drug safety evaluation of ziprasidone

1. Introduction

2. Mechanism of action

3. Clinical applications

4. Safety evaluation

5. Comparison with safety of

other drugs

6. Conclusion

7. Expert opinion

Drug Safety Evaluation

Drug safety evaluation ofziprasidoneLeslie CitromeNew York University School of Medicine, Leslie Citrome, Pomona, NY, USA

Introduction: Ziprasidone is a second-generation antipsychotic approved for

the treatment of schizophrenia and bipolar disorder. The purpose of this

review is to assess the overall safety profile of ziprasidone, including its risk

for prolonging the electrocardiogram (ECG) QT interval.

Areas covered: This paper is a review of product labeling and English language

reports located through PubMed and information available on regulatory

agency websites, with a focus on the safety and tolerability of ziprasidone.

Expert opinion: Although ziprasidone can prolong the ECG QT interval, this has

not resulted in increases in sudden death or cardiac sudden death as noted in a

large, simple trial and supported by almost a decade of real-world use in the

US. Ziprasidone’s principal advantage over some other second-generation anti-

psychotics has been its overall favorable weight and metabolic profile. Similar

to most second-generation antipsychotics, ziprasidone has a lower propen-

sity for extrapyramidal side effects and hyperprolactinemia compared to

first-generation antipsychotics.

Keywords: antipsychotic, bipolar disorder, dosing, QT interval, safety, schizophrenia,

tolerability, ziprasidone

Expert Opin. Drug Saf. (2011) 10(3):437-448

1. Introduction

Ziprasidone hydrochloride (Pfizer, New York, USA) is an oral second-generation (atypical) antipsychotic that was initially approved by the FDA in2001 for the treatment of schizophrenia in adults (Box 1). A year later, a short-acting intramuscular mesylate preparation was approved for the treatment of acuteagitation in adult patients with schizophrenia. Subsequently, oral ziprasidone in2004 received the FDA approval for the treatment of acute manic or mixed episodesassociated with bipolar disorder (with or without psychotic features) in adults. In2009, oral ziprasidone was approved for bipolar disorder maintenance treatmentas an adjunct to lithium or valproate in adults. Although originally submitted forapproval in 1997, commercialization in the US was delayed because of concernsover ziprasidone’s risk for prolongation of the electrocardiogram (ECG) QT inter-val, which could in turn predispose the patient to develop torsades de pointes, apotentially fatal cardiac dysrhythmia. The introduction of ziprasidone in othercountries was also delayed, and in some cases by several additional years. Productlabeling currently states ‘In choosing among treatments, prescribers should be awareof the capacity of ziprasidone to prolong the QT interval and may consider the useof other drugs first.’ However, over time and clinical experience, QT prolongationhas not emerged as a clinically relevant problem for the real-world use of ziprasi-done. Principal advantages of ziprasidone have included its lower propensity tocause weight gain and metabolic disturbances compared to other second-generation antipsychotics. The principal obstacle to ziprasidone’s effective use hasbeen insufficient recognition of the need to dose ziprasidone high enough and toensure that it is administered with at least 500 calories of food. Many reviews ofziprasidone are available in the literature and the reader is referred to several for

10.1517/14740338.2011.560114 © 2011 Informa UK, Ltd. ISSN 1474-0338 437All rights reserved: reproduction in whole or in part not permitted

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more information about ziprasidone’s early development [1,2],clinical trials [3], ziprasidone’s use as an adjunctive agent forthe maintenance treatment of bipolar disorder [4] and issuesrelated to maximizing effectiveness by considering the effectsof dosing and administration with food [5].The purpose of this review is to provide a summary of the

safety of ziprasidone, using the product label [6] as a guide andthe recent literature to place both tolerability and safety intoclinical perspective.

2. Mechanism of action

2.1 PharmacodynamicsAs with most other second-generation antipsychotics,ziprasidone is thought to exert its antipsychotic effects

through antagonism of the dopamine D2 and serotonin5-HT2A receptors [6,7]. However, it appears that the secondarybinding characteristics to other receptors differentiate oneantipsychotic from the other [8]. As per the product label [6],ziprasidone exhibits high in vitro binding affinity for thedopamine D2 and D3; the serotonin 5-HT2A, 5-HT2C,5-HT1A, 5-HT1D and a1-adrenoceptors (Ki values of 4.8,7.2, 0.4, 1.3, 3.4, 2 and 10 nM, respectively); and moderateaffinity for the histamine H1 receptor (Ki = 47 nM). Ziprasi-done functions as an antagonist at the D2, 5-HT2A and5-HT1D receptors, and as an agonist at the 5-HT1A receptor.Ziprasidone also inhibits synaptic reuptake of serotonin andnorepinephrine. No appreciable affinity was observed forother receptor/binding sites tested, including the cholinergicmuscarinic receptor. Certain receptors are associated with

Box 1. Drug summary.

Drug name ZiprasidonePhase LaunchedLaunched indications Oral formulation:

. Treatment of schizophrenia in adults

. Acute treatment as monotherapy of manic or mixed episodesassociated with bipolar I disorder in adults. Maintenance treatment of bipolar I disorder as an adjunct tolithium or valproate in adultsIntramuscular injection:. Acute treatment of agitation in adult patients with schizophrenia

Pharmacology description Dopamine type 2 (D2) and serotonin type 2 (5-HT2) receptor antagonismRoute of administration Oral or intramuscularChemical structure 5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-

1,3-dihydro-2H-indol-2-one

N

S

N

N

NH

O

CI

Pivotal trial(s) . Treatment of schizophrenia: Efficacy was tested in four 4 -- 6 weektrials and one maintenance trial in adult patients with schizophrenia. Acute treatment as monotherapy of manic or mixed episodes associatedwith bipolar I disorder: Efficacy was established in two 3-week trials in adultpatients with manic or mixed episodes. Maintenance treatment of bipolar I disorder as an adjunct to lithium orvalproate: Efficacy was established in one maintenance trial in adult patients. Acute treatment of agitation in schizophrenic patients: Efficacy was establishedin two short-term trials in agitated adult patients with schizophrenia

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and

Citeline (http://informa.citeline.com).

Ziprasidone

438 Expert Opin. Drug Saf. (2011) 10(3)

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certain effects, such as histamine H1 receptor antagonismwith somnolence and antagonism of a1-adrenoceptors withorthostatic hypotension [6-8].

2.2 PharmacokineticsAlthough ziprasidone is well absorbed after oral administration,reaching peak plasma concentrations in 6 -- 8 h, ziprasidoneneeds to be administered with a meal [5,6] as the absorption ofziprasidone is increased up to twofold in the presence offood. Ziprasidone’s activity is primarily due to the parentdrug and not to metabolites. The multiple-dose pharmacoki-netics of ziprasidone is dose-proportional within the recom-mended dose range when administered with food, andziprasidone accumulation is predictable with multiple dosing.Ziprasidone is metabolized primarily in the liver (less than athird of ziprasidone metabolic clearance is mediated byCYP3A4 catalyzed oxidation and approximately two-thirds iscleared via reduction by aldehyde oxidase) and has a mean ter-minal half-life in the plasma of about 7 h. Thus, steady-state concentrations are achieved within 1 -- 3 days of dosing.The mean apparent systemic clearance is 7.5 ml/min/kg. Zipra-sidone is not thought to interfere with the metabolism ofdrugs metabolized by CYP enzymes. Hepatic impairment canmodestly increase exposure to ziprasidone [6].

According to product labeling [6], ziprasidone’s meanapparent volume of distribution is 1.5 l/kg. Ziprasidone ishighly plasma protein-bound (> 99%), binding primarily toalbumin and to a 1-acid glycoprotein. However, the in vitroplasma protein binding of ziprasidone does not appear to bealtered by warfarin or propranolol, two highly protein-bound drugs, nor does ziprasidone appear to alter the bindingof these drugs in human plasma. Ziprasidone is extensivelymetabolized with only a small amount excreted in the urine(< 1%) or feces (< 4%) as unchanged drug.

The intramuscular formulation of ziprasidone has a bio-availability of 100% and peak serum concentrations occurat ~ 60 min with a mean half-life between 2 and 5 h.

3. Clinical applications

The product label [6] summarizes information about the piv-otal clinical trials that support the efficacy of ziprasidone(Table 1). Additional details can be found elsewhere [3,4].Ziprasidone’s efficacy in the treatment of schizophrenia wasestablished in four 4 -- 6 week trials and one maintenance trialin adult patients with schizophrenia. A pooled analysis is alsoavailable for the acute schizophrenia trials and contains addi-tional descriptive information of these trials, not all of whichare available as separate published study reports [9]. The effi-cacy for the intramuscular formulation of ziprasidone for theacute treatment of agitation in patients with schizophreniawas established in two short-term trials in agitated patientswith schizophrenia [10,11].

Acute treatment with ziprasidone as monotherapy ofmanic or mixed episodes associated with bipolar I disorder

was considered efficacious based on two 3-week trials in adultpatients with manic or mixed episodes, with or without psy-chotic features [12,13]. The efficacy of ziprasidone for the main-tenance treatment of bipolar I disorder as an adjunct tolithium or valproate was established in one maintenance trialin adult patients [14].

Product labeling regarding approved dosing differs forschizophrenia versus bipolar disorder, and recommendationsalso differ by regulatory authority [5,6,15]. In the US [6], the rec-ommendations are for the initiation of ziprasidone at 20 mgtwice daily for patients with schizophrenia and that dose adjust-ments should occur at intervals of not < 2 days. For the acutetreatment of manic/mixed episodes of bipolar I disorder dosingis more aggressive, with initiation at 40 mg twice daily and anincrease to 60 or 80 mg twice daily on day 2 of treatment.Other regulatory authorities recommend starting at 40 mgtwice daily for both schizophrenia and bipolar mania, withdaily dosage adjustment on the basis of individual clinical statusup to a maximum of 80 mg twice daily and, that if indicated,the maximum recommended dose may be reached as early asday 3 of treatment [15]. Recommended dosing for the intramus-cular preparation is 10 -- 20 mg up to a maximum dose of40 mg/day [6]; however, the 20 mg dose appears to be moreefficacious [16].

4. Safety evaluation

4.1 Product labeling

4.1.1 Bolded warningsSafety and tolerability data gathered during a drug’s registra-tion program are summarized in product labeling in variousways. These lead to specific recommendations regarding con-traindications, warnings and precautions. Some bold boxedwarnings are found for all antipsychotics, such as the warn-ing regarding increased mortality in elderly patients withdementia-related psychosis [6].

4.1.2 ContraindicationsZiprasidone is contraindicated in patients with a known his-tory of QT prolongation, a recent acute myocardial infarc-tion, uncompensated heart failure or in combination withother drugs that have demonstrated QT prolongation [6].Related to this contraindication is a warning that ziprasidoneshould also be avoided in patients with bradycardia, hypoka-lemia or hypomagnesemia, or congenital prolongation of theQT interval. Ziprasidone is also contraindicated in patientswith known hypersensitivity to it.

4.1.3 Warnings and precautionsAdditional warnings and precautions for ziprasidone are notunique to this agent and include statements regardingneurolepticmalignant syndrome, tardive dyskinesia, hyperglyce-mia and diabetes mellitus, rash, orthostatic hypotension,leukopenia/neutropenia/agranulocytosis, seizures, dysphagia,hyperprolactinemia, potential for cognitive and motor

Citrome

Expert Opin. Drug Saf. (2011) 10(3) 439

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Table

1.Pivotalregistrationtrials

forziprasidoneasnotedin

product

labeling

[6];allare

randomizedplacebo-controlledtrials

withtheexceptionofthe

intramuscularziprasidonetrials

where

theco

ntrolwasintramuscularziprasidone2mg.

Disease

state

NDuration

(weeks)

Ziprasidone

Dose

(s)

Study

outcome

Schizophrenia,acute

139

420mgb.i.d.,

60mgb.i.d.

Onlythe60mgb.i.d.dose

wassuperiorto

placeboontheBPRStotalscore

andtheCGI

severity

score.Thishigherdose

groupwasnotsuperiorto

placeboontheBPRSpsychosis

clusterorontheSANS

Schizophrenia,acute

302

640mgb.i.d.,

80mgb.i.d.

Both

dose

groupswere

superiorto

placeboontheBPRStotalscore,theBPRSpsychosis

cluster,theCGIseverity

score

andthePANSStotalandnegative

subscale

scores.

Although

80mgtw

icedaily

hadanumerically

greatereffect

than40mgtw

icedaily,thedifference

wasnotstatistically

significant

Schizophrenia,acute

419

620mgb.i.d.,

60mgb.i.d.,

100mgb.i.d.

Allthreedose

groupswere

superiorto

placeboonthePANSStotalscore,theBPRStotal

score,theBPRSpsychosisclusterandtheCGIseverity

score.Onlythe100mgtw

icedaily

dose

groupwassuperiorto

placeboonthePANSSnegative

subscale

score.There

wasno

clearevidence

foradose--response

relationship

within

the20mgtw

icedaily

to100mg

twicedaily

dose

range

Schizophrenia,acute

200

45mgb.i.d.,

20mgb.i.d.,

40mgb.i.d.

Noneofthedose

groupswasstatistically

superiorto

placeboonanyoutcomeofinterest

Schizophrenia,

maintenance

294

NA

20mgb.i.d.,

40mgb.i.d.,

80mgb.i.d.

Patients

were

observedfor‘impendingpsychoticrelapse,’definedasCGI-im

provement

score

ofatleast

6(m

uch

worseorvery

much

worse)and/orscoresofatleast

6(m

oderately

severe)onthehostility

oruncooperativeness

itemsofthePANSSontw

oconsecutive

days.

Ziprasidonewassignificantlysuperiorto

placeboin

timeto

relapse,withnosignificant

difference

betw

eenthedifferentdose

groups.

There

were

insufficientdata

toexamine

populationsubsets

basedonageandrace.Examinationofpopulationsubsets

basedon

genderdid

notrevealanydifferentialresponsiveness

Schizophrenia,acutely

agitated

79

1day

2mg,20mg,

upto

4times

Ziprasidoneintramuscular20mgwasstatistically

superiorto

ziprasidoneintramuscular

2mg,asassessedbyAUCoftheBARSat0--4handbyCGIseverity

at4handstudy

endpoint

Schizophrenia,acutely

agitated

117

1day

2mg,10mg,

upto

4times

Ziprasidoneintramuscular10mgwasstatistically

superiorto

ziprasidoneintramuscular

2mg,asassessedbyAUCoftheBARSat0--2h,butnotbyCGIseverity

BipolarIdisorder,acute

manic

ormixedepisodes

210

340--80mg

b.i.d.

Ziprasidonewassignificantlymore

effectivethanplaceboin

reductionoftheMRStotalscore

andtheCGIseverity

score.Themeandaily

dose

ofziprasidonein

thisstudywas132mg

BipolarIdisorder,acute

manic

ormixedepisodes

205

340--80mg

b.i.d.

Ziprasidonewassignificantlymore

effectivethanplaceboin

reductionoftheMRStotalscore

andtheCGIseverity

score.Themeandaily

dose

ofziprasidonein

thisstudywas112mg

BipolarIdisorder,

maintenance

584*

NA

40--80mg

b.i.d.plus

lithium

or

valproate

Ziprasidonewassuperiorto

placeboin

increasingthetimeto

recurrence

ofamoodepisode.

Thetypesofrelapse

events

observedincludeddepressive,manic

andmixedepisodes.

Depressive,manic

andmixedepisodesaccountedfor53,34and13%

,respectively,ofthe

totalnumberofrelapse

events

inthestudy

*A

totalof584subjectswere

treatedin

theopen-labelstabilizationperiod.In

thedouble-blindrandomizationperiod,127subjectswere

treatedwithziprasidoneand112subjectswere

treatedwithplacebo.

AUC:Areaunderthecurve;BARS:Behavioralactivityratingscale;b.i.d.:Twiceaday;

BPRS:Briefpsychiatric

ratingscale;CGI:Clinicalglobalim

pressions;

MRS:Mania

ratingscale;PANSS:Positive

andnegative

syndromescale;

SANS:Scale

forassessingnegative

symptoms.

Ziprasidone


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impairment (due to somnolence), priapism, body temperatureregulation, suicide, patients with concomitant illness and labora-tory tests. Some events are rare; for example, priapism wasreported only once in the premarketing database [6]. However,any medication that can block a1-adrenoceptors can be associ-ated with priapism and appears related to the strength of thebinding affinity for the receptor [17]. For a case report where sur-gical treatment was required, see [18]. Some warnings are ‘class-level’ for all antipsychotics, even though the effect may nothave been observed with ziprasidone in the premarketing trials(e.g., problems with body temperature regulation).

Regarding rash, about 5% of patients in the premarketingtrials of ziprasidone developed rash and/or urticaria [6].

Ziprasidone may induce orthostatic hypotension that may berelated to a1-adrenoceptor antagonism. Actual syncope wasreported in 0.6% of the patients treated with ziprasidone [6].

Antipsychotics can lower the seizure threshold. Duringclinical trials, seizures occurred in 0.4% of patients treatedwith ziprasidone [6].

Product labeling recommends that patients being consid-ered for ziprasidone treatment who are also at risk of signifi-cant electrolyte disturbances should have baseline serumpotassium and magnesium measurements and that low serumpotassium and magnesium should be replaced before proceed-ing with treatment. In particular, patients who are started ondiuretics when receiving ziprasidone require periodic moni-toring of serum potassium and magnesium. Ziprasidoneshould be discontinued in patients who are found to havepersistent QTc measurements > 500 ms [6].

4.1.4 Use in specific populationsGuidance is provided regarding use in specific populations,such as pregnancy (use only if potential benefit justifies thepotential risk), nursing mothers (breast feeding not recom-mended), pediatric use (safety and effectiveness not established)and renal impairment (intramuscular ziprasidone should beadministered with caution to patients with impaired renal func-tion as the cyclodextrin excipient is cleared by renal filtration).Controlled data regarding ziprasidone use in the geriatric popu-lation are limited. Of the total number of subjects in the clinicalstudies of ziprasidone, only 2.4% were aged 65 years andover [6]. However, no overall differences in safety or effectivenesswere observed between these subjects and younger subjects, andother reported clinical experience has not identified differencesin responses between the elderly and younger patients [6]. Theproduct label does note that older patients may tolerate ziprasi-done more poorly, and the clinician should consider a lowerstarting dose, slower titration and careful monitoring duringthe initial dosing period for elderly patients [6].

4.1.5 Adverse events and NNHInformation regarding commonly observed adverse reactions isclinically relevant. The incidence rates listed in the tables of theproduct label permit the calculation of number needed to harm(NNH), and allow the quantification of how often the adverse

event in question could be expected to be encountered in clin-ical practice. The NNH versus placebo provides a frameworkon what to expect and certainly what the patient should watchout for and report back to the clinician. Details on how to cal-culate and further interpret NNH can be found elsewhere [19],but essentially the lower the NNH, the more commonly theadverse event will be encountered. Single-digit NNH valueswill denote an adverse effect that can be encountered daily ina busy clinical practice. Table 2 provides the incidence ratesfor the most common adverse events reported during ziprasi-done clinical trials, defined as those with an incidence of at least5% and at least twice the incidence for placebo reported in theproduct label, as well as the NNH, for schizophrenia (somno-lence, respiratory tract infection), manic and mixed episodesassociated with bipolar disorder (somnolence, extrapyramidalsymptoms, dizziness, akathisia, abnormal vision, asthenia, vom-iting) and intramuscular administration (headache, nausea,somnolence). Also included are those adverse events thatoccurred at an incidence of at least 10% but not necessarilytwice that for placebo. The only single-digit NNH values arefor somnolence and extrapyramidal symptoms for the patientsbeing treated for an acute manic or mixed episode, and forsomnolence for those treated with ziprasidone intramuscular20 mg. A NNH of 6 would mean that for every six patientstreated with oral ziprasidone instead of placebo for an acutemanic or mixed episode of bipolar disorder, one can expectto encounter one additional complaint of somnolence or extra-pyramidal symptoms. Note that this is based on spontaneouslyreported adverse events among patients participating in clinicaltrials and may not be reflective of how often these effects canoccur in patients being treated in day-to-day clinical practicewho would not be eligible for such trials. Moreover, informa-tion regarding the intensity and duration of medication adversereactions is not adequately captured by relying only on thevoluntary spontaneous reporting of adverse events.

4.1.6 Discontinuation because of an adverse eventAmong the patients with schizophrenia participating in theshort-term placebo-controlled trials of ziprasidone, 4.1%(29/702) of ziprasidone-treated patients discontinued treat-ment due to an adverse reaction, compared with 2.2%(6/273) on placebo (NNH 52) [6]. The most common reactionassociated with dropout was rash, including seven dropouts forrash among ziprasidone patients (1%) compared to no placebopatients (NNH 100) [6]. Somnolence led to discontinuation in0.3% of patients in short-term clinical trials [6].

Among the patients with bipolar disorder participating inthe short-term placebo-controlled trials of ziprasidone, 6.5%(18/279) of ziprasidone-treated patients discontinued treat-ment due to an adverse reaction, compared with 3.7%(5/136) on placebo (NNH 37) [6]. The most commonreactions associated with dropout for the patients receivingziprasidone were akathisia, anxiety, depression, dizziness,dystonia, rash and vomiting, with two dropouts for each ofthese [6].

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4.1.7 Drug--drug interactionsDrug--drug interactions can be a safety issue and these aredocumented in the product label [6]. As discussed, abouttwo-thirds of ziprasidone is metabolized via reduction by alde-hyde oxidase. There are no known clinically relevant inhibi-tors or inducers of aldehyde oxidase. Less than a third ofziprasidone metabolic clearance is mediated by CYP catalyzedoxidation; thus, there is a lower likelihood of drug--drug inter-actions related to the P450 system compared to other antipsy-chotics that are almost exclusively metabolized by that route.However, carbamazepine, a potent inducer of CYP3A4 canresult in a decrease in exposure to ziprasidone by about35%. Ketoconazole, a potent inhibitor, can increase exposureto ziprasidone by about 35 -- 40%. [6]. In general, metabolismchanges of 1/3 (increases by inducers and decreases by inhib-itors) are not likely to be clinically relevant in typicalclinical situations.Guidance in the product label regarding drug--drug interac-

tions generally focuses on issues regarding the QT interval.There is also cautionary language regarding using ziprasidonewith other centrally acting drugs as well as with certainantihypertensive agents [6].When formal drug interaction studies were done, no

interactions were observed for ziprasidone combinedwith cimetidine, antacids, lithium, oral contraceptives,dextromethorphan, valproate, benztropine, propranolol orlorazepam [6].

4.2 QT prolongationMany antipsychotics, both first- and second-generation,and including ziprasidone, are associated with QT

prolongation [20]. A prolonged QT is generally considered awarning of the potential for torsades de pointes, a seriousand potentially fatal cardiac dysrhythmia. Consequently, theFDA required the conduct of a specific QT study for ziprasi-done [21]. The product label for ziprasidone [6] discusses a clin-ical trial directly examining the QT prolonging effect of oralziprasidone as compared to other antipsychotics at the timeof maximum plasma concentration when the drug was admin-istered alone as well as when co-administered with a metabolicinhibitor. The mean increase in QTc from baseline for zipra-sidone ranged from ~ 9 to 14 ms greater than for four of thecomparator drugs (risperidone, olanzapine, quetiapine andhaloperidol), but was ~14 ms less than the prolongationobserved for thioridazine. In the presence of metabolic inhibi-tion with ketoconazole 200 mg twice daily, the effect ofziprasidone on QTc length was not augmented. In placebo-controlled trials, oral ziprasidone increased the QTc intervalcompared to placebo by ~10 ms at the highest recommendeddaily dose of 160 mg. More importantly, QTc intervals rarelyexceeded the potentially clinically relevant threshold of500 ms: this occurred in 2/2988 (0.06%) patients whoreceived ziprasidone and in 1/440 (0.23%) patients whoreceived placebo in the clinical trial program.

Reported when ziprasidone was initially approved were10 sudden, unexpected deaths in the 4571 patients who hadreceived ziprasidone in all of the premarketing studies, reflect-ing 1733 patient-years of exposure (0.6 sudden deaths/100patient-years exposure), not significantly different than thefindings with the placebo or active-drug comparators (halo-peridol and risperidone) [21]. There is a case report of a28-year-old woman who developed torsades de pointes while

Table 2. Commonly encountered spontaneously reported adverse events as reported in product labeling

ziprasidone: percentage of patients reporting reaction and NNH vs placebo*.

Disease

state

Adverse

event

Rate with

ziprasidone

Rate with

placebo

NNH

Schizophrenia, acute Somnolence 14% 7% 15Respiratory tract infection 8% 3% 20Extrapyramidal symptoms 14% 8% 17Nausea 10% 7% 34

Bipolar I disorder, acute manicor mixed episodes

Somnolence 31% 12% 6Extrapyramidal symptoms 31% 12% 6Dizziness 16% 7% 12Akathisia 10% 5% 20Abnormal vision 6% 3% 34Asthenia 6% 2% 25Vomiting 5% 2% 34Headache 18% 17% 100Nausea 10% 7% 34

Schizophrenia, acutely agitated(intramuscular formulation)

Headache 10 mg, 13%; 20 mg, 5% 2 mg, 3% 10 mg, 10; 20 mg, 50Nausea 10 mg, 8%; 20 mg, 12% 2 mg, 4% 10 mg, 25; 20 mg, 13Somnolence 10 mg, 8%; 20 mg, 20% 2 mg, 8% 10 mg, ND; 20 mg, 9Dizziness 10 mg, 3%; 20 mg, 10% 2 mg, 3% 10 mg, ND; 20 mg, 15

*Adapted from tables in [6]; for intramuscular ziprasidone, the comparison is with 2 mg rather than placebo.

ND: No difference; NNH: Number needed to harm.

Ziprasidone


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treated with ziprasidone [22]. However, the confounding fac-tors of her also having systemic lupus erythematosus, hypo-thyroidism and severe lithium toxicity make it difficult toascertain causality. Additional cases reported include a55-year-old woman who ingested 6 g of ziprasidone togetherwith an unknown quantity of benztropine, fluoxetine andtrazodone, as well as a pint of rum [23], and another case ofan overdose with ziprasidone, amantadine and ibuprofen ina 30 year-old woman [24].

Additional studies have been undertaken to appraise ziprasi-done’s risk for prolongation of the ECG QT interval. Theeffect of high doses of oral ziprasidone was evaluated in a pro-spective, randomized, open-label, parallel-group study inpatients with schizophrenia or schizoaffective disorder [25].Patients received escalating oral doses of ziprasidone (n = 29)and haloperidol (n = 30) to reach steady-state. Serial ECGsand a serum or plasma sample were collected at the predictedtime of peak exposure to the administered drug. Mean changesfrom baseline in the QTc interval (ms) for ziprasidone were4.5 (95% CI 1.9 -- 7.1), 19.5 (95% CI 15.5 -- 23.4) and22.5 (95% CI 15.7 -- 29.4) for steady-state doses of 40,160 and 320 mg/day, respectively; and for haloperidol-1.2 (95% CI -4.1 -- 1.7), 6.6 (95% CI 1.6 -- 11.7) and7.2 (95% CI 1.4 -- 13.1) for steady-state doses of 2.5, 15 and30 mg/day. No patient in either treatment group experienceda QTc interval of 450 ms or greater, but the QTc intervalincreased 30 ms or more in 11 and 17 ziprasidone-treatedpatients at 160 and 320 mg/day, respectively, and in 3 and5 haloperidol-treated patients at 15 and 30 mg/day, respec-tively. Although the QTc interval in ziprasidone- andhaloperidol-treated patients increased with dose, it was notdose proportional. Treatment with high doses of ziprasidoneor haloperidol did not result in any patient experiencing aQTc interval of 450 ms or greater.

Consistent with the above is a series of 15 in-patients admin-istered ziprasidone at doses of 240 -- 320mg/day [26]. ECGs wererecorded before starting on ziprasidone and at least 1 week after amaximum dose was reached (240 mg/day for eight individuals,300 mg/day for one and 320 mg/day for six). Themean increasein QTc from initial to final was minimal. No QTc increasedby > 20 ms or approached 500 ms.

The effect of high doses of intramuscular ziprasidone on theQT interval has also been tested [27]. Patients with schizophre-nia or schizoaffective disorder were randomized to receivesingle-blind two high-dose intramuscular injections of ziprasi-done (20 and 30 mg) or haloperidol (7.5 and 10 mg) separatedby 4 h. Each dose administration was followed by serial ECGsand blood sampling for plasma levels of the medications. Afterthe first injection, mean (95% CI) changes from baseline were4.6 ms (0.4 -- 8.9) with ziprasidone (n = 25) and 6 ms(1.4 -- 10.5) with haloperidol (n = 24). After the second injec-tion, these values were 12.8 ms (6.7 -- 18.8) and 14.7 ms(10.2 -- 19.2), respectively. None of the patients had a QTcinterval ‡ 480 ms. Two patients in the ziprasidone groupexperienced QTc prolongation ‡ 450 ms (457 and 454 ms)

and QTc changes that exceeded 60 ms (62 and 76 ms) relativeto the time-matched baseline values. With haloperidol, QTcinterval values were < 450 ms with no changes > 60 ms.

Although the premarketing experience for ziprasidone didnot reveal an excess risk of mortality for ziprasidone comparedto other antipsychotic drugs or placebo, the product label [6]

remains cautious and recommends that for patients takingziprasidone who experience symptoms that could indicatethe occurrence of torsade de pointes, for example, dizziness,palpitations or syncope, the prescriber should initiate furtherevaluation, including considering Holter monitoring. How-ever, under most clinical circumstances, ziprasidone may besafely used without ECG monitoring [28].

4.3 Extrapyramidal symptomsCompared to first-generation antipsychotics, ziprasidone hasa low propensity for extrapyramidal side effects. There maybe dose--response regarding extrapyramidal side effects asnoted by the increased use of concomitant use anticholin-ergic medication for higher doses of ziprasidone duringthe short-term clinical trials, particularly when exceeding160 mg/day [21]. Objectively collected data from those trialson the Simpson-Angus Rating Scale (for extrapyramidalsymptoms) and the Barnes Akathisia Scale (for akathisia) didnot generally show a difference between ziprasidone and pla-cebo [6]. Small numbers of case reports of severe extrapyrami-dal adverse reactions have been reported, including cases ofneuroleptic malignant syndrome (all with off-label usagepatterns). For a more complete discussion, see [3].

4.4 Prolactin elevationAs with all agents that can block dopamine D2 receptors, ele-vation in serum prolactin can occur. Significant elevations inprolactin may be associated with decreases in sexual desire,erection and ability to achieve orgasm. In all oral ziprasidonePhase II and Phase III premarketing trials, 20% of patientstreated with ziprasidone had at least one elevated prolactinlevel during treatment (defined as > 22 ng/ml, i.e., 10% abovethe upper limit of normal), compared with 4% of thosetreated with placebo, 46% of those treated with haloperidoland 89% of those treated with risperidone [21]. Ofziprasidone-treated males, 6.6% had at least one prolactinlevel > 35 ng/ml and 1.7% had at least two such values. Ofziprasidone-treated females, 8.5% had at least one prolactinlevel > 50 ng/ml and 3.5% had at least two such values. Allthese values were higher than with placebo, but lower thanwith haloperidol or risperidone [21]. There have been pub-lished reports of persistent hyperprolactinemia with galactor-rhea associated with the use of ziprasidone in women,suggesting that patients be monitored for such adversereactions [3].

4.5 Weight and metabolic variablesArguably the major advantage for ziprasidone over someother second-generation antipsychotics is its low propensity

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for weight gain or adverse metabolic effects. The proportionsof patients meeting a weight gain criterion of at least 7% ofbody weight in the short-term registration trials for schizo-phrenia were 10% for ziprasidone versus 4% for placebo(NNH 17) [6]. A median weight gain of 0.5 kg was observedin the ziprasidone patients compared to no median weightchange in placebo [6]. In this set of clinical trials, weightgain was reported as an adverse reaction in 0.4 and 0.4% ofziprasidone and placebo patients, respectively. In long-term therapy with ziprasidone, the greatest mean weightgain and highest incidence of clinically relevant weight gain(exceeding the 7% threshold) was in patients with low base-line body mass index (BMI) (< 23 kg/m2) versus those witha normal (23 -- 27 kg/m2) or high (> 27 kg/m2) BMI [6].There was a mean weight gain of 1.4 kg for those patientswith a low BMI, no mean change for patients with a normalBMI and a 1.3 kg mean weight loss for patients with a highBMI [6]. There is no apparent dose-effect: a 1-year study ofpatients randomized to one of three doses of ziprasidone orplacebo found a mean weight loss of 3.6 kg on placebo, com-pared with weight losses of 2.7 kg on ziprasidone 40 mg/day,3.2 kg on 80 mg/day and 2.9 kg on 160 mg/day [29]. Notreported in this last study was whether or not weight changewas different for patients with different baseline body weights,or if weight change was different depending on the drug reg-imen prescribed before entering the study. Both are potentialconfounds when evaluating weight change over time.During the 6-month placebo-controlled bipolar mainte-

nance study in adults with ziprasidone as an adjunct to lithiumor valproate, the proportion of patients who gained at least 7%of their body weight during the double-blind period was thesame for both treatment groups (5.6% for both ziprasidoneand placebo treatment groups who completed the 6 monthsof observation for relapse) [6].A meta-analysis that compared antipsychotics estimated the

weight changes that would be associated with 10 weeks oftreatment and found that clozapine would be associatedwith a 3.99 kg weight gain, olanzapine with a 3.51 kg weightgain, risperidone with a 2.00 kg weight gain, ziprasidone witha 0.04 kg weight gain and placebo with a 0.41 weight loss [30].Other studies that have compared ziprasidone with other anti-psychotics have also shown a direct advantage for ziprasidone.For example, in an 8-week study, 8.2% of ziprasidone-treated patients gained at least 7% of their baseline bodyweight compared to 16% for those treated with risperi-done [31]. Several other studies support a low mean weightgain or the observation of weight loss with ziprasidone [32-36].The Clinical Antipsychotic Trials of Intervention Effective-ness (CATIE) was also consistent in this regard [36,37]. InPhase I of CATIE, those randomized to ziprasidone lost amean of 0.1 kg/month compared with gains for the othernewer antipsychotics [36], and similar findings were replicatedwith ziprasidone in one of the pathways for Phase II of theCATIE trial [37]. In the latter, among the 61 patients whogained > 7% of their body weight in Phase I, 42% of those

randomized subsequently to ziprasidone lost > 7% of theirbody weight as compared to 20% for risperidone, 7% for que-tiapine and none for olanzapine [37]. However, there is consid-erable individual variation, as the range of changes in bodyweight (5th to 95th percentile) in Phase I of the CATIE studyfor ziprasidone was from -2.4 to +2.7 kg/month of treatmentin Phase I and -4.1 to +2.6 kg/month of treatment in Phase II.The pattern of weight gain may also differ depending on thestage of illness. For example, among people with schizophre-nia early in their course of illness, weight gain can be morecommon. In the year-long randomized open-label EuropeanFirst Episode Schizophrenia Trial (EUFEST), weight gainof > 7% of baseline was observed in 37% of patients random-ized to ziprasidone (for comparison, the rate for subjectsrandomized to olanzapine was 86%) [38].

Information regarding fasting blood is more limited, asthese were not consistently collected when ziprasidone wasinitially being developed [3]. However, the study thataddressed the QTc interval changes associated with ziprasi-done and antipsychotic comparators also collected informa-tion regarding fasting lipid levels [21]; treatment withziprasidone was associated with the following changes in fast-ing lipid levels: a decrease of 14.5 mg/dl (-7.5%) in the totalcholesterol, a decrease of 11 mg/dl (-8.5%) in the low-density lipoprotein level, no change in the high-density lipoprotein (HDL) level, a decrease of 37 mg/dl inthe triglycerides (-28%) and a decrease of 0.33 (-7.5%) inthe total cholesterol:HDL ratio. Treatment with haloperidolwas associated with significant decreases in all lipid values,including HDL; risperidone treatment was associated with afew small, nonsignificant changes, and olanzapine, quetiapineand thioridazine treatments were all associated with some sig-nificant undesirable changes in lipid values. Results from theCATIE study have been consistent in supporting ziprasidone’smetabolically neutral profile [36,37].

Treatment with ziprasidone has rarely been associated withthe development of diabetes mellitus, but there are exceptions,including an unusual case of a 36-year old male with no previ-ous history of diabetes despite recent treatments witholanzapine and with risperidone, who was switched to ziprasi-done 160 mg/day, and despite a significant weight loss, experi-enced steadily increasing fasting blood glucose levels over thenext several months, up to 375 mg/dl, requiring concomitanttreatment with metformin and associated with a worsening ofblood lipid parameters. All of these findings normalized whenhe was switched from ziprasidone to quetiapine, whileallowing discontinuation of the metformin [39]. During all pre-marketing studies, there were no cases reported of treatment-emergent diabetes mellitus in the ziprasidone-treated patients(3834 patients, 1658 patient-years exposure), compared withone case among those receiving haloperidol (incidence 0.1%)and two in those receiving risperidone (incidence 0.6%) [21].Based on all available data, a November 2003 consensus devel-opment conference jointly convened by the American DiabetesAssociation, American Psychiatric Association, American

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Association of Clinical Endocrinologists and North AmericanAssociation for the Study of Obesity reviewed the associationsbetween the use of antipsychotic drugs and obesity anddiabetes, and concluded that ziprasidone and aripiprazolewere basically neutral with regard to weight gain, risk for devel-oping diabetes mellitus or for developing a worsened lipidprofile, unlike clozapine, olanzapine, risperidone and quetia-pine [40]. Nevertheless, monitoring of weight and metabolicvariables is recommended for all patients receiving anysecond-generation antipsychotic.

4.6 MortalityA 1-year open-label, randomized, postmarketing large simpletrial that enrolled 18,154 patients with schizophrenia receiv-ing either ziprasidone or olanzapine in naturalistic practicein 18 countries was recently reported [41]. The purpose ofthe study was to attempt to quantify the potential mortalitythat could be attributable to causes other than suicide, giventhe QT prolongation that can be observed with ziprasidone.The study itself fulfilled a post-approval commitment byziprasidone’s manufacturer to the FDA and the Swedish Med-ical Products Agency. A total of 205 (1.1%) deaths occurred.There was no difference between the ziprasidone (n = 9077)and olanzapine (n = 9077) treatment arms regarding non-suicide mortality (relative risk 1.02, 95% CI 0.76 -- 1.39).There were no significant differences between the two treat-ment groups on the secondary end points of all-cause mortal-ity, cardiovascular mortality, suicide, sudden death or suddencardiac death. A greater proportion of the ziprasidone cohort(15.1%) required hospitalization compared to the olanzapinecohort (10.9%), yielding a risk ratio of 1.39 (95% CI1.29 -- 1.50) and a NNH of 24 (95% CI 20 -- 31); this wasattributable to psychiatric reasons, and not because of myocar-dial infarction, arrhythmia or diabetic ketoacidosis. Therewere no cases of torsades de pointes observed. The authorsconcluded that despite the known risk of QT prolongationwith ziprasidone, ziprasidone was not associated with an ele-vated risk of non-suicidal mortality relative to olanzapine inreal-world use. The authors acknowledge that the studydesign did not allow evaluation of differences in the specificincidence of uncommon outcomes, such as torsades depointes and sudden death. It was thought that torsades depointes would not be reliably detected during the course ofroutine care because of both its rarity and the absence offrequent ECG testing.

4.7 Doses of ziprasidone in excess of 160 mg/dayInformation regarding the efficacy and safety of ziprasidone atdoses that exceed 160 mg/day among treatment-resistant patients is limited, despite ziprasidone being com-monly used in this manner [42]. There are no publishedrandomized controlled studies of ziprasidone at doses thatexceed 160 mg/day. Uncontrolled reports are available thatdemonstrate some improvement with little in the way ofproblems with tolerability [43,44]. There is also a case report

of a patient with schizophrenia who developed acute dystonicreactions when taking ziprasidone 240 mg/day, even thoughshe did not display any extrapyramidal symptoms withziprasidone 160 mg/day taken for several months [45]. See sec-tion 4.2 for a discussion of studies examining dose and QTprolongation.

5. Comparison with safety of other drugs

Similar to most second-generation antipsychotics, ziprasi-done has a lower propensity for extrapyramidal side effectsand hyperprolactinemia than first-generation antipsychotics.Ziprasidone’s principal advantage over certain other second-generation antipsychotics is its more favorable weight andmetabolic adverse effect profile, a property that appearsshared by aripiprazole [46], iloperidone [47], asenapine [48]

and lurasidone [49]. Ziprasidone’s risk for QT prolongationis similar to that for iloperidone [47]. The requirement foradministration with food is similar to that for lurasidone [49].Ziprasidone has relatively few drug--drug interactionissues, in contrast to many other antipsychotics that aremore extensively metabolized via CYP isoenzymes.

6. Conclusion

Ziprasidone has been commercially available as an oral andas a short-acting intramuscular formulation in the US forclose to a decade. The oral formulation has a number of dif-ferent therapeutic indications. Initial concerns regarding therisk for QT prolongation has not materialized in clinicallysignificant arrhythmias that would make ziprasidone diffi-cult to use. Ziprasidone’s overall safety profile is favorable,particularly in terms of effects on body weight and metabolicvariables. As noted elsewhere [5], the major challenge in theeffective use of ziprasidone is ensuring adequate dosing andadministration with a meal.

7. Expert opinion

Although ziprasidone has been available in the US for almost10 years, it has recently been launched in other countries,such as Canada and China. Some of the delays in introduc-ing this agent in some markets have been due in part to con-cerns by regulatory authorities over the risk of ziprasidonefor prolonging the ECG QT interval. However, real-world use of ziprasidone has not resulted in increased ratesof torsades de pointes or sudden death. The cardiac safetyof ziprasidone is further supported by a large, simple trial [41].As a caveat, controversy exists about the utility of QT pro-longation as a surrogate for torsades de pointes, with sugges-tions that T-wave morphology and other variables may be abetter way of assessing risk [50].

In order to be used as effectively as possible, ziprasidoneshould be dosed within the range of 120 -- 160 mg/day andadministered with a meal [5], and both of these points were

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underappreciated when ziprasidone was initially launched inthe US [42]. There is a potential for other countries to learnfrom this experience and launch ziprasidone with a betterunderstanding of how to use it.Whether or not ziprasidone is efficacious and tolerable at

doses that exceed 160 mg/day remains to be answered.Approaching completion but for which results are not yetavailable is a double-blind clinical trial where out-patients and in-patients with schizophrenia who had not ade-quately responded to ziprasidone 160 mg/day were randomlyassigned to receive ziprasidone 160 or 320 mg/day for8 weeks [51].Individuals respond to different antipsychotics with vary-

ing degrees of symptom resolution and with tolerabilityissues that are difficult to predict. This heterogeneity makesclinical decision-making complex [52]. In general, meta-analyses can help assess mean differences in efficacy measuresbetween groups of patients receiving different antipsy-chotics [53], but in order for a medication to be effective itmust also be tolerable and safe and the patient must be will-ing to take it [52]. Ziprasidone has the potential of addressingkey concerns regarding the adverse effects on body weight

and metabolic variables that can be observed with certainother antipsychotics and this may be attractive to the patientand reassuring to the clinician. Other second-generationantipsychotics are now available that are also potentially‘metabolically-friendly’ and choosing one over the otherwill also depend on actual response in terms of efficacy forthe individual patient, presence of other potential adverseeffects, ease of dosing and cost. The availability of ziprasi-done in a generic preparation in the not too distant futuremay increase its use.

Declaration of interest

No writing assistance was utilized in the production of this arti-cle. L Citrome is a consultant for, has received honoraria from,or has conducted clinical research supported by the following:Abbott Laboratories, AstraZeneca Pharmaceuticals, AvanirPharmaceuticals, Azur Pharma, Inc., Barr Laboratories,Bristol-Myers Squibb, Eli Lilly and Company, Forest ResearchInstitute, GlaxoSmithKline, Janssen Pharmaceuticals, JazzPharmaceuticals, Merck, Novartis, Pfizer, Inc., Sunovion,Valeant Pharmaceuticals and Vanda Pharmaceuticals.

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and diabetes. Diabetes Care

2004;27(2):596-601

41. Strom BL, Eng SM, Faich G,

et al. Comparative mortality

associated with ziprasidone and

olanzapine in real-world use

among 18,154 patients with

schizophrenia: the Ziprasidone

Observational Study of Cardiac

Citrome


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Outcomes (ZODIAC). Am J Psychiatry

2010. [Epub ahead of print]. A much anticipated study report of a

large simple trial done in an effort to

measure potential excess mortality.

42. Citrome L, Jaffe A, Levine J. How

dosing of ziprasidone in a state hospital

system differs from product labeling.


43. Deutschman DA, Deutschman DH.

High-dose ziprasidone in

treatment-resistant schizophrenia

and affective spectrum disorders.


2007;27(5):513-14

44. Mech AW. High-dose ziprasidone

monotherapy in bipolar I disorder

patients with depressed or mixed

episodes. J Clin Psychopharmacol

2008;28(2):240-1

45. Rosenfield PJ, Girgis RR, Gil R.

High-dose ziprasidone-induced acute

dystonia. Prog Neuropsychopharmacol

Biol Psychiatry 2007;31(2):546-7

46. Citrome L. A review of aripiprazole

in the treatment of patients with

schizophrenia or bipolar I disorder.

Neuropsychiatr Dis Treat

2006;2(4):427-43

47. Citrome L. Iloperidone for

schizophrenia: a review of the efficacy

and safety profile for this newly

commercialised second-generation

antipsychotic. Int J Clin Pract

2009;63(8):1237-48

48. Citrome L. Asenapine for schizophrenia

and bipolar disorder: a review of the

efficacy and safety profile for this newly

approved sublingually absorbed

second-generation antipsychotic. Int J

Clin Pract 2009;63(12):1762-84

49. Citrome L. Lurasidone for schizophrenia:

a review of the efficacy and safety profile

for this newly approved

second-generation antipsychotic. Int J

Clin Pract 2011;65(2):189-210

50. Hondeghem LM. Thorough QT/QTc

not so thorough: removes torsadogenic

predictors from the T-wave, incriminates

safe drugs, and misses profibrillatory

drugs. J Cardiovasc Electrophysiol

2006;17(3):337-40

51. Goff D. High-dose ziprasidone versus

conventional dosing in schizophrenia

patients with residual symptoms

(HDZ). NCT00403546.

Available from: http://www.clinicaltrials.

gov/ct2/show/NCT00403546.

[Last accessed 25 January 2011]

52. Volavka J, Citrome L. Oral

antipsychotics for the treatment of

schizophrenia: heterogeneity in efficacy

and tolerability should drive

decision-making.

Expert Opin Pharmacother

2009;10(12):1917-28

53. Leucht S, Corves C, Arbter D, et al.

Second-generation versus first-generation

antipsychotic drugs for schizophrenia:

a meta-analysis. Lancet

2009;373(9657):31-41.. This meta-analysis was one in a series

conducted by Leucht and colleagues

and suggests that there are three

different tiers of antipsychotics in

terms of efficacy, with clozapine in the

top tier; olanzapine, risperidone and

amisulpride in the middle tier; and the

remainder of antipsychotics in the

third tier.

AffiliationLeslie Citrome MD MPH

Professor of Psychiatry,

New York University School of Medicine,

11 Medical Park Drive,

Suite 106, Pomona, NY 10970, USA

Tel: + 1 845 362 2081; Fax: + 1 845 362 8745;

E-mail: [email protected]

Ziprasidone


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drug safety evaluation of ziprasidone

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