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 (ziprasidone) is not approved for the
treatment of patients with 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, and see Drug Interactions under
PRECAUTIONS). 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 BID).
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, such as those with hypokalemia,
hypomagnesemia, or genetic predisposition. 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; Other Events Observed During Post-marketing Use).
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.