Geodon Information
Geodon (Ziprasidone) Boxed Warning
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. Geodon (Ziprasidone) is not approved for the treatment of patients with
Dementia-Related Psychosis [).
Geodon (Ziprasidone) Indications & Usage
Geodon (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. Geodon (Ziprasidone) intramuscular is indicated for acute agitation in schizophrenic
patients. 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 []. 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
Geodon (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 .
Geodon (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 Geodon (Ziprasidone) as monotherapy for the maintenance
treatment of bipolar I disorder has not been systematically evaluated in
controlled clinical trials. [see ].
Geodon (Ziprasidone) intramuscular is indicated for the treatment of acute agitation in
schizophrenic patients for whom treatment with ziprasidone is appropriate and
who need intramuscular antipsychotic medication for rapid control of agitation.
The efficacy of intramuscular ziprasidone for acute agitation in schizophrenia
was established in single day controlled trials of agitated schizophrenic
inpatients.
"Psychomotor agitation" is defined in DSM-IV as "excessive motor activity
associated with a feeling of inner tension." Schizophrenic patients experiencing
agitation often manifest behaviors that interfere with their diagnosis and care,
e.g., threatening behaviors, escalating or urgently distressing behavior, or
self-exhausting behavior, leading clinicians to the use of intramuscular
antipsychotic medications to achieve immediate control of the agitation.
Since there is no experience regarding the safety of administering
ziprasidone intramuscular to schizophrenic patients already taking oral
ziprasidone, the practice of co-administration is not recommended.
Ziprasidone intramuscular is intended for intramuscular use only and should
not be administered intravenously.
Geodon (Ziprasidone) Dosage & Administration
Geodon (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 .
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 Geodon (Ziprasidone) . . No additional benefit was demonstrated for doses
above 20 mg twice daily. Patients should be periodically reassessed to determine
the need for maintenance treatment.
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 .
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.
The recommended dose is 10 mg to 20 mg administered as required up to a
maximum dose of 40 mg per day. Doses of 10 mg may be administered every two
hours; doses of 20 mg may be administered every four hours up to a maximum of 40
mg/day. Intramuscular administration of ziprasidone for more than three
consecutive days has not been studied.
If long-term therapy is indicated, oral ziprasidone hydrochloride capsules
should replace the intramuscular administration as soon as possible.
Since there is no experience regarding the safety of administering
ziprasidone intramuscular to schizophrenic patients already taking oral
ziprasidone, the practice of co-administration is not recommended.
Ziprasidone intramuscular is intended for intramuscular use only and should
not be administered intravenously.
Geodon (Ziprasidone) for Injection (ziprasidone mesylate) should only be administered by
intramuscular injection and should not be administered intravenously.
Single-dose vials require reconstitution prior to administration.
Add 1.2 mL of Sterile Water for Injection to the vial and shake vigorously
until all the drug is dissolved. Each mL of reconstituted solution contains 20
mg ziprasidone. To administer a 10 mg dose, draw up 0.5 mL of the reconstituted
solution. To administer a 20 mg dose, draw up 1.0 mL of the reconstituted
solution. Any unused portion should be discarded. Since no preservative or
bacteriostatic agent is present in this product, aseptic technique must be used
in preparation of the final solution. This medicinal product must not be mixed
with other medicinal products or solvents other than Sterile Water for
Injection. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution and
container permit.
Geodon (Ziprasidone) Dosage Forms & Strengths
Geodon (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:
Geodon (Ziprasidone) Capsules
Capsules Strenght (mg) Imprint
20
396
40
397
60
398
80
399
Geodon (Ziprasidone) for Injection is available in a single-dose vial as ziprasidone
mesylate (20 mg ziprasidone/mL when reconstituted according to label
instructions) . Each mL of ziprasidone mesylate for injection (when
reconstituted) affords a colorless to pale pink solution that contains 20 mg of
ziprasidone and 4.7 mg of methanesulfonic acid solubilized by 294 mg of
sulfobutylether β-cyclodextrin sodium (SBECD).
Geodon (Ziprasidone) Contraindications
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:
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:
Ziprasidone is contraindicated in individuals with a known hypersensitivity
to the product.
Geodon (Ziprasidone) Warnings And Precautions
Ziprasidone use should be avoided in combination with other drugs that are
known to prolong the QTc interval [. 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
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 (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) .
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
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 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.
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.
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.
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 (Ziprasidone) . Although fewer patients have been treated with
Geodon (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. However,
epidemiological studies, which did not include Geodon (Ziprasidone) , suggest an increased risk
of treatment-emergent hyperglycemia-related adverse reactions in patients
treated with the atypical antipsychotics included in these studies. Because
Geodon (Ziprasidone) was not marketed at the time these studies were performed, it is not
known if Geodon (Ziprasidone) 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.
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.
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).
In clinical trial and postmarketing experience, events of
leukopenia/neutropenia have been reported temporally related to antipsychotic
age-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 (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 greater then
1000/mm3) should discontinue Geodon (Ziprasidone) and have their WBC followed until
recovery.
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.
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 .
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 . Tissue culture experiments indicate that
approximately one-third of human breast cancers are prolactin-dependent , 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.
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.
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.
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.
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.
Clinical experience with ziprasidone in patients with certain concomitant
systemic illnesses is limited
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
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.
Geodon (Ziprasidone) Adverse Reactions
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.
Clinical trials for intramuscular ziprasidone included 570 patients and/or
normal subjects who received one or more injections of ziprasidone. Over 325 of
these subjects participated in trials involving the administration of multiple
doses.
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.
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.
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 ()
Bipolar trials (
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
Table 1 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.
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
Following is a list of COSTART terms that reflect treatment-emergent adverse
reactions as defined in the introduction to the section reported by patients treated with ziprasidone in
schizophrenia trials at multiple doses less then 4 mg/day within the database of
3834 patients. All reported reactions are included except those already listed
in Table 1 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 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:
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.
Table 2 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.
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.
Table 4 enumerates the incidence, rounded to the nearest percent, of
treatment-emergent adverse reactions that occurred during acute therapy with
intramuscular ziprasidone in 1% or more of patients.
In these studies, the most commonly observed adverse reactions associated
with the use of intramuscular ziprasidone (incidence of 5% or greater) and
observed at a rate on intramuscular ziprasidone (in the higher dose groups) at
least twice that of the lowest intramuscular ziprasidone group were headache
(13%), nausea (12%), and somnolence (20%).
The following adverse reactions have been identified during post approval use
of Geodon (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 : Tachycardia, torsade de pointes (in the
presence of multiple confounding factors), ; Swollen Tongue; Galactorrhea,
priapism; Facial Droop,
neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with
serotonergic medicinal products), tardive dyskinesia; Insomnia, mania/hypomania; Allergic reaction
(such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash;
Enuresis, urinary
incontinence; Postural
hypotension, syncope.
Geodon (Ziprasidone) 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:
Approximately two-thirds of ziprasidone is metabolized via 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.
An 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
.
Ziprasidone should not be used with any drug that prolongs the QT interval
.
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.
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, 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 at a dose of 800 mg QD for 2 days did not affect ziprasidone
pharmacokinetics.
The co-administration of 30 mL of Maalox® with ziprasidone did not affect the
pharmacokinetics of ziprasidone.
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.
Consistent with 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.
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.
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.
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 .
Geodon (Ziprasidone) Use In Specific Populations
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/mbasis). 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/mbasis). 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.
Geodon (Ziprasidone) should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
The effect of ziprasidone on labor and delivery in humans is unknown.
It is not known whether ziprasidone or its metabolites are excreted in human
milk. It is recommended that women receiving ziprasidone should not
breastfeed.
The safety and effectiveness of ziprasidone in pediatric patients have not
been established.
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).
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
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
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.
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.
Based on 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
results, population pharmacokinetic
evaluation has not revealed any significant pharmacokinetic differences between
smokers and nonsmokers.
Geodon (Ziprasidone) Drug Abuse And 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-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).
Geodon (Ziprasidone) Overdosage
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.
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.
Geodon (Ziprasidone) Description
Geodon (Ziprasidone) Clinical Pharmacology
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.
Ziprasidone exhibited high binding
affinity for the dopamine D and D, the serotonin 5HT, 5HT, 5HT, 5HT,
and α-adrenergic receptors (Ks
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.
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.
Geodon (Ziprasidone) Nonclinical Toxicology
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 .
Ziprasidone was tested in the Ames bacterial mutation assay, the mammalian cell gene mutation mouse lymphoma assay,
the chromosomal aberration assay in human
lymphocytes, and the chromosomal aberration
assay in mouse bone marrow. There was a reproducible mutagenic response in the
Ames assay in one strain of in the
absence of metabolic activation. Positive results were obtained in both the
mammalian cell gene mutation assay and the
chromosomal aberration assay in human
lymphocytes.
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.
Geodon (Ziprasidone) Clinical Studies
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 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.
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.
The efficacy of intramuscular ziprasidone in the management of agitated
schizophrenic patients was established in two short-term, double-blind trials of
schizophrenic subjects who were considered by the investigators to be "acutely
agitated" and in need of IM antipsychotic medication. In addition, patients were
required to have a score of 3 or more on at least 3 of the following items of
the PANSS: anxiety, tension, hostility and excitement. Efficacy was evaluated by
analysis of the area under the curve (AUC) of the Behavioural Activity Rating
Scale (BARS) and Clinical Global Impression (CGI) severity rating. The BARS is a
seven point scale with scores ranging from 1 (difficult or unable to rouse) to 7
(violent, requires restraint). Patients' scores on the BARS at baseline were
mostly 5 (signs of overt activity [physical or verbal], calms down with
instructions) and as determined by investigators, exhibited a degree of
agitation that warranted intramuscular therapy. There were few patients with a
rating higher than 5 on the BARS, as the most severely agitated patients were
generally unable to provide informed consent for participation in premarketing
clinical trials.
Both studies compared higher doses of ziprasidone intramuscular with a 2 mg
control dose. In one study, the higher dose was 20 mg, which could be given up
to 4 times in the 24 hours of the study, at interdose intervals of no less than
4 hours. In the other study, the higher dose was 10 mg, which could be given up
to 4 times in the 24 hours of the study, at interdose intervals of no less than
2 hours.
Geodon (Ziprasidone) How Supplied
Geodon (Ziprasidone) Capsules are differentiated by capsule color/size and are
imprinted in black ink with "Pfizer" and a unique number. Geodon (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:
Package Configuration Capsule Strenght (mg) NDC
Code Imprint
Bottles of 60
20 NDC-0049-3960-60
396
Bottles of 60 40
NDC-0049 -3970-60 397
Bottles of 60
60 NDC-0049-3980-60
398
Bottles of 60 80
NDC-0049-3990-60 399
Unit dose/80
20 NDC-0049-3960-41
396
Unit dose/80
40 NDC-0049-3970-41
397
Unit dose/80
60 NDC-0049-3980-41
398
Unit dose/80
80 NDC-0049-3990-41
399
Geodon (Ziprasidone) Capsules should be stored at 25°C (77°F); excursions permitted to
15–30°C (59–86°F) [See USP Controlled Room Temperature].
Geodon (Ziprasidone) Patient Counseling Information
See .
Please refer to the patient package insert. To assure safe and effective use
of Geodon (Ziprasidone) , the information and instructions provided in the patient information
should be discussed with patients.
Patients should be instructed to take Geodon (Ziprasidone) Capsules with food for optimal
absorption. The absorption of ziprasidone is increased up to two-fold in the
presence of food .
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
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 .
PATIENT SUMMARY OF INFORMATION ABOUT
(ziprasidone HCl)
This summary contains important information about Geodon (Ziprasidone) . It is not meant to
take the place of your doctor's instructions. Read this information carefully
before you take Geodon (Ziprasidone) . Ask your doctor or pharmacist if you do not understand
any of this information or if you want to know more about Geodon (Ziprasidone) .
Geodon (Ziprasidone) is a type of prescription medicine called a psychotropic, also known
as an atypical antipsychotic. Geodon (Ziprasidone) can be used to treat symptoms of
schizophrenia and acute manic or mixed episodes associated with bipolar
disorder. Geodon (Ziprasidone) can also be used as maintenance treatment of bipolar disorder
when added to lithium or valproate.
Only your doctor can know if Geodon (Ziprasidone) is right for you. Geodon (Ziprasidone) may be
prescribed for you if you have schizophrenia or bipolar disorder.
Symptoms of schizophrenia may include:
Symptoms of manic or mixed episodes of bipolar disorder may include:
If you show a response to Geodon (Ziprasidone) , your symptoms may improve. If you continue
to take Geodon (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 Geodon (Ziprasidone) capsules should be taken with
food.
Geodon (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, Geodon (Ziprasidone) should be used only after your doctor has considered
this risk for Geodon (Ziprasidone) against the risks and benefits of other medications
available for treating schizophrenia or bipolar manic and mixed episodes.
Elderly patients with a diagnosis of psychosis related to dementia. Geodon (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 Geodon (Ziprasidone) if:
Only your doctor can decide if Geodon (Ziprasidone) is right for you. Before you start
Geodon (Ziprasidone) , be sure to tell your doctor if you:
Your doctor may want you to get additional laboratory tests to see if Geodon (Ziprasidone)
is an appropriate treatment for you.
There are some medications that may be unsafe to use when taking Geodon (Ziprasidone) , and
there are some medicines that can affect how well Geodon (Ziprasidone) works. While you are on
Geodon (Ziprasidone) , check with your doctor before starting any new prescription or
over-the-counter medications, including natural/herbal remedies.
Because these problems could mean you're having a heart rhythm abnormality,
contact your doctor if you:
Common side effects of Geodon (Ziprasidone) include the following and should also be
discussed with your doctor if they occur:
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 Geodon (Ziprasidone) Professional Package Insert.
In case of an overdose, call your doctor or poison control center right away
or go to the nearest emergency room.
A serious condition called neuroleptic malignant syndrome (NMS) can occur
with all antipsychotic medications including Geodon (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.
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 Geodon (Ziprasidone) , and it is not known if Geodon (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 Geodon (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 Geodon (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 Geodon (Ziprasidone) .
Because Geodon (Ziprasidone) can cause sleepiness, be careful when operating machinery or
driving a motor vehicle.
Since medications of the same drug class as Geodon (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 Geodon (Ziprasidone) .
Call your doctor if you take more than the amount of
Geodon (Ziprasidone) prescribed by your doctor.
Geodon (Ziprasidone) has not been shown to be safe or effective in the treatment of
children and teenagers under the age of 18 years old.
Store Geodon (Ziprasidone) capsules at room temperature (59°–86°F or 15°–30°C).
This sheet is only a summary. Geodon (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 Geodon (Ziprasidone) , talk with your doctor or pharmacist. You can also
visit www.Geodon (Ziprasidone) .com.
Geodon (Ziprasidone) Package Label.principal Display Panel Section
Geodon (Ziprasidone) Package Label.principal Display Panel
