General
Leukopenia, Neutropenia and Agranulocytosis – Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Geodon should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant 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.
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 events 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).
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 also Boxed WARNING, WARNINGS: Increased
Mortality in Elderly Patients with Dementia-Related Psychosis).
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 Carcinogenesis). 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 event 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 event 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.
Use in Patients with Concomitant Illness – Clinical experience
with ziprasidone in patients with certain concomitant systemic illnesses (see Renal
Impairment and Hepatic Impairment under CLINICAL PHARMACOLOGY,
Special Populations) 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 (see QTc Prolongation under WARNINGS
and Orthostatic Hypotension under PRECAUTIONS).
Information for Patients
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.
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 repleted 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).
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:
Pharmacodynamic Interactions
(1) Ziprasidone should not be used with any drug that prolongs
the QT interval (see CONTRAINDICATIONS).
(2) Given the primary CNS effects of ziprasidone, caution
should be used when it is taken in combination with other centrally acting drugs.
(3) Because of its potential for inducing hypotension, ziprasidone
may enhance the effects of certain antihypertensive agents.
(4) Ziprasidone may antagonize the effects of levodopa and
dopamine agonists.
Pharmacokinetic Interactions
The Effect of Other Drugs on Ziprasidone
Carbamazepine – Carbamazepine is an inducer of CYP3A4; administration
of
200 mg BID 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 five 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 two days did
not affect ziprasidone pharmacokinetics.
Antacid – The coadministration of 30 mL of Maalox® with ziprasidone
did not affect the pharmacokinetics of ziprasidone.
In addition, 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.
Effect of Ziprasidone on Other Drugs
In vitro studies revealed little potential for ziprasidone to interfere with
the metabolism of drugs cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and
CYP3A4, and little potential for drug interactions with ziprasidone due to displacement
(see CLINICAL PHARMACOLOGY, Pharmacokinetics).
Lithium – Ziprasidone at a dose of 40 mg BID administered concomitantly
with lithium at a dose of 450 mg BID for 7 days did not affect the steady-state
level or renal clearance of lithium.
Oral Contraceptives – Ziprasidone at a dose of 20 mg BID 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis – 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/m2 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/m2
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 one-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/m2 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 (see Hyperprolactinemia
under PRECAUTIONS, General).
Mutagenesis – Ziprasidone was tested in the Ames bacterial mutation
assay, the
in vitro mammalian cell gene mutation mouse lymphoma assay, the in vitro
chromosomal aberration assay in human lymphocytes, and the in vivo chromosomal
aberration assay in mouse bone marrow. There was a reproducible mutagenic response
in the Ames assay in one strain of S. typhimurium in the absence of metabolic
activation. Positive results were obtained in both the in vitro mammalian
cell gene mutation assay and the in vitro chromosomal aberration assay in
human lymphocytes.
Impairment of Fertility – 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/m2 basis). Fertility rate was reduced at 160 mg/kg/day
(8 times the MRHD on a mg/m2 basis). There was no effect
on fertility at 40 mg/kg/day (2 times the MRHD on a mg/m2
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/m2
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/m2 basis) there
were no treatment-related findings observed in the testes.
Pregnancy – Pregnancy Category C – In animal studies
ziprasidone demonstrated developmental toxicity, including possible teratogenic
effects at doses similar to human therapeutic doses. When ziprasidone was administered
to pregnant rabbits during the period of organogenesis, an increased incidence of
fetal structural abnormalities (ventricular septal defects and other cardiovascular
malformations and kidney alterations) was observed at a dose of 30 mg/kg/day (3
times the MRHD of 200 mg/day on a mg/m2 basis). There
was no evidence to suggest that these developmental effects were secondary to maternal
toxicity. The developmental no-effect dose was 10 mg/kg/day (equivalent to the MRHD
on a mg/m2 basis). In rats, embryofetal toxicity (decreased
fetal weights, delayed skeletal ossification) was observed following administration
of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD on a mg/m2
basis) during organogenesis or throughout gestation, but there was no evidence of
teratogenicity. Doses of 40 and
160 mg/kg/day (2 and 8 times the MRHD on a mg/m2 basis)
were associated with maternal toxicity. The developmental no-effect dose was 5 mg/kg/day
(0.2 times the MRHD on a mg/m2 basis).
There was an increase in the number of pups born dead and a decrease in postnatal
survival through the first 4 days of lactation among the offspring of female rats
treated during gestation and lactation with doses of 10 mg/kg/day (0.5 times the
MRHD on a mg/m2 basis) or greater. Offspring developmental
delays and neurobehavioral functional impairment were observed at doses of 5 mg/kg/day
(0.2 times the MRHD on a mg/m2 basis) or greater. A no-effect
level was not established for these effects.
There are no adequate and well-controlled studies in pregnant women. Ziprasidone
should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Labor and Delivery – The effect of ziprasidone on labor and delivery
in humans is unknown.
Nursing Mothers – It is not known whether, and if so in what amount,
ziprasidone or its metabolites are excreted in human milk. It is recommended that
women receiving ziprasidone should not breast feed.
Pediatric Use – The safety and effectiveness of ziprasidone in
pediatric patients have not been established.
Geriatric Use – Of the approximately 4500 patients treated with
ziprasidone in clinical studies, 2.4% (109) were 65 years of age or over. In general,
there was no indication of any different tolerability of ziprasidone or for reduced
clearance of ziprasidone in the elderly compared to younger adults. 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.