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]
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].
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 at recommended doses 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].
Certain circumstances may increase the risk of the occurrence of torsade de pointes
and/or sudden death in association with the use of drugs that prolong the QTc interval,
including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use
of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation
of the QT interval.
It is recommended that patients being considered for ziprasidone treatment who are
at risk for significant electrolyte disturbances, hypokalemia in particular, have
baseline serum potassium and magnesium measurements. Hypokalemia (and/or hypomagnesemia)
may increase the risk of QT prolongation and arrhythmia. Hypokalemia may result
from diuretic therapy, diarrhea, and other causes. Patients with low serum potassium
and/or magnesium should be repleted with those electrolytes before proceeding with
treatment. It is essential to periodically monitor serum electrolytes in patients
for whom diuretic therapy is introduced during ziprasidone treatment. Persistently
prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia,
but it is not clear that routine screening ECG measures are effective in detecting
such patients. Rather, ziprasidone should be avoided in patients with histories
of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial
infarction, uncompensated heart failure, or cardiac arrhythmia. Ziprasidone should
be discontinued in patients who are found to have persistent QTc measurements >500
msec.
For patients taking ziprasidone who experience symptoms that could indicate the occurrence
of torsade de pointes, e.g., dizziness, palpitations, or syncope, the prescriber
should initiate further evaluation, e.g., Holter monitoring may be useful.
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.
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.
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 events is not completely understood.
However, epidemiological studies, which did not include GEODON, suggest an increased
risk of treatment-emergent hyperglycemia-related adverse events 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 events 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.
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.
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).
Leukopenia, Neutropenia, and Agranulocytosis
In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported
temporally related to antipsychotic age¬nts. 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 <1000/mm3) should discontinue Geodon and have their WBC followed until recovery.
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.
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].
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.
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.
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.
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.
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.
Patients with concomitant illnesses
Clinical experience with ziprasidone in patients with certain concomitant systemic illnesses is limited
[see Use in Specific Populations]
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]
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]
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:
Metabolic Pathway
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.
In Vitro Studies
An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little
inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the
metabolism of drugs primarily metabolized by these enzymes. There is little potential for drug interactions with
ziprasidone due to displacement [See Clinical Pharmacology].
Pharmacodynamic Interactions
Ziprasidone should not be used with any drug that prolongs the QT interval [See Contraindications]. 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.
Pharmacokinetic Interactions
-
Carbamazepine
Carbamazepine is an inducer of CYP3A4; administration of 200 mg twice daily for 21 days resulted in a decrease of
approximately 35% in the AUC of ziprasidone. This effect may be greater when higher doses of carbamazepine are
administered.
-
Ketoconazole
Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the AUC and Cmax of
ziprasidone by about 35-40%. Other inhibitors of CYP3A4 would be expected to have similar effects.
-
Cimetidine
Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics.
-
Antacid
The co-administration of 30 mL of Maalox® with ziprasidone did not affect the pharmacokinetics of ziprasidone.
Lithium
Ziprasidone at a dose of 40 mg twice daily administered concomitantly with lithium at a dose of 450 mg twice daily for
7 days did not affect the steady-state level or renal clearance of lithium. Ziprasidone dosed adjunctively to lithium
in a maintenance trial of bipolar patients did not affect mean therapeutic lithium levels.
Oral Contraceptives
In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of estrogen or progesterone
components. Ziprasidone at a dose of 20 mg twice daily did not affect the pharmacokinetics of concomitantly administered
oral contraceptives, ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg).
Dextromethorphan
Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter
the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no
statistically significant change in the urinary dextromethorphan/dextrorphan ratio.
Valproate
A pharmacokinetic interaction of ziprasidone with valproate is unlikely due to the lack of common metabolic pathways
for the two drugs. Ziprasidone dosed adjunctively to valproate in a maintenance trial of bipolar patients did not
affect mean therapeutic valproate levels.
Other Concomitant Drug Therapy
Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed
evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol, or lorazepam.
Food Interaction
The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The absorption of ziprasidone
is increased up to two-fold in the presence of food [see Clinical Pharmacology].
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling.
Please refer to the patient package insert. To assure safe and effective use of GEODON, the information and
instructions provided in the patient information should be discussed with patients.
Administration with Food
Patients should be instructed to take GEODON Capsules with food for optimal absorption. The absorption of
ziprasidone is increased up to two-fold in the presence of food [see Drug Interactions and Clinical Pharmacology].
QTc Prolongation
Patients should be advised to inform their health care providers of the following: History of QT prolongation;
recent acute myocardial infarction; uncompensated heart failure; prescription of other drugs that have demonstrated
QT prolongation; risk for significant electrolyte abnormalities; and history of cardiac arrhythmia
[see Contraindications and Warnings and Precautions].
Patients should be instructed to report the onset of any conditions that put them at risk for significant
electrolyte disturbances, hypokalemia in particular, including but not limited to the initiation of diuretic
therapy or prolonged diarrhea. In addition, patients should be instructed to report symptoms such as
dizziness, palpitations, or syncope to the prescriber [see Warnings and Precautions].