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. GEODON 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, Drug Interactions]. 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 GEODON 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].
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 bradycardia; 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 less then 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 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.
5.5 Hyperglycemia and Diabetes
Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, has been reported in patients treated with atypical
antipsychotics. There have been few reports of hyperglycemia or diabetes in
patients treated with GEODON. Although fewer patients have been treated with
GEODON, 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. However,
epidemiological studies, which did not include GEODON, suggest an increased risk
of treatment-emergent hyperglycemia-related adverse reactions in patients
treated with the atypical antipsychotics included in these studies. Because
GEODON was not marketed at the time these studies were performed, it is not
known if GEODON is associated with this increased risk. 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.
5.6 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.
5.7 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 α1-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).
5.8 Leukopenia, Neutropenia, and
Agranulocytosis
In clinical trial and postmarketing experience, events of
leukopenia/neutropenia have been reported temporally related to antipsychotic
age- n ts. 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 Geodon
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 greater then
1000/mm3) should discontinue Geodon and have their WBC followed until
recovery.
5.9 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.
5.10 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 ].
5.11 Hyperprolactinemia
As with other drugs that antagonize dopamine D2
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]. 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. 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. 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.
5.12 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.
5.13 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.
5.14 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.
5.15 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.
5.16 Patients with concomitant
illnesses
Clinical experience with ziprasidone in patients with certain concomitant
systemic illnesses is limited [see Use in
Specific Populations, (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, ]
5.17 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]
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/m2 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/m2 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/m2 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/m2 basis) were associated with
maternal toxicity. The developmental no-effect dose was 5 mg/kg/day (0.2 times
the MRHD on a mg/m2 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/m2 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/m2 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.
Geodon 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.
Ziprasidone intramuscular has not been systematically evaluated in elderly
patients (65 years and over).
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.
Intramuscular ziprasidone has not been systematically evaluated in elderly
patients or in patients with hepatic or renal impairment. As the cyclodextrin
excipient is cleared by renal filtration, ziprasidone intramuscular should be
administered with caution to patients with impaired renal function [see Clinical Pharmacology].
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 AUC
0–12 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.
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