ZIPRASIDONE- ziprasidone hydrochloride capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ZIPRASIDONE HYDROCHLORIDE (UNII: 216X081ORU) (ZIPRASIDONE - UNII:6UKA5VEJ6X)
Available from:
Avera McKennan Hospital
INN (International Name):
ZIPRASIDONE HYDROCHLORIDE
Composition:
ZIPRASIDONE 40 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Ziprasidone is indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. When deciding among the alternative treatments available for the condition needing treatment, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs [see Warnings and Precautions (5.2) ]. Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. In many cases this would lead to the conclusion that other drugs should be tried first. Whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known [see Warnings and Precautions (5.2)] . Ziprasidone is indicated for the treatment of schizophrenia. The efficacy
Product summary:
Ziprasidone 40mg capsules NDC 59762-2002-1 bottle of 60 NDC 69189-2003-1 single dose pack with 1 capsule as repackaged by Avera McKennan Hospital Ziprasidone capsules should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].
Authorization status:
New Drug Application Authorized Generic
Authorization number:
69189-2003-1

ZIPRASIDONE- ziprasidone hydrochloride capsule

Avera McKennan Hospital

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Ziprasidone safely and effectively. See full

prescribing information for ziprasidone.

Ziprasidone HCl capsules

Initial U.S. Approval: 2001

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED

PSYCHOSIS

See full prescribing information for complete boxed warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased

risk of death compared to placebo treatment (5.1)

Ziprasidone is not approved for elderly patients with dementia-related psychosis (5.1)

RECENT MAJOR CHANGES

Warnings and Precautions (5.4)

9/2015

INDICATIONS AND USAGE

Ziprasidone is an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of

ziprasidone to prolong the QT interval and may consider the use of other drugs first. (5.2)

Ziprasidone is indicated as an oral formulation for the:

Treatment of schizophrenia. (1.1)

Adults: Efficacy was established in four 4–6 week trials and one maintenance trial in adult patients with schizophrenia.

(14.1)

Acute treatment as monotherapy of manic or mixed episodes associated with bipolar I disorder. (1.2)

Adults: Efficacy was established in two 3-week trials in adult patients with manic or mixed episodes. (14.2)

Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate. (1.2)

Adults: Efficacy was established in one maintenance trial in adult patients. (14.2)

DOSAGE AND ADMINISTRATION

Give oral doses with food.

Schizophrenia: Initiate at 20 mg twice daily. Daily dosage may be adjusted up to 80 mg twice daily. Dose adjustments

should occur at intervals of not less than 2 days. Safety and efficacy has been demonstrated in doses up to 100 mg

twice daily. The lowest effective dose should be used. (2.1)

Acute treatment of manic/mixed episodes of bipolar I disorder: Initiate at 40 mg twice daily. Increase to 60 mg or 80

mg twice daily on day 2 of treatment. Subsequent dose adjustments should be based on tolerability and efficacy within

the range of 40–80 mg twice daily. (2.2)

Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate: Continue treatment at the same dose

on which the patient was initially stabilized, within the range of 40–80 mg twice daily. (2.2)

DOSAGE FORMS AND STRENGTHS

Capsules: 20 mg, 40 mg, 60 mg, and 80 mg (3)

CONTRAINDICATIONS

Do not use in patients with a known history of QT prolongation. (4.1)

Do not use in patients with recent acute myocardial infarction. (4.1)

Do not use in patients with uncompensated heart failure. (4.1)

Do not use in combination with other drugs that have demonstrated QT prolongation. (4.1)

Do not use in patients with known hypersensitivity to ziprasidone. (4.2)

WARNINGS AND PRECAUTIONS

QT Interval Prolongation: Ziprasidone use should be avoided in patients with bradycardia, hypokalemia or

hypomagnesemia, congenital prolongation of the QT interval, or in combination with other drugs that have

demonstrated QT prolongation. (5.2)

Neuroleptic Malignant Syndrome (NMS): Potentially fatal symptom complex has been reported with antipsychotic

drugs. Manage with immediate discontinuation of drug and close monitoring. (5.3)

Severe Cutaneous Adverse Reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and

Stevens-Johnson syndrome has been reported with ziprasidone exposure. DRESS and other Severe Cutaneous

Adverse Reactions (SCAR) are sometimes fatal. Discontinue ziprasidone if DRESS or SCAR are suspected. (5.4)

Tardive Dyskinesia: May develop acutely or chronically. (5.5)

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase

cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain.

(5.6)

Hyperglycemia and Diabetes Mellitus (DM): Monitor all patients for symptoms of hyperglycemia including polydipsia,

polyuria, polyphagia, and weakness. Patients with DM risk factors should undergo blood glucose testing before and

during treatment. (5.6)

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.6)

Weight Gain: Weight gain has been reported. Monitor weight gain. (5.6)

Rash: Discontinue in patients who develop a rash without an identified cause. (5.7)

Orthostatic Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease. (5.8)

Leukopenia, Neutropenia, and Agranulocytosis has been reported with antipsychotics. Patients with a pre-existing low

white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC)

monitored frequently during the first few months of therapy and should discontinue ziprasidone at the first sign of a

decline in WBC in the absence of other causative factors. (5.9)

Seizures: Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold. (5.10)

Potential for Cognitive and Motor impairment: Patients should use caution when operating machinery. (5.13)

Suicide: Closely supervise high-risk patients. (5.16)

ADVERSE REACTIONS

Commonly observed adverse reactions (incidence ≥5% and at least twice the incidence for placebo) were:

Schizophrenia: Somnolence, respiratory tract infection. (6.1)

Manic and Mixed Episodes Associated with Bipolar Disorder: Somnolence, extrapyramidal symptoms, dizziness,

akathisia, abnormal vision, asthenia, vomiting. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC Professional Information Services at

1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Ziprasidone should not be used in combination with other drugs that have demonstrated QT prolongation. (4.1, 7.3)

The absorption of ziprasidone is increased up to two-fold in the presence of food. (7.9)

The full prescribing information contains additional drug interactions. (7)

USE IN SPECIFIC POPULATIONS

Pregnancy: Ziprasidone should be used during pregnancy only if the potential benefit justifies the potential risk. (8.1)

Nursing Mothers: Breast feeding is not recommended. (8.3)

Pediatric Use: Safety and effectiveness for pediatric patients has not been established. (8.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 3/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-

RELATED PSYCHOSIS

1 INDICATIONS AND USAGE

1.1 Schizophrenia

1.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to

Lithium or Valproate)

2 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

2.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to

Lithium or Valproate)

2.3 Dosing in Special Populations

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 QT Prolongation

4.2 Hypersensitivity

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

5.2 QT Prolongation and Risk of Sudden Death

5.3 Neuroleptic Malignant Syndrome (NMS)

5.4 Severe Cutaneous Adverse Reactions

5.5 Tardive Dyskinesia

5.6 Metabolic Changes

5.7 Rash

5.8 Orthostatic Hypotension

5.9 Leukopenia, Neutropenia, and Agranulocytosis

5.10 Seizures

5.11 Dysphagia

5.12 Hyperprolactinemia

5.13 Potential for Cognitive and Motor Impairment

5.14 Priapism

5.15 Body Temperature Regulation

5.16 Suicide

5.17 Patients with concomitant illnesses

5.18 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Metabolic Pathway

7.2 In Vitro Studies

7.3 Pharmacodynamic Interactions

7.4 Pharmacokinetic Interactions

7.5 Lithium

7.6 Oral Contraceptives

7.7 Dextromethorphan

7.8 Valproate

7.9 Other Concomitant Drug Therapy

7.10 Food Interaction

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Age and Gender Effects

8.9 Smoking

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

10 OVERDOSAGE

10.1 Human Experience

10.2 Management of Overdosage

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Schizophrenia

14.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct

to Lithium or Valproate)

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Administration with Food

17.2 QTc Prolongation

17.3 Severe Cutaneous Adverse Reactions

FULL PRESCRIBING INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH

DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an

increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of

10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in

drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated

patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-

treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either

cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with

conventional antipsychotic drugs may increase mortality. The extent to which the findings

of increased mortality in observational studies may be attributed to the antipsychotic drug

as opposed to some characteristic(s) of the patients is not clear. Ziprasidone is not

approved for the treatment of patients with Dementia-Related Psychosis [see Warnings and

Precautions (5.1)]).

1 INDICATIONS AND USAGE

Ziprasidone is indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of

bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment

of bipolar disorder. When deciding among the alternative treatments available for the condition needing

treatment, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the

QT/QTc interval compared to several other antipsychotic drugs [see Warnings and Precautions (5.2)].

Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de

pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. In

Sections or subsections omitted from the full prescribing information are not listed.

many cases this would lead to the conclusion that other drugs should be tried first. Whether ziprasidone

will cause torsade de pointes or increase the rate of sudden death is not yet known [see Warnings and

Precautions (5.2)].

1.1 Schizophrenia

Ziprasidone is indicated for the treatment of schizophrenia. The efficacy of oral ziprasidone was

established in four short-term (4- and 6-week) controlled trials of adult schizophrenic inpatients and in

one maintenance trial of stable adult schizophrenic inpatients [see Clinical Studies (14.1)].

1.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an

Adjunct to Lithium or Valproate)

Ziprasidone is indicated as monotherapy for the acute treatment of manic or mixed episodes associated

with bipolar I disorder. Efficacy was established in two 3-week monotherapy studies in adult patients

[see Clinical Studies (14.2)].

Ziprasidone is indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I

disorder. Efficacy was established in a maintenance trial in adult patients. The efficacy of ziprasidone

as monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated

in controlled clinical trials [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

Dose Selection

Ziprasidone capsules should be administered at an initial daily dose of 20 mg twice daily with food. In

some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to

80 mg twice daily. Dosage adjustments, if indicated, should generally occur at intervals of not less than

2 days, as steady-state is achieved within 1 to 3 days. In order to ensure use of the lowest effective

dose, patients should ordinarily be observed for improvement for several weeks before upward dosage

adjustment.

Efficacy in schizophrenia was demonstrated in a dose range of 20 mg to 100 mg twice daily in short-

term, placebo-controlled clinical trials. There were trends toward dose response within the range of 20

mg to 80 mg twice daily, but results were not consistent. An increase to a dose greater than 80 mg twice

daily is not generally recommended. The safety of doses above 100 mg twice daily has not been

systematically evaluated in clinical trials [see Clinical Studies (14.1)].

Maintenance Treatment

While there is no body of evidence available to answer the question of how long a patient treated with

ziprasidone should remain on it, a maintenance study in patients who had been symptomatically stable and

then randomized to continue ziprasidone or switch to placebo demonstrated a delay in time to relapse for

patients receiving ziprasidone [see Clinical Studies (14.1)]. No additional benefit was demonstrated for

doses above 20 mg twice daily. Patients should be periodically reassessed to determine the need for

maintenance treatment.

2.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an

Adjunct to Lithium or Valproate)

Acute Treatment of Manic or Mixed Episodes

Dose Selection-Oral ziprasidone should be administered at an initial daily dose of 40 mg twice daily

with food. The dose may then be increased to 60 mg or 80 mg twice daily on the second day of

treatment and subsequently adjusted on the basis of tolerance and efficacy within the range 40 mg–80

mg twice daily. In the flexible-dose clinical trials, the mean daily dose administered was approximately

120 mg [see Clinical Studies (14.2)].

Maintenance Treatment (as an adjunct to lithium or valproate)

Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40

mg–80 mg twice daily with food. Patients should be periodically reassessed to determine the need for

maintenance treatment [see Clinical Studies (14.2)].

2.3 Dosing in Special Populations

Oral: Dosage adjustments are generally not required on the basis of age, gender, race, or renal or

hepatic impairment. Ziprasidone is not approved for use in children or adolescents.

3 DOSAGE FORMS AND STRENGTHS

Ziprasidone capsules are differentiated by capsule color/size and are imprinted in black ink with "G" and

a unique number. Ziprasidone capsules are supplied for oral administration in 20 mg (blue/white), 40 mg

(blue/blue), 60 mg (white/white), and 80 mg (blue/white) capsules. They are supplied in the following

strengths and package configurations:

Ziprasidone Capsules

Capsule Strength (mg)

Imprint

20

2001

40

2002

60

2003

80

2004

4 CONTRAINDICATIONS

4.1 QT Prolongation

Because of ziprasidone's dose-related prolongation of the QT interval and the known association of

fatal arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated:

in patients with a known history of QT prolongation (including congenital long QT syndrome)

in patients with recent acute myocardial infarction

in patients with uncompensated heart failure

Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT

interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT

interval cannot be excluded. Therefore, ziprasidone should not be given with:

dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine,

chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine,

mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or

tacrolimus.

other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and

have this effect described in the full prescribing information as a contraindication or a boxed or

bolded warning [see Warnings and Precautions (5.2)].

4.2 Hypersensitivity

Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased

risk of death. Ziprasidone is not approved for the treatment of dementia-related psychosis. [see Boxed

Warning]

5.2 QT Prolongation and Risk of Sudden Death

Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc

interval [see Contraindications (4.1), Drug Interactions (7.4)]. Additionally, clinicians should be alert to

the identification of other drugs that have been consistently observed to prolong the QTc interval. Such

drugs should not be prescribed with ziprasidone. Ziprasidone should also be avoided in patients with

congenital long QT syndrome and in patients with a history of cardiac arrhythmias [see Contraindications

(4)].

A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs

effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the

trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered

alone. In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration

while the drug was co-administered with an inhibitor of the CYP4503A4 metabolism of the drug.

In the first phase of the study, the mean change in QTc from baseline was calculated for each drug,

using a sample-based correction that removes the effect of heart rate on the QT interval. The mean

increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for

four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was

approximately 14 msec less than the prolongation observed for thioridazine.

In the second phase of the study, the effect of ziprasidone on QTc length was not augmented by the

presence of a metabolic inhibitor (ketoconazole 200 mg twice daily).

In placebo-controlled trials, oral ziprasidone increased the QTc interval compared to placebo by

approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials with oral

ziprasidone, the electrocardiograms of 2/2988 (0.06%) patients who received ziprasidone and 1/440

(0.23%) patients who received placebo revealed QTc intervals exceeding the potentially clinically

relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case suggested a role of

ziprasidone. One patient had a history of prolonged QTc and a screening measurement of 489 msec;

QTc was 503 msec during ziprasidone treatment. The other patient had a QTc of 391 msec at the end of

treatment with ziprasidone and upon switching to thioridazine experienced QTc measurements of 518

and 593 msec.

Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de

pointes and with sudden unexplained death. The relationship of QT prolongation to torsade de pointes is

clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations

may also increase risk, or increase it in susceptible individuals. Although torsade de pointes has not

been observed in association with the use of ziprasidone in premarketing studies and experience is too

limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of

multiple confounding factors) [see Adverse Reactions (6.2)].

A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular

haloperidol as a control, was conducted in patient volunteers. In the trial, ECGs were obtained at the

time of maximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or

haloperidol (7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular

ziprasidone is 50% higher than the recommended therapeutic dose. The mean change in QTc from

baseline was calculated for each drug, using a sample-based correction that removes the effect of heart

rate on the QT interval. The mean increase in QTc from baseline for ziprasidone was 4.6 msec

following the first injection and 12.8 msec following the second injection. The mean increase in QTc

from baseline for haloperidol was 6.0 msec following the first injection and 14.7 msec following the

second injection. In this study, no patients had a QTc interval exceeding 500 msec.

As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in

patients taking ziprasidone at recommended doses. The premarketing experience for ziprasidone did not

reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo, but

the extent of exposure was limited, especially for the drugs used as active controls and placebo.

Nevertheless, ziprasidone's larger prolongation of QTc length compared to several other antipsychotic

drugs raises the possibility that the risk of sudden death may be greater for ziprasidone than for other

available drugs for treating schizophrenia. This possibility needs to be considered in deciding among

alternative drug products [see Indications and Usage (1)].

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death

in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2)

hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and

(4) presence of congenital prolongation of the QT interval.

It is recommended that patients being considered for ziprasidone treatment who are at risk for significant

electrolyte disturbances, hypokalemia in particular, have baseline serum potassium and magnesium

measurements. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and

arrhythmia. Hypokalemia may result from diuretic therapy, diarrhea, and other causes. Patients with low

serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with

treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy

is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the

risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are

effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of

significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction,

uncompensated heart failure, or cardiac arrhythmia. Ziprasidone should be discontinued in patients who

are found to have persistent QTc measurements >500 msec.

For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsade

de pointes, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation,

e.g., Holter monitoring may be useful.

5.3 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS)

has been reported in association with administration of antipsychotic drugs. Clinical manifestations of

NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability

(irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs

may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal

failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is

important to exclude cases where the clinical presentation includes both serious medical illness (e.g.,

pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and

symptoms (EPS). Other important considerations in the differential diagnosis include central

anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other

drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring;

and (3) treatment of any concomitant serious medical problems for which specific treatments are

available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction

of drug therapy should be carefully considered. The patient should be carefully monitored, since

recurrences of NMS have been reported.

5.4 Severe Cutaneous Adverse Reactions

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with ziprasidone

exposure. DRESS consists of a combination of three or more of the following: cutaneous reaction

(such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic

complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. DRESS is

sometimes fatal. Discontinue ziprasidone if DRESS is suspected.

Other severe cutaneous adverse reactions

Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with

ziprasidone exposure. Severe cutaneous adverse reactions are sometimes fatal. Discontinue ziprasidone

if severe cutaneous adverse reactions are suspected.

5.5 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients

undergoing treatment with antipsychotic drugs. Although the prevalence of the syndrome appears to be

highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates

to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are

believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs

administered to the patient increase. However, the syndrome can develop, although much less

commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may

remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself,

however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may

possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term

course of the syndrome is unknown.

Given these considerations, ziprasidone should be prescribed in a manner that is most likely to minimize

the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for

patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for

whom alternative, equally effective, but potentially less harmful treatments are not available or

appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of

treatment producing a satisfactory clinical response should be sought. The need for continued treatment

should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation

should be considered. However, some patients may require treatment with ziprasidone despite the

presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase

cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia,

and body weight gain. While all of the drugs in the class have been shown to produce some metabolic

changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or

hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics. There

have been few reports of hyperglycemia or diabetes in patients treated with ziprasidone. Although

fewer patients have been treated with ziprasidone, it is not known if this more limited experience is the

sole reason for the paucity of such reports. Assessment of the relationship between atypical

antipsychotic use and glucose abnormalities is complicated by the possibility of an increased

background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of

diabetes mellitus in the general population. Given these confounders, the relationship between atypical

antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. Precise

risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical

antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics

should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes

mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics

should undergo fasting blood glucose testing at the beginning of treatment and periodically during

treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of

hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop

symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood

glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was

discontinued; however, some patients required continuation of antidiabetic treatment despite

discontinuation of the suspect drug.

Pooled data from short-term, placebo-controlled studies in schizophrenia and bipolar disorder are

presented in Tables 1–4. Note that for the flexible dose studies in both schizophrenia and bipolar

disorder, each subject is categorized as having received either low (20–40 mg BID) or high (60–80 mg

BID) dose based on the subject's modal daily dose. In the tables showing categorical changes, the

percentages (% column) are calculated as 100×(n/N).

Table 1: Glucose Mean Change from Baseline in Short-Term (up to 6 weeks), Placebo-

Controlled, Fixed-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with

Schizophrenia

Mean Random Glucose Change from Baseline mg/dL (N)

Zipras idone

Placebo

5 mg BID

20 mg BID

40 mg BID

60 mg BID

80 mg BID

100 mg BID

-1.1 (N=45)

+2.4 (N=179)

-0.2 (N=146)

-0.5 (N=119)

-1.7 (N=104)

+4.1 (N=85)

+1.4 (N=260)

Table 2: Glucose Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled,

Fixed-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Schizophrenia

Laboratory

Analyte

Category Change (at least once) from Baseline

Treatment

Arm

N

n (%)

Random

Glucose

Normal to High (<100 mg/dL to ≥126 mg/dL)

Ziprasidone

77 (17.6%)

Placebo

26 (15.4%)

Borderline to High (≥100 mg/dL and <126 mg/dL to

≥126 mg/dL)

Ziprasidone

54 (34.0%)

Placebo

22 (33.3%)

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean

change from baseline in random glucose for ziprasidone 20–40 mg BID was -3.4 mg/dL (N=122); for

ziprasidone 60–80 mg BID was +1.3 mg/dL (N=10); and for placebo was +0.3 mg/dL (N=71).

Table 3: Glucose Mean Change from Baseline in Short-Term (up to 6 weeks), Placebo-

Controlled, Flexible-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Bipolar

Dis order

*

"Random" glucose measurements—fasting/non-fasting status unknown

*

"Random" glucose measurements – fasting/non-fasting status unknown

*

Mean Fasting Glucose Change from Baseline mg/dL (N)

Zipras idone

Placebo

Low Dose: 20–40 mg BID

High Dose: 60–80 mg BID

+0.1 (N=206)

+1.6 (N=166)

+1.4 (N=287)

Table 4: Glucose Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled,

Flexible-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Bipolar Disorder

Laboratory

Analyte

Category Change (at least once) from Baseline

Treatment

Arm

N

n (%)

Fasting

Glucose

Normal to High (<100 mg/dL to ≥126 mg/dL)

Ziprasidone

5 (1.8%)

Placebo

2 (1.0%)

Borderline to High (≥100 mg/dL and <126 mg/dL to

≥126 mg/dL)

Ziprasidone

12 (15.2%)

Placebo

7 (9.9%)

Dys lipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from short-term, placebo-controlled studies in schizophrenia and bipolar disorder are

presented in Tables 5–8.

Table 5: Lipid Mean Change from Baseline in Short-Term (up to 6 weeks), Placebo-Controlled,

Fixed-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

Mean Lipid Change from Baseline mg/dL (N)

Laboratory

Analyte

Zipras idone

Placebo

5 mg BID 20 mg BID 40 mg BID 60 mg BID 80 mg BID 100 mg BID

T riglycerides

-12.9

(N=45)

-9.6

(N=181)

-17.3

(N=146)

-0.05

(N=120)

-16.0

(N=104)

+0.8 (N=85)

-18.6

(N=260)

Total

Cholesterol

-3.6

(N=45)

-4.4

(N=181)

-8.2

(N=147)

-3.6 (N=120)

-10.0

(N=104)

-3.6 (N=85) -4.7 (N=261)

Table 6: Lipid Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-

Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

Laboratory

Analyte

Category Change (at least once) from Baseline

Treatment

Arm

N

n (%)

T riglycerides

Increase by ≥50 mg/dL

Ziprasidone

232 (34.1%)

Placebo

53 (20.4%)

Normal to High (<150 mg/dL to ≥200 mg/dL)

Ziprasidone

63 (14.7%)

Placebo

12 (7.9%)

Borderline to High (≥150 mg/dL and <200 mg/dL to

≥200 mg/dL)

Ziprasidone

43 (46.7%)

Placebo

12 (29.3%)

Total

Cholesterol

Increase by ≥40 mg/dL

Ziprasidone

76 (11.1%)

Placebo

26 (10.0%)

Normal to High (<200 mg/dL to ≥240 mg/dL)

Ziprasidone

15 (3.9%)

Placebo

0 (0.0%)

Fasting

*

Fasting

*

"Random" lipid measurements, fasting/non-fasting status unknown

*

Borderline to High (≥200 mg/dL and <240 mg/dL to

≥240 mg/dL)

Ziprasidone

56 (27.1%)

Placebo

22 (26.8%)

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean

change from baseline in random triglycerides for ziprasidone 20–40 mg BID was +26.3 mg/dL (N=15);

for ziprasidone 60–80 mg BID was -39.3 mg/dL (N=10); and for placebo was +12.9 mg/dL (N=9). In

long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change

from baseline in random total cholesterol for ziprasidone 20–40 mg BID was +2.5 mg/dL (N=14); for

ziprasidone 60–80 mg BID was -19.7 mg/dL (N=10); and for placebo was -28.0 mg/dL (N=9).

Table 7: Lipid Mean Change from Baseline in Short-Term (up to 6 weeks), Placebo-Controlled,

Flexible-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Bipolar Disorder

Laboratory Analyte

Mean Change from Baseline mg/dL (N)

Zipras idone

Placebo

Low Dose: 20–40 mg BID

High Dose: 60–80 mg BID

Fasting Triglycerides

+0.95 (N=206)

-3.5 (N=165)

+8.6 (N=286)

Fasting Total

Cholesterol

-2.8 (N=206)

-3.4 (N=165)

-1.6 (N=286)

Fasting LDL Cholesterol

-3.0 (N=201)

-3.1 (N=158)

-1.97 (N=270)

Fasting HDL cholesterol

-0.09 (N=206)

+0.3 (N=165)

-0.9 (N=286)

Table 8: Lipid Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled,

Flexible-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Bipolar Disorder

Laboratory

Analyte

Category Change (at least once) from Baseline

Treatment

Arm

N

n (%)

Fasting

T riglycerides

Increase by ≥50 mg/dL

Ziprasidone

66 (17.8%)

Placebo

62 (21.7%)

Normal to High (<150 mg/dL to ≥200 mg/dL)

Ziprasidone

15 (6.7%)

Placebo

13 (7.3%)

Borderline to High (≥150 mg/dL and <200 mg/dL to

≥200 mg/dL)

Ziprasidone

16 (27.6%)

Placebo

14 (29.8%)

Fasting Total

Cholesterol

Increase by ≥40 mg/dL

Ziprasidone

30 (8.1%)

Placebo

13 (4.5%)

Normal to High (<200 mg/dL to ≥240 mg/dL)

Ziprasidone

5 (2.5%)

Placebo

2 (1.3%)

Borderline to High (≥200 mg/dL and <240 mg/dL to

≥240 mg/dL)

Ziprasidone

10 (9.4%)

Placebo

15 (17.2%)

Fasting LDL

Cholesterol

Increase by ≥30 mg/dL

Ziprasidone

39 (10.9%)

Placebo

17 (6.3%)

Normal to High (<100 mg/dL to ≥160 mg/dL)

Ziprasidone

0 (0%)

Placebo

1 (1.1%)

Borderline to High (≥100 mg/dL and <160 mg/dL to

≥160 mg/dL)

Ziprasidone

18 (9.3%)

Placebo

14 (9.9%)

Fasting HDL Normal (>=40 mg/dL) to Low (<40 mg/dL)

Ziprasidone

22 (7.8%)

Placebo

24 (10.9%)

"Random" lipid measurements, fasting/non-fasting status unknown

*

Fasting

*

Fasting

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Monitoring of weight is recommended.

Pooled data from short-term, placebo-controlled studies in schizophrenia and bipolar disorder are

presented in Tables 9–10.

Table 9: Weight Mean Changes in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-Dose,

Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

Zipras idone

Placebo

5 mg BID

20 mg BID

40 mg BID

60 mg BID 80 mg BID

100 mg BID

Mean Weight (kg) Changes from Baseline (N)

+0.3 (N=40)

+1.0 (N=167)

+1.0 (N=135)

+0.7 (N=109)

+1.1 (N=97)

+0.9 (N=74)

-0.4 (227)

Proportion of Patients with ≥7% Increase in Weight from Baseline (N)

0.0% (N=40)

9.0%

(N=167)

10.4%

(N=135)

7.3% (N=109)15.5% (N=97)

10.8%

(N=74)

4.0% (N=227)

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean

change from baseline weight for ziprasidone 20–40 mg BID was -2.3 kg (N=124); for ziprasidone 60–

80 mg BID was +2.5 kg (N=10); and for placebo was -2.9 kg (N=72). In the same long-term studies, the

proportion of subjects with 7% increase in weight from baseline for ziprasidone 20–40 mg BID was

5.6% (N=124); for ziprasidone 60–80 mg BID was 20.0% (N=10), and for placebo was 5.6% (N=72). In

a long-term (at least 1 year), placebo-controlled, fixed-dose study in schizophrenia, the mean change

from baseline weight for ziprasidone 20 mg BID was -2.6 kg (N=72); for ziprasidone 40 mg BID was -

3.3 kg (N=69); for ziprasidone 80 mg BID was -2.8 kg (N=70) and for placebo was -3.8 kg (N=70). In

the same long-term fixed-dose schizophrenia study, the proportion of subjects with 7% increase in

weight from baseline for ziprasidone 20 mg BID was 5.6% (N=72); for ziprasidone 40 mg BID was

2.9% (N=69); for ziprasidone 80 mg BID was 5.7% (N=70) and for placebo was 2.9% (N=70).

Table 10: Summary of Weight Change in Short-Term (up to 6 weeks), Placebo-Controlled,

Flexible-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Bipolar Disorder:

Zipras idone

Placebo

Low Dose: 20–40 mg BID

High Dose : 60–80 mg BID

Mean Weight (kg) Changes from Baseline (N)

+0.4 (N=295)

+0.4 (N=388)

+0.1 (N=451)

Proportion of Patients with ≥ 7% Increase in Weight from Baseline (N)

2.4% (N=295)

4.4% (N=388)

1.8% (N=451)

Schizophrenia - The proportions of patients meeting a weight gain criterion of ≥ 7% of body weight

were compared in a pool of four 4- and 6-week placebo-controlled schizophrenia clinical trials,

revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared

to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no

median weight change in placebo patients. In this set of clinical trials, weight gain was reported as an

adverse reaction in 0.4% and 0.4% of ziprasidone and placebo patients, respectively. During long-term

therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI)

revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (> 7%

of body weight) in patients with low BMI (<23) compared to normal (23–27) or overweight patients

(>27). There was a mean weight gain of 1.4 kg for those patients with a "low" baseline BMI, no mean

Fasting

*

Note that in the High Dose group, there were 2 subjects with modal 200 mg total daily dose and 1 subject with

modal 100 mg total daily dose.

change for patients with a "normal" BMI, and a 1.3 kg mean weight loss for patients who entered the

program with a "high" BMI.

Bipolar Disorder – During a 6-month placebo-controlled bipolar maintenance study in adults with

ziprasidone as an adjunct to lithium or valproate, the incidence of clinically significant weight gain (≥

7% of body weight) during the double-blind period was 5.6% for both ziprasidone and placebo

treatment groups who completed the 6 months of observation for relapse. Interpretation of these

findings should take into consideration that only patients who adequately tolerated ziprasidone entered

the double-blind phase of the study, and there were substantial dropouts during the open label phase.

5.7 Rash

In premarketing trials with ziprasidone, about 5% of patients developed rash and/or urticaria, with

discontinuation of treatment in about one-sixth of these cases. The occurrence of rash was related to

dose of ziprasidone, although the finding might also be explained by the longer exposure time in the

higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness,

e.g., elevated WBCs. Most patients improved promptly with adjunctive treatment with antihistamines or

steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these reactions were

reported to recover completely. Upon appearance of rash for which an alternative etiology cannot be

identified, ziprasidone should be discontinued.

5.8 Orthostatic Hypotension

Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some

patients, syncope, especially during the initial dose-titration period, probably reflecting its α -

adrenergic antagonist properties. Syncope was reported in 0.6% of the patients treated with ziprasidone.

Ziprasidone should be used with particular caution in patients with known cardiovascular disease

(history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities),

cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration,

hypovolemia, and treatment with antihypertensive medications).

5.9 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported

temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been

reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count

(WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a

history of drug induced leukopenia/neutropenia should have their complete blood count (CBC)

monitored frequently during the first few months of therapy and should discontinue ziprasidone at the

first sign of decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of

infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia

(absolute neutrophil count <1000/mm3) should discontinue ziprasidone and have their WBC followed

until recovery.

5.10 Seizures

During clinical trials, seizures occurred in 0.4% of patients treated with ziprasidone. There were

confounding factors that may have contributed to the occurrence of seizures in many of these cases. As

with other antipsychotic drugs, ziprasidone should be used cautiously in patients with a history of

seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia.

Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.11 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration

pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with

advanced Alzheimer's dementia. Ziprasidone and other antipsychotic drugs should be used cautiously in

patients at risk for aspiration pneumonia [see Boxed Warning].

5.12 Hyperprolactinemia

As with other drugs that antagonize dopamine D receptors, ziprasidone elevates prolactin levels in

humans. Increased prolactin levels were also observed in animal studies with this compound, and were

associated with an increase in mammary gland neoplasia in mice; a similar effect was not observed in

rats [see Nonclinical Toxicology (13.1)]. Tissue culture experiments indicate that approximately one-third

of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the

prescription of these drugs is contemplated in a patient with previously detected breast cancer. Neither

clinical studies nor epidemiologic studies conducted to date have shown an association between

chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is

considered too limited to be conclusive at this time.

Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been

reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin

levels is unknown for most patients. Long-standing hyperprolactinemia when associated with

hypogonadism may lead to decreased bone density.

5.13 Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction in patients treated with ziprasidone. In the 4- and

6-week placebo-controlled trials, somnolence was reported in 14% of patients on ziprasidone

compared to 7% of placebo patients. Somnolence led to discontinuation in 0.3% of patients in short-term

clinical trials. Since ziprasidone has the potential to impair judgment, thinking, or motor skills, patients

should be cautioned about performing activities requiring mental alertness, such as operating a motor

vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that

ziprasidone therapy does not affect them adversely.

5.14 Priapism

One case of priapism was reported in the premarketing database. While the relationship of the reaction

to ziprasidone use has not been established, other drugs with alpha-adrenergic blocking effects have

been reported to induce priapism, and it is possible that ziprasidone may share this capacity. Severe

priapism may require surgical intervention.

5.15 Body Temperature Regulation

Although not reported with ziprasidone in premarketing trials, disruption of the body's ability to reduce

core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when

prescribing ziprasidone for patients who will be experiencing conditions which may contribute to an

elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving

concomitant medication with anticholinergic activity, or being subject to dehydration.

5.16 Suicide

The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder, and close

supervision of high-risk patients should accompany drug therapy. Prescriptions for ziprasidone should

be written for the smallest quantity of capsules consistent with good patient management in order to

reduce the risk of overdose.

5.17 Patients with concomitant illnesses

Clinical experience with ziprasidone in patients with certain concomitant systemic illnesses is limited

[see Use in Specific Populations (8.6), (8.7)].

Ziprasidone has not been evaluated or used to any appreciable extent in patients with a recent history of

myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from

premarketing clinical studies. Because of the risk of QTc prolongation and orthostatic hypotension with

ziprasidone, caution should be observed in cardiac patients [see Warnings and Precautions (5.2), (5.8)].

5.18 Laboratory Tests

Patients being considered for ziprasidone treatment that are at risk of significant electrolyte

disturbances should have baseline serum potassium and magnesium measurements. Low serum

potassium and magnesium should be replaced before proceeding with treatment. Patients who are started

on diuretics during ziprasidone therapy need periodic monitoring of serum potassium and magnesium.

Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements

>500 msec [see Warnings and Precautions (5.2)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

Clinical trials for oral ziprasidone included approximately 5700 patients and/or normal subjects exposed

to one or more doses of ziprasidone. Of these 5700, over 4800 were patients who participated in

multiple-dose effectiveness trials, and their experience corresponded to approximately 1831 patient-

years. These patients include: (1) 4331 patients who participated in multiple-dose trials, predominantly

in schizophrenia, representing approximately 1698 patient-years of exposure as of February 5, 2000;

and (2) 472 patients who participated in bipolar mania trials representing approximately 133 patient-years

of exposure. An additional 127 patients with bipolar disorder participated in a long-term maintenance

treatment study representing approximately 74.7 patient-years of exposure to ziprasidone. The

conditions and duration of treatment with ziprasidone included open-label and double-blind studies,

inpatient and outpatient studies, and short-term and longer-term exposure.

Adverse reactions during exposure were obtained by collecting voluntarily reported adverse

experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses,

ECGs, and results of ophthalmologic examinations.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at

least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment

emergent if it occurred for the first time or worsened while receiving therapy following baseline

evaluation.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials with Oral Ziprasidone

The following findings are based on the short-term placebo-controlled premarketing trials for

schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of

two 3-week flexible-dose trials) in which ziprasidone was administered in doses ranging from 10 to

200 mg/day.

Commonly Observed Adverse Reactions in Short Term-Placebo-Controlled Trials

The following adverse reactions were the most commonly observed adverse reactions associated with

the use of ziprasidone (incidence of 5% or greater) and not observed at an equivalent incidence among

placebo-treated patients (ziprasidone incidence at least twice that for placebo):

Schizophrenia trials (see Table 11)

Somnolence

Respiratory Tract Infection

Bipolar trials (see Table 12)

Somnolence

Extrapyramidal Symptoms which includes the following adverse reaction terms: extrapyramidal

syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of

these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania

trials.

Dizziness which includes the adverse reaction terms dizziness and lightheadedness.

Akathisia

Abnormal Vision

Asthenia

Vomiting

SCHIZOPHRENIA

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-

Controlled Trials of Oral Ziprasidone

Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies

discontinued treatment due to an adverse reaction, compared with about 2.2% (6/273) on placebo. The

most common reaction associated with dropout was rash, including 7 dropouts for rash among

ziprasidone patients (1%) compared to no placebo patients [see Warnings and Precautions (5.7)].

Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated

Patients in Short-Term, Oral, Placebo-Controlled Trials

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse

reactions that occurred during acute therapy (up to 6 weeks) in predominantly patients with

schizophrenia, including only those reactions that occurred in 2% or more of patients treated with

ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the

incidence in placebo-treated patients.

Table 11: Treatment-Emergent Adverse Reaction Incidence In Short-Term

Oral Placebo-Controlled Trials – Schizophrenia

Percentage of Patients Reporting Reaction

Body System/Adverse

Reaction

Zipras idone

(N=702)

Placebo

(N=273)

Body as a Whole

Asthenia

Accidental Injury

Chest Pain

Cardiovas cular

Tachycardia

Diges tive

Nausea

Constipation

Dyspepsia

Diarrhea

Dry Mouth

Anorexia

Nervous

Extrapyramidal Symptoms

Somnolence

Akathisia

Dizziness

Res piratory

Respiratory Tract Infection

Rhinitis

Cough Increased

Skin and Appendages

Rash

Fungal Dermatitis

Special Senses

Abnormal Vision

Dose Dependency of Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials

An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of

adverse reaction to dose for the following reactions: asthenia, postural hypotension, anorexia, dry

mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor,

rhinitis, rash, and abnormal vision.

Extrapyramidal Symptoms (EPS) - The incidence of reported EPS (which included the adverse

reaction terms extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis

and twitching) for ziprasidone-treated patients in the short-term, placebo-controlled schizophrenia trials

was 14% vs. 8% for placebo. Objectively collected data from those trials on the Simpson-Angus Rating

Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference

between ziprasidone and placebo.

Dystonia - Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may

occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include:

spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty,

difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses,

they occur more frequently and with greater severity with high potency and at higher doses of first

generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age

groups.

Vital Sign Changes - Ziprasidone is associated with orthostatic hypotension [see Warnings and

Precautions (5.8)]

ECG Changes - Ziprasidone is associated with an increase in the QTc interval [see Warnings and

Precautions (5.2)]. In the schizophrenia trials, ziprasidone was associated with a mean increase in heart

rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients.

Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Ziprasidone

Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in

the introduction to the ADVERSE REACTIONS section reported by patients treated with ziprasidone

in schizophrenia trials at multiple doses >4 mg/day within the database of 3834 patients. All reported

reactions are included except those already listed in Table 11 or elsewhere in labeling, those reaction

terms that were so general as to be uninformative, reactions reported only once and that did not have a

substantial probability of being acutely life-threatening, reactions that are part of the illness being

Extrapyramidal Symptoms includes the following adverse reaction terms: extrapyramidal

syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching.

None of these adverse reactions occurred individually at an incidence greater than 5% in

schizophrenia trials.

Dizziness includes the adverse reaction terms dizziness and lightheadedness.

treated or are otherwise common as background reactions, and reactions considered unlikely to be drug-

related. It is important to emphasize that, although the reactions reported occurred during treatment with

ziprasidone, they were not necessarily caused by it.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency

according to the following definitions:

Frequent - adverse reactions occurring in at least 1/100 patients (≥1.0% of patients) (only those not

already listed in the tabulated results from placebo-controlled trials appear in this listing);

Infrequent - adverse reactions occurring in 1/100 to 1/1000 patients (in 0.1–1.0% of patients)

Rare – adverse reactions occurring in fewer than 1/1000 patients (<0.1% of patients).

Body as a Whole

Frequent

abdominal pain, flu syndrome, fever, accidental fall, face edema,

chills, photosensitivity reaction, flank pain, hypothermia, motor

vehicle accident

Cardiovascular System

Frequent

tachycardia, hypertension, postural hypotension

Infrequent

bradycardia, angina pectoris, atrial fibrillation

Rare

first degree AV block, bundle branch block, phlebitis, pulmonary

embolus, cardiomegaly, cerebral infarct, cerebrovascular accident,

deep thrombophlebitis, myocarditis, thrombophlebitis

Digestive System

Frequent

anorexia, vomiting

Infrequent

rectal hemorrhage, dysphagia, tongue edema

Rare

gum hemorrhage, jaundice, fecal impaction, gamma glutamyl

transpeptidase increased, hematemesis, cholestatic jaundice, hepatitis,

hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena

Endocrine

Rare

hypothyroidism, hyperthyroidism, thyroiditis

Hemic and Lymphatic System

Infrequent

anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia,

lymphadenopathy

Rare

thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis,

basophilia, lymphedema, polycythemia, thrombocythemia

Metabolic and Nutritional Disorders

Infrequent

thirst, transaminase increased, peripheral edema, hyperglycemia,

creatine phosphokinase increased, alkaline phosphatase increased,

hypercholesteremia, dehydration, lactic dehydrogenase increased,

albuminuria, hypokalemia

Rare

BUN increased, creatinine increased, hyperlipemia,

hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia,

hyponatremia, hypoproteinemia, glucose tolerance decreased, gout,

hyperchloremia, hyperuricemia, hypocalcemia,

hypoglycemicreaction, hypomagnesemia, ketosis, respiratory

alkalosis

Musculoskeletal System

Frequent

myalgia

Infrequent

tenosynovitis

Rare

myopathy

Nervous System

Frequent

agitation, extrapyramidal syndrome, tremor, dystonia, hypertonia,

dyskinesia, hostility, twitching, paresthesia, confusion, vertigo,

hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis,

hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia,

akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome,

choreoathetosis, diplopia, incoordination, neuropathy

Infrequent

paralysis

Rare

myoclonus, nystagmus, torticollis, circumoral paresthesia,

opisthotonos, reflexes increased, trismus

Respiratory System

Frequent

dyspnea

Infrequent

pneumonia, epistaxis

Rare

hemoptysis, laryngismus

Skin and Appendages

Infrequent

maculopapular rash, urticaria, alopecia, eczema, exfoliative

dermatitis, contact dermatitis, vesiculobullous rash

Special Senses

Frequent

fungal dermatitis

Infrequent

conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia

Rare

eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis

Urogenital System

Infrequent

impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia,

female lactation, polyuria, urinary retention metrorrhagia, male sexual

dysfunction, anorgasmia, glycosuria

Rare

gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual

dysfunction, uterine hemorrhage

BIPOLAR DISORDER

Acute Treatment of Manic or Mixed Episodes

Adverse Reactions Associated with Discontinuation of Treatment in Short Term, Placebo-

Controlled Trials

Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies

discontinued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The

most common reactions associated with dropout in the ziprasidone-treated patients were akathisia,

anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these reactions

among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no

placebo patients for the remaining adverse reactions.

Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated

Patients in Short-Term, Oral, Placebo-Controlled Trials

Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse

reactions that occurred during acute therapy (up to 3 weeks) in patients with bipolar mania, including

only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the

incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.

Table 12: Treatment-Emergent Adverse Reactions Incidence In Short-Term

Oral Placebo-Controlled Trials – Manic and Mixed Episodes Associated with

Bipolar Disorder

Percentage of Patients Reporting Reaction

Body System/Adverse

Reaction

Zipras idone

(N=279)

Placebo

(N=136)

Body as a Whole

Headache

Asthenia

Accidental Injury

Cardiovas cular

Hypertension

Diges tive

Nausea

Diarrhea

Dry Mouth

Vomiting

Increased Salivation

Tongue Edema

Dysphagia

Mus culos keletal

Myalgia

Nervous

Somnolence

Extrapyramidal Symptoms

Dizziness

Akathisia

Anxiety

Hypesthesia

Speech Disorder

Res piratory

Pharyngitis

Dyspnea

Skin and Appendages

Fungal Dermatitis

Special Senses

Abnormal Vision

Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences

in the adverse reaction occurrence on the basis of this demographic factor.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ziprasidone. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reaction reports not listed above that have been received since market introduction include rare

occurrences of the following : Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of

multiple confounding factors), [see Warnings and Precautions (5.2)]; Digestive System Disorders: Swollen

Tongue; Reproductive System and Breast Disorders: Galactorrhea, priapism; Nervous System Disorders:

Facial Droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with

serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania;

Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema,

orofacial edema, urticaria), rash, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS);

Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension,

syncope.

7 DRUG INTERACTIONS

Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic

(alteration of plasma levels). The risks of using ziprasidone in combination with other drugs have been

evaluated as described below. All interactions studies have been conducted with oral ziprasidone.

Based upon the pharmacodynamic and pharmacokinetic profile of ziprasidone, possible interactions

could be anticipated:

7.1 Metabolic Pathway

Approximately two-thirds of ziprasidone is metabolized via a combination of chemical reduction by

glutathione and enzymatic reduction by aldehyde oxidase. There are no known clinically relevant

inhibitors or inducers of aldehyde oxidase. Less than one-third of ziprasidone metabolic clearance is

mediated by cytochrome P450 catalyzed oxidation.

7.2 In Vitro Studies

An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little

inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely

interfere with the metabolism of drugs primarily metabolized by these enzymes. There is little potential

for drug interactions with ziprasidone due to displacement [see Clinical Pharmacology (12.3)].

Extrapyramidal Symptoms includes the following adverse reaction terms: extrapyramidal

syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching.

None of these adverse reactions occurred individually at an incidence greater than 10% in

bipolar mania trials.

Dizziness includes the adverse reaction terms dizziness and lightheadedness.

7.3 Pharmacodynamic Interactions

Ziprasidone should not be used with any drug that prolongs the QT interval [see Contraindications (4.1)].

Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination

with other centrally acting drugs.

Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain

antihypertensive agents.

Ziprasidone may antagonize the effects of levodopa and dopamine agonists.

7.4 Pharmacokinetic Interactions

Carbamazepine

Carbamazepine is an inducer of CYP3A4; administration of 200 mg twice daily for 21 days resulted in a

decrease of approximately 35% in the AUC of ziprasidone. This effect may be greater when higher

doses of carbamazepine are administered.

Ketoconazole

Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the AUC

and Cmax of ziprasidone by about 35–40%. Other inhibitors of CYP3A4 would be expected to have

similar effects.

Cimetidine

Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics.

Antacid

The co-administration of 30 mL of Maalox® with ziprasidone did not affect the pharmacokinetics of

ziprasidone.

7.5 Lithium

Ziprasidone at a dose of 40 mg twice daily administered concomitantly with lithium at a dose of 450 mg

twice daily for 7 days did not affect the steady-state level or renal clearance of lithium. Ziprasidone

dosed adjunctively to lithium in a maintenance trial of bipolar patients did not affect mean therapeutic

lithium levels.

7.6 Oral Contraceptives

In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of estrogen or

progesterone components. Ziprasidone at a dose of 20 mg twice daily did not affect the

pharmacokinetics of concomitantly administered oral contraceptives, ethinyl estradiol (0.03 mg) and

levonorgestrel (0.15 mg).

7.7 Dextromethorphan

Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not

alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite,

dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan

ratio.

7.8 Valproate

A pharmacokinetic interaction of ziprasidone with valproate is unlikely due to the lack of common

metabolic pathways for the two drugs. Ziprasidone dosed adjunctively to valproate in a maintenance trial

of bipolar patients did not affect mean therapeutic valproate levels.

7.9 Other Concomitant Drug Therapy

Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has

not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine,

propranolol, or lorazepam.

7.10 Food Interaction

The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The

absorption of ziprasidone is increased up to two-fold in the presence of food [see Clinical

Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

In animal studies ziprasidone demonstrated developmental toxicity, including possible teratogenic

effects at doses similar to human therapeutic doses. When ziprasidone was administered to pregnant

rabbits during the period of organogenesis, an increased incidence of fetal structural abnormalities

(ventricular septal defects and other cardiovascular malformations and kidney alterations) was observed

at a dose of 30 mg/kg/day (3 times the MRHD of 200 mg/day on a mg/m basis). There was no evidence

to suggest that these developmental effects were secondary to maternal toxicity. The developmental no-

effect dose was 10 mg/kg/day (equivalent to the MRHD on a mg/m basis). In rats, embryofetal toxicity

(decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to

160 mg/kg/day (0.5 to 8 times the MRHD on a mg/m basis) during organogenesis or throughout

gestation, but there was no evidence of teratogenicity. Doses of 40 and 160 mg/kg/day (2 and 8 times

the MRHD on a mg/m basis) were associated with maternal toxicity. The developmental no-effect dose

was 5 mg/kg/day (0.2 times the MRHD on a mg/m basis).

There was an increase in the number of pups born dead and a decrease in postnatal survival through the

first 4 days of lactation among the offspring of female rats treated during gestation and lactation with

doses of 10 mg/kg/day (0.5 times the MRHD on a mg/m basis) or greater. Offspring developmental

delays and neurobehavioral functional impairment were observed at doses of 5 mg/kg/day (0.2 times the

MRHD on a mg/m basis) or greater. A no-effect level was not established for these effects.

There are no adequate and well-controlled studies in pregnant women. Ziprasidone should be used

during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for

extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation,

hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.

These complications have varied in severity; while in some cases symptoms have been self-limited, in

other cases neonates have required intensive care unit support and prolonged hospitalization.

Ziprasidone should be used during pregnancy only if the potential benefit justifies the potential risk to

the fetus.

8.2 Labor and Delivery

The effect of ziprasidone on labor and delivery in humans is unknown.

8.3 Nursing Mothers

It is not known whether ziprasidone or its metabolites are excreted in human milk. It is recommended that

women receiving ziprasidone should not breastfeed.

8.4 Pediatric Use

The safety and effectiveness of ziprasidone in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over. No

overall differences in safety or effectiveness were observed between these subjects and younger

subjects, and other reported clinical experience has not identified differences in responses between the

elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to

ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting

dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients.

8.6 Renal Impairment

Because ziprasidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal

impairment alone is unlikely to have a major impact on the pharmacokinetics of ziprasidone. The

pharmacokinetics of ziprasidone following 8 days of 20 mg twice daily dosing were similar among

subjects with varying degrees of renal impairment (n=27), and subjects with normal renal function,

indicating that dosage adjustment based upon the degree of renal impairment is not required. Ziprasidone

is not removed by hemodialysis.

8.7 Hepatic Impairment

As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be

expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg twice daily for 5 days in

subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in

of 13% and 34% in Childs-Pugh Class A and B, respectively, compared to a matched control

group (n=14). A half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in

the control group.

8.8 Age and Gender Effects

In a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference in the

pharmacokinetics of ziprasidone between men and women or between elderly (>65 years) and young (18

to 45 years) subjects. Additionally, population pharmacokinetic evaluation of patients in controlled trials

has revealed no evidence of clinically significant age or gender-related differences in the

pharmacokinetics of ziprasidone. Dosage modifications for age or gender are, therefore, not

recommended.

8.9 Smoking

Based on in vitro studies utilizing human liver enzymes, ziprasidone is not a substrate for CYP1A2;

smoking should therefore not have an effect on the pharmacokinetics of ziprasidone. Consistent with

these in vitro results, population pharmacokinetic evaluation has not revealed any significant

pharmacokinetic differences between smokers and nonsmokers.

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

Ziprasidone has not been systematically studied, in animals or humans, for its potential for abuse,

tolerance, or physical dependence. While the clinical trials did not reveal any tendency for drug-

0–12

seeking behavior, these observations were not systematic and it is not possible to predict on the basis of

this limited experience the extent to which ziprasidone will be misused, diverted, and/or abused once

marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such

patients should be observed closely for signs of ziprasidone misuse or abuse (e.g., development of

tolerance, increases in dose, drug-seeking behavior).

10 OVERDOSAGE

10.1 Human Experience

In premarketing trials involving more than 5400 patients and/or normal subjects, accidental or intentional

overdosage of oral ziprasidone was documented in 10 patients. All of these patients survived without

sequelae. In the patient taking the largest confirmed amount, 3,240 mg, the only symptoms reported were

minimal sedation, slurring of speech, and transitory hypertension (200/95).

Adverse reactions reported with ziprasidone overdose included extrapyramidal symptoms, somnolence,

tremor, and anxiety. [see Adverse Reactions (6.2)]

10.2 Management of Overdosage

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and

ventilation. Intravenous access should be established, and gastric lavage (after intubation, if patient is

unconscious) and administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizure, or dystonic reaction of the head and neck following overdose

may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately and should include continuous

electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is

administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-

prolonging effects that might be additive to those of ziprasidone.

Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous

fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not

be used, since beta stimulation combined with α antagonism associated with ziprasidone may worsen

hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of

bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.

In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. There

is no specific antidote to ziprasidone, and it is not dialyzable. The possibility of multiple drug

involvement should be considered. Close medical supervision and monitoring should continue until the

patient recovers.

11 DESCRIPTION

Ziprasidone is available as capsules (ziprasidone hydrochloride) for oral administration. Ziprasidone is

a psychotropic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic

agents. It has a molecular weight of 412.94 (free base), with the following chemical name: 5-[2-[4-(1,2-

benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one. The empirical formula

of C

H ClN OS (free base of ziprasidone) represents the following structural formula:

Ziprasidone capsules contain a monohydrochloride, monohydrate salt of ziprasidone. Chemically,

ziprasidone hydrochloride monohydrate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-

chloro-1,3-dihydro-2H-indol-2-one, monohydrochloride, monohydrate. The empirical formula is

H ClN OS · HCl · H O and its molecular weight is 467.42. Ziprasidone hydrochloride

monohydrate is a white to slightly pink powder.

Ziprasidone capsules are supplied for oral administration in 20 mg (blue/white), 40 mg (blue/blue), 60

mg (white/white), and 80 mg (blue/white) capsules. Ziprasidone capsules contain ziprasidone

hydrochloride monohydrate, lactose, pregelatinized starch, and magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is

unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through

a combination of dopamine type 2 (D ) and serotonin type 2 (5HT ) antagonism. As with other drugs

having efficacy in bipolar disorder, the mechanism of action of ziprasidone in bipolar disorder is

unknown.

12.2 Pharmacodynamics

Ziprasidone exhibited high in vitro binding affinity for the dopamine D and D , the serotonin 5HT

, 5HT

, 5HT

, and α -adrenergic receptors (K s of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM,

respectively), and moderate affinity for the histamine H receptor (K =47 nM). Ziprasidone functioned

as an antagonist at the D 5HT

, and 5HT

receptors, and as an agonist at the 5HT

receptor.

Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was

exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC

>1

µM). Antagonism at receptors other than dopamine and 5HT with similar receptor affinities may

explain some of the other therapeutic and side effects of ziprasidone. Ziprasidone's antagonism of

histamine H receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism

of α -adrenergic receptors may explain the orthostatic hypotension observed with this drug.

12.3 Pharmacokinetics

Oral Pharmacokinetics

Ziprasidone's activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of

ziprasidone are dose-proportional within the proposed clinical dose range, and ziprasidone

accumulation is predictable with multiple dosing. Elimination of ziprasidone is mainly via hepatic

metabolism with a mean terminal half-life of about 7 hours within the proposed clinical dose range.

Steady-state concentrations are achieved within one to three days of dosing. The mean apparent

systemic clearance is 7.5 mL/min/kg. Ziprasidone is unlikely to interfere with the metabolism of drugs

metabolized by cytochrome P450 enzymes.

Absorption: Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations

in 6 to 8 hours. The absolute bioavailability of a 20 mg dose under fed conditions is approximately

60%. The absorption of ziprasidone is increased up to two-fold in the presence of food.

Distribution: Ziprasidone has a mean apparent volume of distribution of 1.5 L/kg. It is greater than 99%

bound to plasma proteins, binding primarily to albumin and α -acid glycoprotein. The in vitro plasma

protein binding of ziprasidone was not altered by warfarin or propranolol, two highly protein-bound

drugs, nor did ziprasidone alter the binding of these drugs in human plasma. Thus, the potential for drug

interactions with ziprasidone due to displacement is minimal.

Metabolism and Elimination: Ziprasidone is extensively metabolized after oral administration with only a

small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug. Ziprasidone is primarily

cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole (BITP)

sulphoxide, BITP-sulphone, ziprasidone sulphoxide, and S-methyl dihydroziprasidone. Approximately

20% of the dose is excreted in the urine, with approximately 66% being eliminated in the feces.

Unchanged ziprasidone represents about 44% of total drug-related material in serum. In vitro studies

using human liver subcellular fractions indicate that S-methyldihydroziprasidone is generated in two

steps. These studies indicate that the reduction reaction is mediated primarily by chemical reduction by

glutathione as well as by enzymatic reduction by aldehyde oxidase and the subsequent methylation is

mediated by thiol methyltransferase. In vitro studies using human liver microsomes and recombinant

enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of

ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of excretory

metabolites, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450

catalyzed oxidation and approximately two-thirds via reduction. There are no known clinically relevant

inhibitors or inducers of aldehyde oxidase.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenes is

Lifetime carcinogenicity studies were conducted with ziprasidone in Long Evans rats and CD-1 mice.

Ziprasidone was administered for 24 months in the diet at doses of 2, 6, or 12 mg/kg/day to rats, and 50,

100, or 200 mg/kg/day to mice (0.1 to 0.6 and 1 to 5 times the maximum recommended human dose

[MRHD] of 200 mg/day on a mg/m basis, respectively). In the rat study, there was no evidence of an

increased incidence of tumors compared to controls. In male mice, there was no increase in incidence of

tumors relative to controls. In female mice, there were dose-related increases in the incidences of

pituitary gland adenoma and carcinoma, and mammary gland adenocarcinoma at all doses tested (50 to

200 mg/kg/day or 1 to 5 times the MRHD on a mg/m basis). Proliferative changes in the pituitary and

mammary glands of rodents have been observed following chronic administration of other antipsychotic

agents and are considered to be prolactin-mediated. Increases in serum prolactin were observed in a 1-

month dietary study in female, but not male, mice at 100 and 200 mg/kg/day (or 2.5 and 5 times the

MRHD on a mg/m basis). Ziprasidone had no effect on serum prolactin in rats in a 5-week dietary study

at the doses that were used in the carcinogenicity study. The relevance for human risk of the findings of

prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.12)].

Mutagenes is

Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro mammalian cell gene mutation

mouse lymphoma assay, the in vitro chromosomal aberration assay in human lymphocytes, and the in vivo

chromosomal aberration assay in mouse bone marrow. There was a reproducible mutagenic response in

the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Positive results

were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal

aberration assay in human lymphocytes.

Impairment of Fertility

Ziprasidone was shown to increase time to copulation in Sprague-Dawley rats in two fertility and early

embryonic development studies at doses of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD of 200

mg/day on a mg/m basis). Fertility rate was reduced at 160 mg/kg/day (8 times the MRHD on a mg/m

basis). There was no effect on fertility at 40 mg/kg/day (2 times the MRHD on a mg/m basis). The

effect on fertility appeared to be in the female since fertility was not impaired when males given 160

mg/kg/day (8 times the MRHD on a mg/m basis) were mated with untreated females. In a 6-month study

in male rats given 200 mg/kg/day (10 times the MRHD on a mg/m basis) there were no treatment-related

findings observed in the testes.

14 CLINICAL STUDIES

14.1 Schizophrenia

The efficacy of oral ziprasidone in the treatment of schizophrenia was evaluated in 5 placebo-

controlled studies, 4 short-term (4- and 6-week) trials and one maintenance trial. All trials were in adult

inpatients, most of whom met DSM III-R criteria for schizophrenia. Each study included 2 to 3 fixed

doses of ziprasidone as well as placebo. Four of the 5 trials were able to distinguish ziprasidone from

placebo; one short-term study did not. Although a single fixed-dose haloperidol arm was included as a

comparative treatment in one of the three short-term trials, this single study was inadequate to provide a

reliable and valid comparison of ziprasidone and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies. The Brief

Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) are both

multi-item inventories of general psychopathology usually used to evaluate the effects of drug

treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory

behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for

assessing actively psychotic schizophrenic patients. A second widely used assessment, the Clinical

Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the

manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for

Assessing Negative Symptoms (SANS) was employed for assessing negative symptoms in one trial.

The results of the oral ziprasidone trials in schizophrenia follow:

In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone (20 and 60 mg

twice daily) with placebo, only the 60 mg dose was superior to placebo on the BPRS total score and

the CGI severity score. This higher dose group was not superior to placebo on the BPRS psychosis

cluster or on the SANS.

In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone (40 and 80 mg

twice daily) with placebo, both dose groups were superior to placebo on the BPRS total score, the

BPRS psychosis cluster, the CGI severity score and the PANSS total and negative subscale scores.

Although 80 mg twice daily had a numerically greater effect than 40 mg twice daily, the difference

was not statistically significant.

In a 6-week, placebo-controlled trial (n=419) comparing 3 fixed doses of ziprasidone (20, 60, and

100 mg twice daily) with placebo, all three dose groups were superior to placebo on the PANSS

total score, the BPRS total score, the BPRS psychosis cluster, and the CGI severity score. Only the

100 mg twice daily dose group was superior to placebo on the PANSS negative subscale score.

There was no clear evidence for a dose-response relationship within the 20 mg twice daily to 100

mg twice daily dose range.

In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone (5, 20, and 40

mg twice daily), none of the dose groups was statistically superior to placebo on any outcome of

interest.

A study was conducted in stable chronic or subchronic (CGI-S ≤5 at baseline) schizophrenic

inpatients (n=294) who had been hospitalized for not less than two months. After a 3-day single-blind

placebo run-in, subjects were randomized to one of 3 fixed doses of ziprasidone (20 mg, 40 mg, or

80 mg twice daily) or placebo and observed for relapse. Patients were observed for "impending

psychotic relapse," defined as CGI-improvement score of ≥6 (much worse or very much worse)

and/or scores ≥6 (moderately severe) on the hostility or uncooperativeness items of the PANSS on

two consecutive days. Ziprasidone was significantly superior to placebo in time to relapse, with no

significant difference between the different dose groups. There were insufficient data to examine

population subsets based on age and race. Examination of population subsets based on gender did not

reveal any differential responsiveness.

14.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an

Adjunct to Lithium or Valproate)

Acute Manic and Mixed Episodes Associated with Bipolar I Disorder

The efficacy of ziprasidone was established in 2 placebo-controlled, double-blind, 3-week

monotherapy studies in patients meeting DSM-IV criteria for bipolar I disorder, manic or mixed episode

with or without psychotic features. Primary rating instruments used for assessing manic symptoms in

these trials were: (1) the Mania Rating Scale (MRS), which is derived from the Schedule for Affective

Disorders and Schizophrenia-Change Version (SADS-CB) with items grouped as the Manic Syndrome

subscale (elevated mood, less need for sleep, excessive energy, excessive activity, grandiosity), the

Behavior and Ideation subscale (irritability, motor hyperactivity, accelerated speech, racing thoughts,

poor judgment) and impaired insight; and (2) the Clinical Global Impression-Severity of Illness Scale

(CGI-S), which was used to assess the clinical significance of treatment response.

The results of the oral ziprasidone trials in adult bipolar I disorder, manic/mixed episode follow: in a 3-

week placebo-controlled trial (n=210), the dose of ziprasidone was 40 mg twice daily on Day 1 and 80

mg twice daily on Day 2. Titration within the range of 40–80 mg twice daily (in 20 mg twice daily

increments) was permitted for the duration of the study. Ziprasidone was significantly more effective

than placebo in reduction of the MRS total score and the CGI-S score. The mean daily dose of

ziprasidone in this study was 132 mg. In a second 3-week placebo-controlled trial (n=205), the dose of

ziprasidone was 40 mg twice daily on Day 1. Titration within the range of 40–80 mg twice daily (in 20

mg twice daily increments) was permitted for the duration of study (beginning on Day 2). Ziprasidone

was significantly more effective than placebo in reduction of the MRS total score and the CGI-S score.

The mean daily dose of ziprasidone in this study was 112 mg.

Maintenance Therapy

The efficacy of ziprasidone as adjunctive therapy to lithium or valproate in the maintenance treatment of

bipolar I disorder was established in a placebo-controlled trial in patients who met DSM-IV criteria for

bipolar I disorder. The trial included patients whose most recent episode was manic or mixed, with or

without psychotic features. In the open-label phase, patients were required to be stabilized on

ziprasidone plus lithium or valproic acid for at least 8 weeks in order to be randomized. In the double-

blind randomized phase, patients continued treatment with lithium or valproic acid and were randomized

to receive either ziprasidone (administered twice daily totaling 80 mg to 160 mg per day) or placebo.

Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized

during the stabilization phase. The primary endpoint in this study was time to recurrence of a mood

episode (manic, mixed or depressed episode) requiring intervention, which was defined as any of the

following: discontinuation due to a mood episode, clinical intervention for a mood episode (e.g.,

initiation of medication or hospitalization), or Mania Rating Scale score ≥ 18 or a MADRS score ≥18

(on 2 consecutive assessments no more than 10 days apart). A total of 584 subjects were treated in the

open-label stabilization period. In the double-blind randomization period, 127 subjects were treated with

ziprasidone, and 112 subjects were treated with placebo. Ziprasidone was superior to placebo in

increasing the time to recurrence of a mood episode. The types of relapse events observed included

depressive, manic, and mixed episodes. Depressive, manic, and mixed episodes accounted for 53%,

34%, and 13%, respectively, of the total number of relapse events in the study.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ziprasidone 40mg capsules

NDC 59762-2002-1 bottle of 60

NDC 69189-2003-1 single dose pack with 1 capsule as repackaged by Avera McKennan Hospital

Ziprasidone capsules should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to

86°F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (17.4).

Please refer to the patient package insert. To assure safe and effective use of ziprasidone, the

information and instructions provided in the patient information should be discussed with patients.

17.1 Administration with Food

Patients should be instructed to take ziprasidone capsules with food for optimal absorption. The

absorption of ziprasidone is increased up to two-fold in the presence of food [see Drug Interactions

(7.8) and Clinical Pharmacology (12.3)].

17.2 QTc Prolongation

Patients should be advised to inform their health care providers of the following: History of QT

prolongation; recent acute myocardial infarction; uncompensated heart failure; prescription of other

drugs that have demonstrated QT prolongation; risk for significant electrolyte abnormalities; and history

of cardiac arrhythmia [see Contraindications (4.1) and Warnings and Precautions (5.2)].

Patients should be instructed to report the onset of any conditions that put them at risk for significant

electrolyte disturbances, hypokalemia in particular, including but not limited to the initiation of diuretic

therapy or prolonged diarrhea. In addition, patients should be instructed to report symptoms such as

dizziness, palpitations, or syncope to the prescriber [see Warnings and Precautions (5.2)].

17.3 Severe Cutaneous Adverse Reactions

Patients should be instructed to report to their health care provider at the earliest onset any signs or

symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms

(DRESS) or with severe cutaneous adverse reactions, such as Stevens-Johnson syndrome [see Warnings

and Precautions (5.4)].

17.4 FDA-Approved Patient Labeling

LAB-0549-6.0

PATIENT SUMMARY OF INFORMATION ABOUT

Ziprasidone Capsules

(ziprasidone HCl)

Information for patients taking ziprasidone or their caregivers

This summary contains important information about ziprasidone. It is not meant to take the place of your

doctor's instructions. Read this information carefully before you take ziprasidone. Ask your doctor or

pharmacist if you do not understand any of this information or if you want to know more about

ziprasidone.

What Is ziprasidone?

Ziprasidone is a type of prescription medicine called a psychotropic, also known as an atypical

antipsychotic. Ziprasidone can be used to treat symptoms of schizophrenia and acute manic or mixed

episodes associated with bipolar disorder. Ziprasidone can also be used as maintenance treatment of

bipolar disorder when added to lithium or valproate.

Who Should Take ziprasidone?

Only your doctor can know if ziprasidone is right for you. ziprasidone may be prescribed for you if you

have schizophrenia or bipolar disorder.

Symptoms of schizophrenia may include:

hearing voices, seeing things, or sensing things that are not there (hallucinations)

beliefs that are not true (delusions)

unusual suspiciousness (paranoia)

becoming withdrawn from family and friends

Symptoms of manic or mixed episodes of bipolar disorder may include:

extremely high or irritable mood

increased energy, activity, and restlessness

racing thoughts or talking very fast

easily distracted

little need for sleep

If you show a response to ziprasidone, your symptoms may improve. If you continue to take ziprasidone

there is less chance of your symptoms returning. Do not stop taking the capsules even when you feel

better without first discussing it with your doctor.

It is also important to remember that ziprasidone capsules should be taken with food.

What is the most important safety information I should know about ziprasidone?

Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.

Elderly patients with a diagnosis of psychosis related to dementia treated with antipsychotics are

at an increased risk of death when compared to patients who are treated with placebo (a sugar

pill).

Ziprasidone is an effective drug to treat the symptoms of schizophrenia and the manic or mixed episodes

of bipolar disorder. However, one potential side effect is that it may change the way the electrical

current in your heart works more than some other drugs. The change is small and it is not known

whether this will be harmful, but some other drugs that cause this kind of change have in rare cases

caused dangerous heart rhythm abnormalities. Because of this, ziprasidone should be used only after

your doctor has considered this risk for ziprasidone against the risks and benefits of other medications

available for treating schizophrenia or bipolar manic and mixed episodes.

Your risk of dangerous changes in heart rhythm can be increased if you are taking certain other

medicines and if you already have certain abnormal heart conditions. Therefore, it is important to

tell your doctor about any other medicines that you take, including non-prescription medicines,

supplements, and herbal medicines. You must also tell your doctor about any heart problems you

have or have had.

Who should NOT take ziprasidone?

Elderly patients with a diagnosis of psychosis related to dementia. Ziprasidone is not approved for the

treatment of these patients.

Anything that can increase the chance of a heart rhythm abnormality should be avoided. Therefore, do

not take ziprasidone if:

You have certain heart diseases, for example, long QT syndrome, a recent heart attack, severe heart

failure, or certain irregularities of heart rhythm (discuss the specifics with your doctor)

You are currently taking medications that should not be taken in combination with ziprasidone, for

example, dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine,

thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin,

halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate,

probucol or tacrolimus.

What To Tell Your Doctor Before You Start Ziprasidone

Only your doctor can decide if ziprasidone is right for you. Before you start ziprasidone, be sure to tell

your doctor if you:

have had any problem with the way your heart beats or any heart related illness or disease

any family history of heart disease, including recent heart attack

have had any problem with fainting or dizziness

are taking or have recently taken any prescription medicines

are taking any over-the-counter medicines you can buy without a prescription, including

natural/herbal remedies

have had any problems with your liver

are pregnant, might be pregnant, or plan to get pregnant

are breast feeding

are allergic to any medicines

have ever had an allergic reaction to ziprasidone or any of the other ingredients of ziprasidone

capsules. Ask your doctor or pharmacist for a list of these ingredients

have low levels of potassium or magnesium in your blood

Your doctor may want you to get additional laboratory tests to see if ziprasidone is an appropriate

treatment for you.

Ziprasidone And Other Medicines

There are some medications that may be unsafe to use when taking ziprasidone, and there are some

medicines that can affect how well ziprasidone works. While you are on ziprasidone, check with your

doctor before starting any new prescription or over-the-counter medications, including natural/herbal

remedies.

How To Take ziprasidone

Take ziprasidone only as directed by your doctor.

Swallow the capsules whole.

Take ziprasidone capsules with food.

It is best to take ziprasidone at the same time each day.

Ziprasidone may take a few weeks to work. It is important to be patient.

Do not change your dose or stop taking your medicine without your doctor's approval.

Remember to keep taking your capsules, even when you feel better.

Possible Side Effects

Because these problems could mean you're having a heart rhythm abnormality, contact your doctor

IMMEDIATELY if you:

Faint or lose consciousness

Feel a change in the way that your heart beats (palpitations)

Common side effects of ziprasidone include the following and should also be discussed with your

doctor if they occur:

Feeling unusually tired or sleepy

Nausea or upset stomach

Constipation

Dizziness

Restlessness

Abnormal muscle movements, including tremor, shuffling, and uncontrolled involuntary movements

Diarrhea

Rash

Increased cough / runny nose

If you develop any side effects that concern you, talk with your doctor. It is particularly important to tell

your doctor if you have diarrhea, vomiting, or another illness that can cause you to lose fluids. Your

doctor may want to check your blood to make sure that you have the right amount of important salts after

such illnesses.

For a list of all side effects that have been reported, ask your doctor or pharmacist for the ziprasidone

Professional Package Insert.

What To Do For An Overdose

In case of an overdose, call your doctor or poison control center right away or go to the nearest

emergency room.

Other Important Safety Information

A serious condition called neuroleptic malignant syndrome (NMS) can occur with all antipsychotic

medications including ziprasidone. Signs of NMS include very high fever, rigid muscles, shaking,

confusion, sweating, or increased heart rate and blood pressure. NMS is a rare but serious side effect

that could be fatal. Therefore, tell your doctor if you experience any of these signs.

Delayed-onset drug reaction called drug reaction with eosinophilia and systemic symptoms (DRESS)

can occur with ziprasidone. Signs of DRESS may include rash, fever, and swollen lymph nodes. Other

severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome can occur with

ziprasidone. Signs of Stevens-Johnson syndrome may include rash with blisters which could include

ulcers in mouth, skin shedding, fever and target-like spots in the skin. DRESS and other SCAR are

sometimes fatal; therefore, tell your doctor immediately if you experience any of these signs.

Adverse reactions related to high blood sugar (hyperglycemia), sometimes serious, have been reported

in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or

diabetes in patients treated with ziprasidone, and it is not known if ziprasidone is associated with these

reactions. Patients treated with an atypical antipsychotic should be monitored for symptoms of

hyperglycemia.

Dizziness caused by a drop in your blood pressure may occur with ziprasidone, especially when you

first start taking this medication or when the dose is increased. If this happens, be careful not to stand up

too quickly, and talk to your doctor about the problem.

Before taking ziprasidone, tell your doctor if you are pregnant or plan on becoming pregnant. It is

advised that you don't breast feed an infant if you are taking ziprasidone.

Because ziprasidone can cause sleepiness, be careful when operating machinery or driving a motor

vehicle.

Since medications of the same drug class as ziprasidone may interfere with the ability of the body to

adjust to heat, it is best to avoid situations involving high temperature or humidity.

It is best to avoid consuming alcoholic beverages while taking ziprasidone.

Call your doctor immediately if you take more than the amount of ziprasidone prescribed by your doctor.

Ziprasidone has not been shown to be safe or effective in the treatment of children and teenagers under

the age of 18 years old.

Keep ziprasidone and all medicines out of the reach of children.

How To Store ziprasidone

Store ziprasidone capsules at room temperature (59°F to 86°F or 15°C to 30°C).

For More Information About ziprasidone

This sheet is only a summary. Ziprasidone is a prescription medicine and only your doctor can decide if

it is right for you. If you have any questions or want more information about ziprasidone, talk with your

doctor or pharmacist.

This product's label may have been updated. For current full prescribing information, please visit

www.greenstonellc.com

LAB-0550-4.0

September 2015

PRINCIPAL DISPLAY PANEL

ZIPRASIDONE

ziprasidone hydrochloride capsule

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code

(S ource )

NDC:6 9 18 9 -20 0 3(NDC:59 76 2-

20 0 2)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ZIPRASIDO NE HYDRO CHLO RIDE (UNII: 216 X0 8 1ORU) (ZIPRASIDONE - UNII:6 UKA5VEJ6 X)

ZIPRASIDONE

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE, UNSPECIFIED FO RM (UNII: J2B2A4N9 8 G)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

Product Characteristics

Color

BLUE

S core

no sco re

S hap e

CAPSULE

S iz e

14mm

Flavor

Imprint Code

G;20 0 2

Contains

Avera McKennan Hospital

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 9 18 9 -20 0 3-1

1 in 1 DOSE PACK; Type 0 : No t a Co mbinatio n Pro duct

0 2/0 9 /20 16

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA AUTHORIZED GENERIC

NDA0 20 8 25

0 2/0 9 /20 16

Labeler -

Avera McKennan Hospital (068647668)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Avera McKennan Ho spital

0 6 8 6 476 6 8

relabel(6 9 18 9 -20 0 3) , repack(6 9 18 9 -20 0 3)

Revised: 3/2017

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