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 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 reactions is not completely understood. However, epidemiological studies, which did not include GEODON, suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics included in these studies. Because GEODON was not marketed at the time these studies were performed, it is not known if GEODON is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
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 agents. Agranulocytosis (including fatal cases) has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue 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
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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.
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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.
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Cimetidine
Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics.
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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].