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Ziprasidone


Special Alerts

Atypical Antipsychotics and Hyperglycemia - Update: August, 2004

The Food and Drug Administration (FDA) has concluded that the labeling for all atypical antipsychotics should be revised to highlight the potential for diabetes, weight gain, and dyslipidemia. The information has been summarized by a consensus panel (Diabetes Care 2004; 27:596-601). Severe hyperglycemia, including ketosis, has been documented in patients receiving this class of medications. Clozapine and olanzapine have been most clearly associated with these effects, while risperidone and quetiapine have produced discrepant results. Aripiprazole and ziprasidone are associated with little or no diabetes, but have not been used as extensively as the other agents implicated. It is difficult to define a causal relationship in this complex patient population, since the baseline risk of diabetes may be elevated. Patients with established diabetes (or with risk factors such as a family history or obesity) should be monitored closely for changes in glucose control. Measurement of fasting blood glucose at the beginning of therapy and periodic monitoring during therapy are recommended. A "Dear Healthcare Professional" letter was previously posted for some of the atypical antipsychotics to alert clinicians to these issues. Pfizer Pharmaceuticals, the manufacturer of Geodon® (ziprasidone) recently notified healthcare providers that product labeling has been updated to reflect these changes.

Additional information available at http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#geodon (last accessed September 2, 2004)


Pronunciation

 (zi PRAY si done)


U.S. Brand Names

 Geodon®


Synonyms

 Zeldox; Ziprasidone Hydrochloride; Ziprasidone Mesylate


Generic Available

 No


Use

 Treatment of schizophrenia; treatment of acute manic or mixed episodes associated with bipolar disorder with or without psychosis; acute agitation in patients with schizophrenia


Use - Unlabeled/Investigational

 Tourette's syndrome


Pregnancy Risk Factor

 C


Pregnancy Implications

 Developmental toxicity demonstrated in animals. There are no adequate and well-controlled studies in pregnant women. Use only if potential benefit justifies risk to the fetus.


Lactation

 Excretion in breast milk unknown/not recommended


Contraindications

 Hypersensitivity to ziprasidone or any component of the formulation; history (or current) prolonged QT; congenital long QT syndrome; recent myocardial infarction; history of arrhythmias; uncompensated heart failure; concurrent use of other QTc-prolonging agents including amiodarone, arsenic trioxide, bretylium, chlorpromazine, cisapride, class Ia antiarrhythmics (quinidine, procainamide), dofetilide, dolasetron, droperidol, halofantrine, ibutilide, levomethadyl, mefloquine, mesoridazine, pentamidine, pimozide, probucol, some quinolone antibiotics (moxifloxacin, sparfloxacin, gatifloxacin), sotalol, tacrolimus, and thioridazine


Warnings/Precautions

 May result in QTc prolongation (dose-related), which has been associated with the development of malignant ventricular arrhythmias (torsade de pointes) and sudden death. Observed prolongation was greater than with other atypical antipsychotic agents (risperidone, olanzapine, quetiapine), but less than with thioridazine. Avoid hypokalemia, hypomagnesemia. Use caution in patients with bradycardia. Discontinue in patients found to have persistent QTc intervals >500 msec. Patients with symptoms of dizziness, palpitations, or syncope should receive further cardiac evaluation.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Disturbances of temperature regulation have been reported with antipsychotics (not reported in premarketing trials of ziprasidone). Antipsychotic use may also be associated with neuroleptic malignant syndrome (NMS). Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or other medications which may predispose).

Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. There is limited documentation with ziprasidone and specific risk associated with this agent is not known. Use caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control.

Cognitive and/or motor impairment (sedation) is common with ziprasidone, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use; use with caution in patients at risk of aspiration pneumonia (ie, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). Use caution in patients with renal or hepatic impairment. Ziprasidone has been associated with a fairly high incidence of rash (5%); discontinue if alternative etiology is not identified. Safety and efficacy have not been established in pediatric patients.

The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.


Adverse Reactions

 Note: Although minor QTc prolongation (mean 10 msec at 160 mg/day) may occur more frequently (incidence not specified), clinically-relevant prolongation (>500 msec) was rare (0.06%) and less than placebo (0.23%).

>10%:

Central nervous system: Extrapyramidal symptoms (2% to 31%), somnolence (8% to 31%), headache (3% to 18%), dizziness (3% to 16%)

Gastrointestinal: Nausea (4% to 12%)

1% to 10%:

Cardiovascular: Chest pain (5%), postural hypotension (5%), hypertension (2% to 3%), bradycardia (2%), tachycardia (2%), vasodilation (1%), chills, confusion, delirium, facial edema, hostility, orthostatic hypotension, vertigo

Central nervous system: Akathisia (2% to 10%), anxiety (2% to 5%) insomnia (3%), agitation (2%), speech disorder (2%), personality disorder (2%), psychosis (1%), akinesia, amnesia, ataxia, coordination abnormal, dystonia, fever, hypothermia, oculogyric crisis

Dermatologic: Rash (4%), fungal dermatitis (2%)

Endocrine & metabolic: Dysmenorrhea (2%)

Gastrointestinal: Weight gain (10%), constipation (2% to 9%), dyspepsia (1% to 8%), diarrhea (3% to 5%), vomiting (3% to 5%), salivation increased (4%), xerostomia (1% to 5%), tongue edema (3%), abdominal pain (2%), anorexia (2%), dysphagia (2%), rectal hemorrhage (2%), tooth disorder (1%), buccoglossal syndrome

Genitourinary: Priapism (1%)

Local: Injection site pain (7% to 9%)

Neuromuscular & skeletal: Weakness (2% to 6%), hypesthesia (2%), myalgia (2%), paresthesia (2%), back pain (1%), cogwheel rigidity (1%), hypertonia (1%), abnormal gait, choreoathetosis, dysarthria, dyskinesia, hyperkinesia, hypokinesia, hypotonia, neuropathy, tremor, twitching

Ocular: Vision abnormal (3% to 6%), diplopia

Respiratory: Infection (8%), rhinitis (1% to 4%), cough (3%), pharyngitis (3%), dyspnea (2%)

Miscellaneous: Diaphoresis (2%), furunculosis (2%), flu syndrome (1%), photosensitivity reaction, withdrawal syndrome

<1%: Abnormal ejaculation, abnormal gait, accidental fall, akinesia, albuminuria, alkaline phosphatase increased, alopecia, amenorrhea, amnesia, anemia, angina, anorgasmia, atrial fibrillation, ataxia, AV block (first degree), basophilia, blepharitis, BUN increased, bundle branch block, cardiomegaly, cataract, cerebral infarction, chills, cholestatic jaundice, choreoathetosis, circumoral paresthesia, confusion, conjunctivitis, contact dermatitis, CPK increased, creatinine (serum) increased, dehydration, delirium, dry eyes, dysphagia, ecchymosis, eczema, eosinophilia, epistaxis, exfoliative dermatitis, fecal impaction, fatty liver, fever, flank pain, GGT increased, gingival bleeding, gout, gynecomastia, hematemesis, hemoptysis, hematuria, hepatitis, hepatomegaly, hostility, hypercholesterolemia, hyper-/hypoglycemia, hyper-/hypokalemia, hyperlipemia, hyper-/hypothyroidism, hyperuricemia, hypesthesia, hypocalcemia, hypokinesia, hypomagnesemia, hyponatremia, hypoproteinemia, hypotonia, jaundice, keratitis, keratoconjunctivitis, ketosis, lactation (female), laryngismus, LDH increased, leukocytosis, leukoplakia (mouth), lymphadenopathy, lymphedema, lymphocytosis, maculopapular rash, melena, menorrhagia, metrorrhagia, monocytosis, motor vehicle accident, myocarditis, myoclonus, myopathy, neuropathy, nocturia, nystagmus, ocular hemorrhage, phlebitis, polycythemia, oliguria, opisthotonos, peripheral edema, photophobia, pneumonia, polyuria, pulmonary embolism, QTc prolongation >500 msec (0.06%), respiratory alkalosis, seizure (0.4%), sexual dysfunction (male and female), stroke, syncope (0.6%), tenosynovitis, thirst, thrombocytopenia, thrombocythemia, thrombophlebitis, thyroiditis, tinnitus, tongue edema, torticollis, transaminases increased, tremor, trismus, urinary retention, urticaria, uterine hemorrhage, vaginal hemorrhage, vertigo, vesiculobullous rash, visual field defect


Overdosage/Toxicology

 Reported symptoms include somnolence, slurring of speech, and hypertension. Acute extrapyramidal symptoms may also occur. Treatment is symptom-directed and supportive. Not removed by dialysis.


Drug Interactions

 Substrate (minor) of CYP1A2, 3A4; Inhibits CYP2D6 (weak), 3A4 (weak)

Amphetamines: Efficacy may be diminished by antipsychotics; in addition, amphetamines may increase psychotic symptoms; avoid concurrent use

Antihypertensives: Concurrent use of ziprasidone with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Carbamazepine: May decrease serum concentrations of ziprasidone (AUC is decreased by 35%); other enzyme-inducing agents may share this potential

CNS depressants: Sedative effects may be additive with ziprasidone; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol, and other sedative agents

Ketoconazole: May increase serum concentrations of ziprasidone (AUC is increased by 35% to 40%); other CYP3A4 inhibitors may share this potential. QTc prolongation was not demonstrated.

Levodopa: Ziprasidone may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Potassium- or magnesium-depleting agents: May increase the risk of serious arrhythmias with ziprasidone; includes many diuretics, aminoglycosides, cyclosporine, and amphotericin; monitor serum potassium and magnesium levels closely

QTc-prolonging agents: May result in additive effects on cardiac conduction, potentially resulting in malignant or lethal arrhythmias; concurrent use is contraindicated. Includes amiodarone, arsenic trioxide, bretylium, chlorpromazine, cisapride; class Ia antiarrhythmics (quinidine, procainamide); dofetilide, dolasetron, droperidol, halofantrine, ibutilide, levomethadyl, mefloquine, mesoridazine, pentamidine, pimozide, probucol; some quinolone antibiotics (moxifloxacin, sparfloxacin, gatifloxacin); sotalol, tacrolimus, and thioridazine.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Administration with food increases serum levels twofold. Grapefruit juice may increase serum concentration of ziprasidone.

Herb/Nutraceutical: St John's wort may decrease serum levels of ziprasidone, due to a potential effect on CYP3A4. This has not been specifically studied. Avoid kava kava, chamomile (may increase CNS depression).


Stability

Capsule: Store at controlled room temperature of 15°C to 30°C (59°F to 86°F).

Vials for injection: Store at controlled room temperature of 15°C to 30°C (59°F to 86°F); protect from light. Each vial should be reconstituted with 1.2 mL SWI; shake vigorously; will form a pale, pink solution containing 20 mg/mL ziprasidone. Following reconstitution, injection may be stored at room temperature up to 24 hours, or up to 7 days if refrigerated; protect from light.


Mechanism of Action

 Ziprasidone is a benzylisothiazolylpiperazine antipsychotic. The exact mechanism of action is unknown. However, in vitro radioligand studies show that ziprasidone has high affinity for D2, D3, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT1D, and alpha1 adrenergic; moderate affinity for histamine H1 receptors; and no appreciable affinity for alpha2 adrenergic receptors, beta adrenergic, 5-HT3, 5-HT4, cholinergic, mu, sigma, or benzodiazepine receptors. Ziprasidone functions as an antagonist at the D2, 5-HT2A, and 5-HT1D receptors and as an agonist at the 5-HT1A receptor. Ziprasidone moderately inhibits the reuptake of serotonin and norepinephrine.


Pharmacodynamics/Kinetics

Absorption: Well absorbed

Distribution: Vd: 1.5 L/kg

Protein binding: 99%, primarily to albumin and alpha1-acid glycoprotein

Metabolism: Extensively hepatic, primarily via aldehyde oxidase; less than 1 /3 of total metabolism via CYP3A4 and CYP1A2 (minor)

Bioavailability: Oral (with food): 60% (up to twofold increase with food); I.M.: 100%

Half-life elimination: Oral: 7 hours; I.M.: 2-5 hours

Time to peak: Oral: 6-8 hours; I.M.: 60 minutes

Excretion: Feces (66%) and urine (20%) as metabolites; little as unchanged drug (1% urine, 4% feces)

Clearance: 7.5 mL/minute/kg


Dosage

Children and Adolescents: Tourette's syndrome (unlabeled use): Oral: 5-40 mg/day

Adults:

Bipolar mania: Oral: Initial: 40 mg twice daily (with food)

Adjustment: May increase to 60 or 80 mg twice daily on second day of treatment; average dose 40-80 mg twice daily

Schizophrenia: Oral: Initial: 20 mg twice daily (with food)

Adjustment: Increases (if indicated) should be made no more frequently than every 2 days; ordinarily patients should be observed for improvement over several weeks before adjusting the dose

Maintenance: Range 20-100 mg twice daily; however, dosages >80 mg twice daily are generally not recommended

Acute agitation (schizophrenia): I.M.: 10 mg every 2 hours or 20 mg every 4 hours; maximum: 40 mg/day; oral therapy should replace I.M. administration as soon as possible

Elderly: No dosage adjustment is recommended; consider initiating at a low end of the dosage range, with slower titration

Dosage adjustment in renal impairment:

Oral: No dosage adjustment is recommended

I.M.: Cyclodextrin, an excipient in the I.M. formulation, is cleared by renal filtration; use with caution.

Ziprasidone is not removed by hemodialysis.

Dosage adjustment in hepatic impairment: No dosage adjustment is recommended


Administration

Oral: Administer with food.

Injection: For I.M. administration only.


Monitoring Parameters

 Vital signs; serum potassium and magnesium; fasting lipid profile and fasting blood glucose/Hgb A1c (prior to treatment, at 3 months, then annually); BMI, personal/family history of obesity, waist circumference; blood pressure; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms. Weight should be assessed prior to treatment, at 4 weeks, 8 weeks, 12 weeks, and then at quarterly intervals. Consider titrating to a different antipsychotic agent for a weight gain 5% of the initial weight. The value of routine ECG screening or monitoring has not been established.


Patient Education

 Use this mediation exactly as directed; do not alter dosage or discontinue without consulting prescriber - may take 2-3 weeks to achieve desired results. Do not share this medication with anyone else. Avoid alcohol, caffeine, other prescription or OTC medication unless approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. If diabetic, you may experience increased blood sugars. Monitor blood sugars closely. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks hazardous tasks until response to drug is known); dry mouth, nausea, or GI upset (small, frequent meals, good mouth care, sucking lozenges or chewing gum may help); postural hypotension (rise slowly when changing position from lying or sitting to standing or when climbing stairs); urinary retention (void before taking medication); or constipation (increased exercise, fluids, fruit, or fiber may help). Report immediately persistent CNS effects (eg, trembling, altered gait or balance, excessive sedation, seizures, unusual muscle or skeletal movements, excessive anxiety, hallucinations, nightmares, suicidal thoughts, or confusion); swelling or pain in breasts (male or female); altered menstrual pattern; sexual dysfunction; alteration in urinary pattern; vision changes; rash; respiratory difficulty; or chest pain or palpitations. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.


Additional Information

 The increased potential to prolong QTc, as compared to other available antipsychotic agents, should be considered in the evaluation of available alternatives.


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Child/Adolescent Considerations

 Twenty-eight children 7-17 years of age with Tourette's syndrome and chronic tic disorder were randomly assigned to ziprasidone or placebo for 56 days. Ziprasidone was initiated at 5 mg/day and titrated to a maximum of 40 mg/day (Sallee, 2000).

Sallee FR, Kurlan R, Goetz CG, et al, "Ziprasidone Treatment of Children and Adolescents With Tourette's Syndrome: A Pilot Study," J Am Acad Child Adolesc Psychiatry , 2000, 39(3):292-9.


Dosage Forms

Capsule, as hydrochloride: 20 mg, 40 mg, 60 mg, 80 mg

Injection, powder for reconstitution, as mesylate: 20 mg


References

American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity, "Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes," Diabetes Care , 2004, 27(2):596-601.

Davis JM, Chen N, and Glick ID, "A Meta-Analysis of the Efficacy of Second-Generation Antipsychotics," Arch Gen Psychiatry , 2003, 60(6):553-64.

Sallee FR, Kurlan R, Goetz CG, et al, "Ziprasidone Treatment of Children and Adolescents With Tourette's Syndrome: A Pilot Study," J Am Acad Child Adolesc Psychiatry , 2000, 39(3):292-9.


International Brand Names

 Geodon® (CO, IE, IL); Zeldox® (AT, DE, DK, ES, HR, PL, SE, SG, YU)


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