“utility,” which they defined as a combination of efficacy
for target symptoms (positive symptoms, aggression, agita-
tion, hostility), speed of onset, and good safety/tolerability.
Considerations affecting safety/tolerability, in their estima-
tion, included a reduced risk of EPS, dystonia, akathisia,
orthostatic hypotension, excessive sedation, and dysphoria;
a desire to safeguard the patient’s overall health; and a lack
of drug-drug interactions. The panel also placed greater
emphasis on selecting agents with a low incidence of seri-
ous side effects (eg, significant hypotension in a dehydrated
patient) than on selecting medications whose side effects,
if annoying, were nonetheless transient and tolerable (eg,
headache or nausea).
The panel concluded that IM formulations of second-gen-
eration antipsychotics appear generally to meet the criteria
for an ideal agent because available data indicate that they
facilitate rapid control of acute agitation with less sedation
and a lower risk of movement disorders and dysphoria than
conventional agents, while also treating any underlying psy-
chosis. According to a majority of the panelists, one justifi-
cation for choosing a conventional over a second-generation
agent is if the patient has a history of responding well to
conventional agents and specifically requests one. The need
to select the safest medication possible was highlighted by
recent findings that patients treated with antipsychotics in
the PES are likely to be older and to have more abnormal
laboratory values than other adult patients in emergency set-
tings,33 and are thus at higher risk of drug side effects and
drug-drug interactions.
Although clinicians do not usually weigh long-term
safety and efficacy when deciding on acute treatment,
the panel advised them to consider agents with favor-
able long-term data supporting continued recovery. This
leads to a strong recommendation to use second-gen-
eration antipsychotics instead of older neuroleptics such as
haloperidol. Long-term outcomes that are desirable include
improvement in negative symptoms and cognition, translat-
ing into better functional outcomes. Long-term tolerabil-
ity issues that need to be considered include propensity for
EPS, tardive dyskinesia, and metabolic syndrome.
Patient Involvement in Treatment Decisions
According to the panel, clinicians should attempt to
involve patients in treatment decisions to the greatest extent
possible. Even very agitated individuals, they noted, can
make decisions about treatment if the options and relevant
issues are presented clearly and information is repeated as
12 Vol 10 – No 9 (Suppl 11)
 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
needed. For example, patients given haloperidol in the past
should be offered the option of other agents less likely to
leave them feeling “drugged” or “groggy.” This, it could be
explained, might enable them to better partner with their
caregivers and, thus potentially, avoid hospitalization. And,
of course, patient preferences regarding medication should
be respected—a point made clear by panelists who reported
treating individuals who either requested second-genera-
tion antipsychotics because of good past experiences or were
adamantly opposed to treatment with older agents that had
left them unable to “focus or hold a conversation.”
Use of Concomitant Lorazepam
Current data indicate that it is safe to use concomitant
lorazepam with ziprasidone IM if agitation has not been
adequately managed with monotherapy or the patient is
experiencing insomnia. One of the panelists, Dr. Zimbroff,
noted that he typically waits 30–45 minutes after inject-
ing ziprasidone IM before giving lorazepam IM 2 mg. He
estimated that lorazepam IM is required in ~10% of cases
to reduce agitation to a manageable level. Dr. Zimbroff
added that the two agents cannot be given in the same
syringe, owing to reconstitution requirements.
Using the Same Agent for Both IM and Oral Treatment
While acknowledging a lack of data on this issue, the panel
pointed to several factors that favor continuing treatment
with the same agent when follow-up oral therapy is needed.
These include convenience, ease of transition (eg, the patient
has already consented to receiving a particular drug), and
avoidance of polypharmacy. In addition, response to and
toleration of the IM formulation predict a favorable course
with the oral agent. A positive experience with the IM for-
mulation may also foster a positive attitude toward, and bet-
ter adherence to, oral treatment with the same agent.
Transition to Oral Ziprasidone
Serum concentrations of ziprasidone 1 hour after admin-
istration of the 20-mg IM dose (range 144–359 ng/mL)57
are similar to maximum serum concentrations (Cmax)
observed with the 80 mg BID oral dose (range 121–326
ng/mL; see Slide 5).20 In addition, trials of oral ziprasi-
done in acute mania have employed an 80 mg BID dosage
on day 2 without incidence.58 In view of these facts, the
majority of the panelists were comfortable transitioning
patients from ziprasidone IM to oral ziprasidone 80 mg
BID, and at least one panelist, Dr. Zimbroff, said that this
has been his practice since soon after the introduction of
the IM formulation. Panelists favoring this approach felt
that transitioning patients immediately to 80 mg BID of
oral ziprasidone was likely to enhance efficacy. Assuming
the patient is willing to take an oral drug, they considered
it reasonable to administer the first oral dose within 1–2
hours of the IM dose, since the Tmax of the oral medica-
tion occurs much later (8 hours postdose) than that of the
IM agent (≤30–45 minutes postdose).20 However, a few
CNS Spectrums, September 2005
panelists expressed the desire to see more safety data on
transition dosages, particularly since IM/oral transition
studies of ziprasidone in emergency settings had used
lower oral dosages. Finally, the panel stressed the need to
give oral ziprasidone with food to maximize bioavailability
(by 100%), while noting that administration with food is
not a relevant concern with the IM formulation.
Formulary Issues: Cost/Benefit Analysis
A model using initial drug costs and outlays for managing
associated side effects indicates that, despite a higher whole-
sale acquisition price, ziprasidone IM is ~10% more cost
effective than haloperidol IM in the treatment of ED patients
with acute psychotic agitation.59 According to the model,
cost savings result directly from lower rates of acute EPS and
dystonia, which were 1.1% and 0%, respectively, with zipra-
sidone IM versus 2.4% and 14.3% with haloperidol IM on
day 1 of the randomized, parallel-group study25 from which
the data were drawn.
On the basis of clinical experience and preliminary find-
ings concerning restraint time and time to disposition, the
panel also concluded that ziprasidone IM works at least as
quickly as haloperidol but with fewer side effects, such as
EPS, excessive sedation (particularly when combined with
a benzodiazepine), or akathisia, which can worsen agitation.
Its use might thus enable staff to complete clinical assess-
ments and discharge patients from emergency settings more
quickly than is customary with conventional antipsychotics.
Furthermore, if patients have a more positive subjective
perception of ziprasidone IM than of conventional agents,
as clinical trials and experience suggest,17 the result may be
an improved therapeutic alliance and better adherence to
subsequent treatment, with additional savings possible from
minimizing “revolving-door” treatment.
Cost considerations governing the use of ziprasidone IM
versus haloperidol IM in the ICU include the frequent need
for multiple injections of haloperidol and the consequent
demands on nursing time.
Directions for Future Research
The panel recommended that additional clinical trials
(particularly double-blind, randomized trials) be conducted
in a variety of clinical settings and in patients with diverse
diagnoses (Slide 12). Specifically, studies are needed to
compare the relative efficacy and tolerability of ziprasidone
IM, haloperidol IM, and olanzapine IM in agitated patients
in the PES and medical ED and in delirious patients in the
ICU. With respect to the ICU, relevant outcome measures
would include time to weaning off a ventilator, patient
ability to cooperate with care, drug interactions and side
effects, improvement in agitation, and time in the ICU.
The panel recommended consideration of two additional
assessment tools for use in these studies—the Richmond
Agitation Sedation Score60 for measuring agitation, and
the Confusion Assessment Method for the Intensive
Care Unit61 for measuring delirium in the ICU.
13 Vol 10 – No 9 (Suppl 11)
 Clinical Information Monograph
FOCUSING ON ISSUES IMPACTING PRACTICE AND PATIENT CARE
Slide 12
Directions for Future Research
Additional studies are needed to:
• Compare the relative efficacy and tolerability of IM ziprasidone, halo-
peridol, and olanzapine in agitated patients in the PES, ED, and ICU.
• Examine the use of both higher doses and multiple doses of IM and
oral ziprasidone in these settings.
• Compare the effects of IM ziprasidone, olanzapine, and haloperidol in
the first 2–3 hours of treatment, with response assessed at 15-minute
intervals.
• Compare combination treatment with IM ziprasidone or haloperidol
plus lorazepam, since such combinations reflect real-world practices.
• Examine both time to disposition and staff safety in patients given
ziprasidone IM.
• Compare the different IM agents in patients who present with alcohol
intoxication.
• Examine the use of ziprasidone IM in agitated patients with acute
mania or dementia.
• Evaluate the combine use of ziprasidone IM and benzodiazepines in
the ICU, since rapid-acting agents are usually needed to ensure
immediate sedation and safety while ziprasidone takes effect.
IM=intramuscular; PES=psychiatric evaluation service; ED=emergency department; ICU=intensive
care unit.
Limitations
Many of the recommendations in this monograph derive
from a consensus of expert opinion. Because expert medi-
cal opinion may change with time, it is important for
clinicians to keep abreast of the current literature on IM
treatments for agitated patients. Additionally, it is impera-
tive to recognize that some of the recommendations here
may reflect the experiences of individual panelists.
Summary and Conclusion
Ziprasidone, the first second-generation antipsychotic avail-
able in IM formulation, is approved by the FDA for the indica-
tion of acute agitation in patients with schizophrenia. Clinical
trials have shown ziprasidone IM to produce significant and
rapid reduction in agitation, and to effect at least the same or
greater improvement in psychotic symptoms, agitation, and
hostility as haloperidol IM while having greater tolerability,
including a lower burden of movement disorders. In clinical
trials, its concomitant administration with benzodiazepines
has occurred without adverse consequence.
The most common adverse events associated with zipra-
sidone IM have been insomnia, headache, and dizziness in
fixed-dose trials, and both insomnia and hypertension in
flexible-dose trials. Although clinical trials evaluating the
efficacy of ziprasidone IM were not powered to detect dose-
dependent differences in side effects, data suggest a low
likelihood of dose dependency and no consistent pattern of
escalating incidence of side effects with escalating ziprasi-
done doses. The effects of ziprasidone IM on the QTc interval
in studies designed to measure QTc prolongation at maximal
serum drug concentrations are small and statistically compa-
rable to those of haloperidol IM.40
Studies evaluating the transition from IM to oral ziprasi-
done have shown that serum concentrations of ziprasidone
CNS Spectrums, September 2005
IM 20 mg are higher than those of oral ziprasidone 80 mg
BID. Thus, patients who tolerate ziprasidone IM 20 mg
have already achieved ziprasidone plasma levels higher than
would be expected with an initial oral dose of 80 mg BID
(160 mg/day).
Findings from randomized clinical trials establishing the
safety and efficacy of ziprasidone IM have been corroborated
in naturalistic studies in real-world treatment settings (psy-
chiatric ED, medical ED, ICU) where patients are suffering
from extreme agitation or have a recent history of alcohol
or substance abuse. Under these circumstances, statistically
significant improvement in agitation has been demonstrated
at 15 minutes, and clinically significant improvement at 30
minutes, of administration of ziprasidone IM without regard
to the underlying etiology of agitation.
Additional trials of ziprasidone IM in agitated patients in
a variety of clinical settings (PES, medical ED, and ICU) are
warranted to generate comparative risk/benefit data with
conventional agents and other second-generation antipsy-
chotics. Until these studies are completed, best clinical prac-
tice indicates that parenteral treatments for acutely agitated
patients should be chosen on the basis of their overall util-
ity—ie, efficacy for target symptoms, including psychosis
if present; speed of onset; a good tolerability/safety profile;
and ability to facilitate a smooth transition from IM to oral
maintenance therapy. Agents with a good safety/tolerability
profile, such as ziprasidone IM, may be more cost effective
than older agents with lower acquisition costs, owing to a
reduced incidence of acute adverse effects (eg, acute dystonia)
requiring extended periods of observation.
Treating physicians should attempt to solicit patient pref-
erence with respect to medication and, generally, to engage
patient cooperation in treatment decisions. This should be
done with an eye to avoiding hospitalization, fostering an
easy transition to oral maintenance therapy, and improving
long-term treatment adherence.
It is the hope of the panelists contributing to this mono-
graph that their evaluation of the ziprasidone IM clinical
data, as well as their own clinical experience with this
agent, may help fellow physicians use ziprasidone IM in the
best manner possible to improve the treatment of agitated
patients in various treatment settings.
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