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Ziprasidone

Hazardous Substances DataBank Number
7745
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1 Human Health Effects

1.1 Toxicity Summary

IDENTIFICATION AND USE: Ziprasidone is indicated for the treatment of schizophrenia. Ziprasidone is indicated as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Ziprasidone is indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder. HUMAN EXPOSURE AND TOXICITY: In the patient taking the largest confirmed amount, 3240 mg, the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95). In post-marketing use, adverse events reported in association with ziprasidone overdose generally included extrapyramidal symptoms, somnolence, tremor, and anxiety. Previously reported pediatric ziprasidone overdoses describe a syndrome of sedation, tachycardia, hypotonia, and coma. In pediatric ziprasidone overdose, QTc prolongation and hypotension have also been illustrated, but seizures have not been reported. An interesting case of ziprasidone intoxication involving the development of pinpoint pupils unresponsive to naloxone has been reported. This phenomenon has been reported before with overdose of olanzapine, a similar atypical antipsychotic. The mechanism of miosis associated with overdose of atypical antipsychotics is unclear but is likely related to interference with central innervation of the pupil. Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. In one study, oral ziprasidone prolonged the QT interval on ECG by a mean of 9-14 msec more than that observed in patients receiving risperidone, olanzapine, quetiapine, or haloperidol, but approximately 14 msec less than that observed in patients receiving thioridazine. A ziprasidone overdose with quantitative serum levels of a pediatric patient in coma and with pinpoint pupils illustrating that ingestion of just 1 pill may result to profound mental status and respiratory depression in a child. Positive results were obtained in an in vitro chromosomal aberration assay in human lymphocytes. Psychiatric patients treated with atypical antipsychotic medications should be closely monitored for rhabdomyolysis during correction of hyponatremia, thus permitting prompt therapy to limit its complications. ANIMAL STUDIES: Lifetime carcinogenicity studies were conducted with ziprasidone in rats and 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 sq m 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 an mg/sq m 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 1-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 an mg/sq m 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. Ziprasidone failed to induce significant weight gain during weeks 1-3, however, significant weight gain was observed on day 28 at 2.5 mg/kg (p < 0.05). Ziprasidone had no effect on food intake at any time point. A significant reduction in water intake (p < 0.05) was observed during the first week of treatment with 2.5 mg/kg ziprasidone. Ziprasidone had no effect on intra-abdominal fat weight, wet or dry uterine weight or plasma prolactin levels. All ziprasidone treated animals displayed a normal four-day estrous cycle. In rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day during organogenesis or throughout gestation, but there was no evidence of teratogenicity. Doses of 40 and 160 mg/kg/day were associated with maternal toxicity. Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro mammalian cell gene mutation mouse lymphoma assay, 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 the in vitro mammalian cell gene mutation assay.

1.2 Human Toxicity Excerpts (Complete)

/SIGNS AND SYMPTOMS/ In premarketing trials involving more than 5400 patients and/or normal subjects, accidental or intentional overdosage of oral ziprasidone was documented in 10 patients. All of these patients survived without sequelae. In the patient taking the largest confirmed amount, 3,240 mg, the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95). Adverse reactions reported with ziprasidone overdose included extrapyramidal symptoms, somnolence, tremor, and anxiety.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/SIGNS AND SYMPTOMS/ We describe the first ziprasidone overdose with quantitative serum levels of a pediatric patient in coma and with pinpoint pupils. This case is an important contribution to the pediatric ziprasidone literature because it illustrates that ingestion of just 1 pill may result to profound mental status and respiratory depression in a child. H.C., a 30-month-old girl, presented to the emergency department approximately 30 minutes after an accidental ingestion of an adult family member's medication. The child was found on the floor surrounded by numerous pills and was witnessed to have ingested at least 1 tablet by a caregiver. After finding the child with the pills, the family observed the child for a brief period but transported her to the hospital after she became lethargic and unresponsive. The child received 2 doses of 0.4 mg of intravenous naloxone without change in her neurologic status. The child then underwent a rapid sequence intubation for airway protection and subsequently received gastrointestinal decontamination with 15 g of activated charcoal via the orogastric tube. Ziprasidone is an atypical antipsychotic drug that was approved by the Food and Drug Administration in February 2001 for the general treatment of schizophrenia in adults. Previously reported pediatric ziprasidone overdoses describe a syndrome of sedation, tachycardia, hypotonia, and coma consistent with that of the patient described in this paper. In pediatric ziprasidone overdose, QTc prolongation and hypotension have also been illustrated, but seizures have not been reported. An interesting aspect of this case is the development of pinpoint pupils unresponsive to naloxone. This phenomenon has been reported before with overdose of olanzapine, a similar atypical antipsychotic. The mechanism of miosis associated with overdose of atypical antipsychotics is unclear but is likely related to interference with central innervation of the pupil. Pupil size is maintained by a balance between sympathetic and parasympathetic neurohumeral tones. We propose that an overdose of an alpha-1 receptor blocking agent, such as ziprasidone, results in unopposed parasympathetic stimulation resulting in miosis.
Fasano CJ et al; Pediatr Emerg Care 25 (4): 258-9 (2009)
/SIGNS AND SYMPTOMS/ Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Analyses of seventeen placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6 - to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (ie, aripiprazole, olanzapine, quetiapine, risperidone) compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
/SIGNS AND SYMPTOMS/ Orthostatic hypotension and associated adverse effects (e.g., dizziness, tachycardia, syncope) may occur during ziprasidone therapy in some patients, particularly during the initial dosage titration period, because of the drug's alpha1-adrenergic blocking activity. Syncope was reported in 0.6% of ziprasidone-treated patients in clinical studies. Ziprasidone should be used with particular caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
/SIGNS AND SYMPTOMS/ Seizures occurred in 0.4% of patients receiving ziprasidone in clinical trials. Ziprasidone should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
/CASE REPORTS/ Prolongation of the QT interval can result in an occurrence of ventricular arrhythmias (eg, torsades de pointes) and/or sudden death. In one study, oral ziprasidone prolonged the QT interval on ECG by a mean of 9-14 msec more than that observed in patients receiving risperidone, olanzapine, quetiapine, or haloperidol, but approximately 14 msec less than that observed in patients receiving thioridazine. ...
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
/CASE REPORTS/ Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal disorder characterized by fever, muscular rigidity, delirium, and autonomic instability. Although the classic presentation of NMS has been most commonly associated with the typical neuroleptic medications, sporadic cases in association with atypical neuroleptic medications have been reported. We describe a case report of a pediatric patient with NMS associated with the use of the atypical antipsychotic medication ziprasidone hydrochloride. After a MEDLINE search of relevant literature (key terms: atypical antipsychotic, ziprasidone, neuroleptic malignant syndrome, and NMS; years: 1995-2004), no reports of NMS in association with ziprasidone in the pediatric population were identified. The patient was a 15-year-old male adolescent with a history of schizoaffective disorder treated with ziprasidone capsules, 80 mg QD for 8 weeks prior to presentation. He was brought to the emergency department because the family noted that the child had a tactile fever; was rigid, diaphoretic, tremulous, and difficult to arouse; and had persistent urinary incontinence. The patient was admitted to the pediatric intensive care unit, where he remained rigid and unresponsive except for incoherent speech. He was treated for a presumptive diagnosis of NMS with IV dantrolene sodium (2 mg/kg q6h) to reduce the sequele of NMS; urinary alkalinization with sodium bicarbonate to maintain a urinary pH of 6.5 to 7.0; cardiac, pulse oximetry, and vital sign monitoring; and supportive care, including IV saline hydration. We present this case to alert physicians of the possibility of NMS in adolescent patients treated with ziprasidone.
Leibold J et al; Clin Ther 26 (7): 1105-8 (2004)
/CASE REPORTS/ Clinically significant hypothermia is a commonly evaluated condition in emergency medicine. Most cases are related to prolonged exposure to the environment, infection, or endocrinopathies. Presented here is a case of hypothermia likely induced by an atypical antipsychotic medication. A 69-year-old incarcerated man presented to our emergency department with an oral temperature of 85 degrees F (29.4 degrees C). The patient was taking ziprasidone (Geodon, Pfizer, New York, NY) 80 mg twice daily. Atypical antipsychotic medications have been implicated in numerous cases of clinically significant hypothermia. The mechanism of action for antipsychotics has not been fully elucidated, but the hypothermia induced by this class of medications is believed to be driven through the antagonism of the dopamine (D(1-4)) and 5-hydroxytryptamine-2 (5-HT2) receptors. It has been theorized that under normal conditions, there is a balance between dopamine acting to reduce the body temperature and 5-HT2 acting to elevate body temperature. Atypical antipsychotics, particularly ziprasidone, appear to have a higher affinity to antagonize the 5-HT2 receptor and less at the D(2) receptor, therefore creating an imbalance favoring the lowering of core body temperature. Other theories include the antagonism of alpha(1) receptors by these medications causing vasodilatation and shunting of blood to the skin causing profound heat loss. An antipsychotic medication can be the sole cause of hypothermia or it can be one of a number of possible causes coexisting in the individual with hypothermia.
Gibbons GM et al; Am J Emerg Med 26 (6): 737.e1-2 (2008)
/CASE REPORTS/ Antipsychotic medications are commonLy associated with adverse cutaneous reactions (ACRs) in approximately 5% of patients. Angio-oedema accompanying urticaria is one of the most serious ACRs. The 36-year-old female patient who was diagnosed with Paranoid schizophrenia 6 years ago, was commenced on ziprasidone 120 mg/day. On day 30 of the treatment, the patient presented urticarial papules and plaques all over the body and angio-oedema in the face. The patient was diagnosed as Urticaria + Angio-oedema. The development of ACRs after the initation of ziprasidone monotherapy, disappearance of lesions after the discontinuation of this antipsychotic, and positive intradermal skin test all suggests a possible causal relationship between ACRs and ziprasidone. To our knowledge, this is the first reported case of urticaria and angio-oedema due to ziprasidone monotherapy. Ziprasidone is a valid and effective choice amongst antipsychotic medications, but this case calls for caution regarding ACRs at the time of prescribing.
Akkaya C et al; J Psychopharmacol 21 (5): 550-2 (2007)
/CASE REPORTS/ Tardive laryngeal dystonia, a rare form of dystonic syndrome, was only reported to be induced by typical antipsychotics. Here, we report one case of ziprasidone-induced tardive laryngeal dystonia in a schizophrenic female patient, who showed dysphonia, hoarseness and dyspnea after taking ziprasidone 120 mg/day for 8 months. These symptoms were significantly improved after discontinuing ziprasidone and increasing the dose of trihexyphenidyl for 1 week. Although atypical antipsychotics are associated with a lower risk of extrapyramidal symptoms, caution should be taken for any tardive dystonic movement when using these medications.
Tsia CS et al; Gen Hosp Psychiatry 30 (3): 277-9 (2008)
/CASE REPORTS/ According to premarketing studies, at least 1% of ziprasidone-treated patients exhibited hypertension; however, this figure is not necessarily attributable to the drug. A PubMed/MEDLINE search yielded no articles describing hypertension as a possible adverse event associated with oral ziprasidone therapy. We describe a 53-year-old African-American woman with hypertension and schizophrenia whose blood pressure increased during ziprasidone therapy. She experienced no similar blood pressure increases during therapy with four other atypical antipsychotics. Her mean systolic blood pressure during ziprasidone treatment (158 mm Hg) was significantly higher than before (141 mm Hg) and after (135 mm Hg) treatment. Also, her mean diastolic blood pressure during ziprasidone treatment (88 mm Hg) was significantly higher than after treatment (79 mm Hg). Linear regression analysis demonstrated that the patient's systolic blood pressure increased significantly with ziprasidone dose (regression coefficient [B] = 0.22 mm Hg x day/mg, 95% confidence interval 0.10-0.34, p=0.001). Thus, after adjusting for the effect of antihypertensive doses, an increase of 40 mg/day in ziprasidone yielded an increase of 8.8 mm Hg in systolic blood pressure. For unknown (perhaps genetic) reasons, this patient may have been particularly sensitive to ziprasidone. Clinicians prescribing ziprasidone in patients with hypertension should be aware that their hypertension could worsen with the addition of ziprasidone. If this occurs, replacement of ziprasidone with a different antipsychotic should be considered.
Villanueva N et al; Pharmacotherapy 26 (9): 1352-7 (2006)
/CASE REPORTS/ Ziprasidone is an atypical antipsychotic with a highly specific receptorbinding profile that has been shown to be effective for both positive and negative symptoms of schizophrenia. The agent has been associated with a low frequency of extrapyramidal symptoms and sedative and anticholinergic effects. Four cases of acute ziprasidone overdose were recorded in the database of the department of pharmacovigilance of Pfizer-Spain from January 2003 (when ziprasidone was first marketed in Spain) to October 2004. The doses taken were 780, 1120, 4400, and 4480 mg. In two cases, an excessive ingestion of other drugs such as benzodiazepines and sedative hypnotics was also noted. None of the four cases showed cardiac adverse effects, and the QTc interval was within the normal range in all patients. No relevant neurologic clinical signs were observed, except for mild drowsiness in three cases. Evaluation of these four cases, as well as review of the literature, showed that an overdose of ziprasidone alone, in patients without risk factors that contraindicate its use, is relatively safe.
Gomez-Criado MS et al; Pharmacotherapy 25 (11): 1660-5 (2005)
/CASE REPORTS/ Second-generation antipsychotics presumably lack the typical side effects of conventional antipsychotics. A 34 year old Caucasian woman with ICD-10 diagnosis of Recurrent depressive disorder with current moderate symptoms, and with a history of repeated self-injury was treated with lithium, clonazepam and ziprasidone. On the ninth day of ziprasidone administration, galactorrhea appeared. After 36 days of ziprasidone therapy, galactorrhea persisted. The prolactin plasma level was 28 ng/mL. Thyroid tests (TSH,T3,T4) and the lithium plasma level were within the normal range during ziprasidone treatment. Two weeks after the ziprasidone withdrawal, galactorrhea disappeared and the prolactin level decreased down to 18 ng/mL. Psychiatrists should be aware that even second-generation antipsychotics, including ziprasidone, have a propensity to cause side-effects associated with the dopamine D2 receptor blockade, such as galactorrhea.
Kopecek M et al; Neuro Endocrinol Lett 26 (1): 69-70 (2005)
/CASE REPORTS/ To report a case of rhabdomyolysis related to correction of hyponatremia secondary to psychogenic polydipsia, possibly complicated by the use of ziprasidone. A 50-year-old white man treated for 3 weeks with ziprasidone 40 mg twice daily for chronic paranoid schizophrenia was admitted to the intensive care unit after a witnessed generalized seizure. Marked hypotonic hyponatremia was present secondary to psychogenic polydipsia. After correction of hyponatremia with intravenous NaCl 0.9%, he developed a substantial elevation in the creatine kinase level without any evidence of muscle trauma, stiffness, or swelling or any signs of neuroleptic malignant syndrome. Renal failure or compartment syndrome did not complicate the clinical picture. It is well known that severe hyponatremia can cause neurologic complications such as stupor, seizures, and even coma. Hyponatremia from water intoxication (n = 28) and its correction with intravenous fluids (n = 2) may cause non-neurologic complications such as rhabdomyolysis. An explanation may lie within the calcium-sodium exchange mechanism across the skeletal myocyte or the failure of cell volume regulation secondary to extracellular hypo-osmolality. Neuroleptic medications have been linked to the development of rhabdomyolysis, with antipsychotics being the primary offenders. As of August 2005, there has been only one reported case of rhabdomyolysis related to correction of hyponatremia complicated by an atypical antipsychotic (clozapine). It is possible that ziprasidone, like clozapine, may enhance muscle cell permeability leading to rhabdomyolysis under similar conditions. Psychiatric patients treated with atypical antipsychotic medications should be closely monitored for rhabdomyolysis during correction of hyponatremia, thus permitting prompt therapy to limit its complications.
Zaidi AN; Ann Pharmacother 39 (10): 1726-31 (2005)
/CASE REPORTS/ We present the case of an 18-year-old man, who was admitted with an obsessive compulsive disorder (OCD) since 17 years old. He had symmetry and contamination obsessions and cleaning compulsions, and had been treated with fluoxetine 40 mg/day for 2 months. The patient was not taking additional psychotropic medication. We made ziprasidone augmentation to the treatment. First day, ziprasidone 40 mg bid was applied. Four hours after the evening dose, the patient complained about distress. He demonstrated a notable torticollis and dystonic posture to his left side. Intramuscular biperiden lactate (5 mg) was given, and dystonic symptoms resolved within 30 min. Ziprasidone is a new atypical antipsychotic with reported low potential for extrapyramidal side effects. To our knowledge, acute dystonic reaction with initial doses of ziprasidone in adult has not been reported yet. This case report describes a male patient with OCD developed acute dystonia shortly after initial doses (80 mg/day) of ziprasidone and discusses precautions in antipsychotic use.
Yumru M et al; Prog Neuropsychopharmacol Biol Psychiatry 30 (4): 745-7 (2006)
/CASE REPORTS/ We describe the first ziprasidone overdose with quantitative serum levels of a pediatric patient in coma and with pinpoint pupils. This case is an important contribution to the pediatric ziprasidone literature because it illustrates that ingestion of just 1 pill may result to profound mental status and respiratory depression in a child. H.C., a 30-month-old girl, presented to the emergency department approximately 30 minutes after an accidental ingestion of an adult family member's medication. The child was found on the floor surrounded by numerous pills and was witnessed to have ingested at least 1 tablet by a caregiver. After finding the child with the pills, the family observed the child for a brief period but transported her to the hospital after she became lethargic and unresponsive. The child received 2 doses of 0.4 mg of intravenous naloxone without change in her neurologic status. The child then underwent a rapid sequence intubation for airway protection and subsequently received gastrointestinal decontamination with 15 g of activated charcoal via the orogastric tube. Ziprasidone is an atypical antipsychotic drug that was approved by the Food and Drug Administration in February 2001 for the general treatment of schizophrenia in adults. Previously reported pediatric ziprasidone overdoses describe a syndrome of sedation, tachycardia, hypotonia, and coma consistent with that of the patient described in this paper. In pediatric ziprasidone overdose, QTc prolongation and hypotension have also been illustrated, but seizures have not been reported. An interesting aspect of this case is the development of pinpoint pupils unresponsive to naloxone. This phenomenon has been reported before with overdose of olanzapine, a similar atypical antipsychotic. The mechanism of miosis associated with overdose of atypical antipsychotics is unclear but is likely related to interference with central innervation of the pupil. Pupil size is maintained by a balance between sympathetic and parasympathetic neurohumeral tones. We propose that an overdose of an alpha-1 receptor blocking agent, such as ziprasidone, results in unopposed parasympathetic stimulation resulting in miosis.
Fasano CJ et al; Pediatr Emerg Care 25 (4): 258-9 (2009).
/CASE REPORTS/ Medication-induced prolongation of the Q-T interval, which may result in arrhythmias such as torsades de pointes, has long been associated with the antiarrhythmic class of medications. Recently, however, many classes of non-cardiac medications, such as antihistamines, antipsychotics, and antimicrobials, have been associated with secondary Q-T interval prolongation and the risk of torsades de pointes. This potentially deadly treatment complication came to psychiatry's general attention in the United States with the failed new drug application of sertindole. Sertindole was linked to cases of sudden cardiac death, syncope, and Q-T interval prolongation. The failure of sertindole to make it to the marketplace, coupled with the reports of arrhythmias and sudden cardiac death with other antipsychotics, have ensured that Q-T interval and torsades de pointes will remain a significant clinical issue for psychiatrists for years to come. It is with these important points in mind that we would like to present a case where torsades de pointes developed in a young woman who was being treated with multiple non-cardiac medications, one of which was ziprasidone. This case represents the first report in which torsades de pointes developed in an individual being treated with ziprasidone. This case also underscores the critical importance of communication between consultation psychiatrists, medical consultees, and the patient's primary psychiatrist.
Heinrich TW et al; Psychosomatics 47 (3): 264-8 (2006)
/CASE REPORTS/ Ziprasidone is an atypical antipsychotic approved for the treatment of schizophrenia and bipolar mania in adults and is used off label in children and adolescents. Despite increasing use of ziprasidone in both adult and pediatric populations, there remains a paucity of reports describing unintentional pediatric exposures. The following report describes a patient with isolated ziprasidone ingestion who required intubation secondary to respiratory failure. A 15-month-old previously healthy boy presented to the emergency department shortly after his father found him with approximately five partially dissolved 80-mg ziprasidone tablets in his mouth. The child was flaccid and lethargic with no eye opening, withdrawing from pain only. Two hours after arrival, he developed worsening CNS depression with inability to protect his airway and underwent endotracheal intubation. A serum ziprasidone level was 330 ng/mL by LC/MS. The patient was extubated approximately 14 hr later and was discharged from the hospital shortly thereafter in good health without neurological sequelae. Isolated pediatric ingestion of ziprasidone resulting in the need for significant medical intervention has not been previously reported. We report a case of respiratory failure requiring intubation following accidental ziprasidone ingestion with confirmatory serum levels.
Gresham C, Ruha AM; J Med Toxicol 6 (1): 41-3 (2010)
/SURVEILLANCE/ Ziprasidone is an atypical antipsychotic associated with QTc prolongation during therapeutic use. We characterized the clinical manifestations associated with ziprasidone overdoses, in particular the incidence and severity of QTc prolongation. Four regional poison centers prospectively collected ziprasidone overdose data from August 1, 2003 to October 1, 2005. Cases were included if they were followed to known medical outcome and comprised single-substance ziprasidone exposures or with co-ingestants not associated with prolongation of the QTc interval. Fifty-six ziprasidone exposures met inclusion criteria. The most common clinical effects were drowsiness (N=38, 67.9%) and tachycardia (N=19, 33.9%). QTc prolongation (>0.500 second) occurred in only one patient. Seven patients had QTc intervals of 0.450 to 0.500 second. Medical outcomes were coded as no effect (13, 23.2%), minor effect (21, 35.5%), moderate effect (20, 35.7%), or major effect (2, 3.4%). Common clinical effects following ziprasidone overdose are drowsiness and tachycardia. Clinically significant QTc prolongation occurs infrequently.
Klein-Schwartz W et al; Clin Toxicol (Phila) 45 (7): 782-6 (2007)
/GENOTOXICITY/ Positive results were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/OTHER TOXICITY INFORMATION/ Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Ziprasidone is not approved for the treatment of patients with Dementia-Related Psychosis.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/OTHER TOXICITY INFORMATION/ Suicide is an attendant risk with psychotic illness or bipolar disorder; high-risk patients should be closely supervised. Ziprasidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497

1.3 Populations at Special Risk (Complete)

Ziprasidone should be used with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer's dementia).
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
The manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
The manufacturer states that ziprasidone should be avoided in patients with congenital prolongation of the QT interval or a history of cardiac arrhythmias and in those receiving concomitant therapy with other drugs that prolong the QTC interval.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496

2 Emergency Medical Treatment

2.1 Antidote and Emergency Treatment (Complete)

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Intravenous access should be established and gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects that might be additive to those of ziprasidone. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with a antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension. In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. There is no specific antidote to ziprasidone, and it is not dialyzable. The possibility of multiple drug involvement should be considered. Close medical supervision and monitoring should continue until the patient recovers.
US Natl Inst Health; DailyMed. Current Medication Information for GEODON (ziprasidone hydrochloride) capsule, GEODON (ziprasidone mesylate) injection, powder, lyophilized, for solution (September 2007). Available from, as of June 23, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=9532
Emergency and supportive measures: 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. 2. Treat coma, seizures, hypotension, and hyperthermia if they occur. 3. Monitor vital signs ECG for at least 6 hours and admit the patient for at least 24 hours if there are signs of significant intoxication. Children with antipsychotic intoxication should be evaluated for possible intentional abuse. /Antipsychotic drugs/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 119-20
Specific drugs and antidotes. There is no specific antidote.1. Dystonic reactions. Give diphenhydramine ... or benztropine ... . 2. QRS interval prolongation: treat quinidine-like cardiotoxic effects with bicarbonate ... . 3. Hypotension from these drugs probably involves vasodilation caused by alpha-1 receptor blockade. Treat with iv fluids and, if needed a vasoconstrictor such as norepinephrine or phenylephrine. Theoretically, drugs with beta-2 activity (eg, epinephrine, isoproterenol) may worsen hypotension. 4. QT prolongation and torsade may respond to magnesium infusion or overdrive pacing. /Antipsychotic drugs/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 120
Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antipsychotic drugs/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 120
Enhanced elimination. Owing to extensive tissue distribution, these drugs are not effectively removed by dialysis or hemoperfusion. Repeat-dose activated charcoal has not been evaluated. /Antipsychotic drugs/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 120
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1

3 Animal Toxicity Studies

3.1 Non-Human Toxicity Excerpts (Complete)

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Increases in serum prolactin were observed in a 1-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/sq m basis).
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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/sq m 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/sq m basis).
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The aim of this study was to investigate effects of ziprasidone on weight gain and reproductive function in female rats. Ziprasidone (1 and 2.5 mg/kg ip) or vehicle was administered once daily for 28 days and body weight, food and water intake measured, in addition to histological examination of vaginal lavage to determine the stage of the estrous cycle. On day 28, the rats were sacrificed and the uterine weights recorded, intra-abdominal fat weight and plasma prolactin levels measured. Ziprasidone failed to induce significant weight gain during weeks 1-3, however, significant weight gain was observed on day 28 at 2.5 mg/kg (p < 0.05). Ziprasidone had no effect on food intake at any time point. A significant reduction in water intake (p < 0.05) was observed during the first week of treatment with 2.5 mg/kg ziprasidone. Ziprasidone had no effect on intra-abdominal fat weight, wet or dry uterine weight or plasma prolactin levels. All ziprasidone treated animals displayed a normal four-day estrous cycle.
Fell MJ et al; Behav Brain Res 160 (2): 338-43 (2005)
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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. Fertility rate was reduced at 160 mg/kg/day. There was no effect on fertility at 40 mg/kg/day (2 times the MRHD on a mg/sq m basis). The effect on fertility appeared to be in the female since fertility was not impaired when males given 160 mg/kg/day were mated with untreated females.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a 6-month study in male rats given 200 mg/kg/day there were no treatment-related findings observed in the testes.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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. 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.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day during organogenesis or throughout gestation, but there was no evidence of teratogenicity. Doses of 40 and 160 mg/kg/day were associated with maternal toxicity. The developmental no-effect dose was 5 mg/kg/day.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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 or greater.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Offspring developmental delays and neurobehavioral functional impairment were observed /in rats/ at doses of 5 mg/kg/day or greater. A no-effect level was not established for these effects.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/GENOTOXICITY/ Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro mammalian cell gene mutation mouse lymphoma assay, ... 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 the in vitro mammalian cell gene mutation assay ...
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
/OTHER TOXICITY INFORMATION/ 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.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a

4 Metabolism / Pharmacokinetics

4.1 Metabolism / Metabolites (Complete)

Ziprasidone is extensively metabolized in the liver principally via reduction by aldehyde oxidase with minimal excretion of unchanged drug in urine or feces. About one-third of ziprasidone's metabolic clearance is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole (BITP) sulphoxide, BITP-sulphone, ziprasidone sulphoxide, and S-methyl-dihydroziprasidone.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
In vitro studies using human liver subcellular fractions indicate that S-methyl-dihydroziprasidone is generated in two steps. The data indicate that the reduction reaction is mediated by aldehyde oxidase and the subsequent methylation is mediated by thiol methyltransferase.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
In vitro studies using human liver microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of excretory metabolites, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation and approximately two-thirds via reduction by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
The metabolism and excretion of ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-+++chloroindolin-2-one hydrochloride hydrate) were studied in Long Evans rats after oral administration of a single dose of a mixture of 14C- and 3H-labeled ziprasidone. ... Ziprasidone was extensively metabolized in rats, and only a small amount of ziprasidone was excreted as unchanged drug. Twelve metabolites were identified ... The structures of eight metabolites were unambiguously confirmed by coelution on HPLC with synthetic standards, and four additional metabolites were partially identified. There was a gender-related difference in the excretion of urinary metabolites in Long Evans rats. The major route of metabolism in male rats involved N-dealkylation. In female rats the major metabolites were due to oxidation at the benzisothiazole ring. Based on the structures of these metabolites, four major and two minor routes of metabolism of ziprasidone were identified. The major routes included 1) N-dealkylation of the ethyl side chain attached to the piperazinyl nitrogen, 2) oxidation at the sulfur, resulting in the formation of sulfoxide and sulfone, 3) oxidation on the benzisothiazole moiety (other than sulfur), and 4) hydration of the C==N bond and subsequent oxidation at the sulfur of the benzisothiazole moiety. The minor routes involved N-oxidation on the piperazine ring and hydrolysis of the oxindole moiety.
Prakash C et al; Drug Metab Dispos 25 (2): 206-18 (1997)

4.2 Absorption, Distribution and Excretion (Complete)

Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations in 6 to 8 hours. 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.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
The bioavailability of ziprasidone administered intramuscularly is 100%. After intramuscular administration of single doses, peak serum concentrations typically occur at approximately 60 minutes post-dose or earlier ...
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Steady-state concentrations are achieved within one to three days of dosing. The mean apparent systemic clearance is 7.5 mL/min/kg.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Ziprasidone has a mean apparent volume of distribution of 1.5 L/kg. It is greater than 99% bound to plasma proteins, binding primarily to albumin and alpha1-acid glycoprotein.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Ziprasidone's activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of ziprasidone are dose-proportional within the proposed clinical dose range, and ziprasidone accumulation is predictable with multiple dosing.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the feces. Unchanged ziprasidone represents about 44% of total drug-related material in serum.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg BID for 5 days in subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in AUC 0-12 of 13% and 34% in Childs-Pugh Class A and B, respectively, compared to a matched control group (n=14). A half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
To compare the pharmacokinetics of ziprasidone in healthy young (18-45 years) men and women, and healthy elderly (> or = 65 years) men and women. Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day(-1), in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1-8, for up to 12 hr after dosing on day 1 and for up to 96 hr after dosing on day 8. The resulting data were used to derive pharmacokinetic parameters of ziprasidone in each age and gender group. Steady-state serum concentrations of ziprasidone were achieved within 2-3 days. The steady-state pharmacokinetics of ziprasidone, determined 8 days after the initiation of treatment, were similar in the young men, elderly men and young women. Assessment of gender effects by analysis of variance revealed statistically significant differences in Cmax (85 vs. 69 ng mL(-1) and tmax (3.19 vs. 4.81 hr) but no differences in AUC(0,12 hr) or lambda(z). Assessment of age effects by analysis of variance revealed statistically significant differences in AUC(0,12 hr) (560 vs. 465 ng mL(-1) hr), Cmax (85 vs. 69 ng mL(-1) and lambda(z) (0.126 vs. 0.197 L hr(-1) but no difference in tmax. Assessment of age and gender effects by analysis of covariance, with body weight as the covariate, did not reveal any significant differences. The mean t(1/2), z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 hr, respectively. Standard deviations of the means for the pharmacokinetic parameters for the elderly women tended to be large.
Wilner KD et al; Br J Clin Pharmacol 49 (Suppl 1): 15S-20S (2000)
The metabolism and excretion of ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-+++chloroindolin-2-one hydrochloride hydrate) were studied in Long Evans rats after oral administration of a single dose of a mixture of 14C- and 3H-labeled ziprasidone. The radioactive dose was quantitatively recovered over 7 days in both male and female rats. The percentage of the dose excreted in urine, bile, and feces of rats was 21.6, 19.2, and 55.6%, respectively. The total excretion in urine and bile suggested that at least 41% of the drug was absorbed. Absorption of ziprasidone was rapid, and the mean plasma concentrations of the unchanged drug and metabolites were slightly higher in the female rats than in the males. The maximal plasma concentrations for ziprasidone and metabolites were reached at 1 hr in both male and female rats. Based on AUC (0-12 hr) values, approximately 59 and 52% of the circulating radioactivity (average of 14C and 3H) was attributable to metabolites in male and female rats, respectively. ...
Prakash C et al; Drug Metab Dispos 25 (2): 206-18 (1997)
... The pharmacokinetics of intramuscular ziprasidone include rapid attainment of therapeutic drug level (time to reach peak serum concentration [tmax]
Preskorn SH; Clin Pharmacokinet 44 (11): 1117-33 (2005)

4.3 Biological Half-Life (Complete)

Elimination of ziprasidone is mainly via hepatic metabolism with a mean terminal half-life of about 7 hours within the proposed clinical dose range.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
The mean t(1/2), z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 hr, respectively.
Wilner KD et al; Br J Clin Pharmacol 49 (Suppl 1): 15S-20S (2000)

4.4 Mechanism of Action (Complete)

Ziprasidone is a benzisothiazolyl piperazine-derivative antipsychotic agent that is chemically unrelated to other currently available antipsychotic agents (eg, butyrophenones, phenothiazines) and has been referred to as an atypical or second-generation antipsychotic agent. The exact mechanism of antipsychotic action of ziprasidone has not been fully elucidated but, like that of other atypical antipsychotic agents (eg, olanzapine, risperidone), may involve antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors. As with other drugs that are effective in bipolar disorder, the precise mechanism of antimanic action of ziprasidone has not been fully elucidated. Antagonism of various other receptors (eg, histamine H1 receptors, alpha1-adrenergic receptors) may contribute to other therapeutic and adverse effects (eg, orthostatic hypotension, somnolence) observed with ziprasidone.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2507
Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D, and alpha1-adrenergic receptors (Ki s of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and moderate affinity for the histamine H1 receptor (Ki=47 nM). Ziprasidone functioned as an antagonist at the D2, 5HT2A, and 5HT1D receptors, and as an agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC50 >1 uM).
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone. Ziprasidone's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism of alpha1-adrenergic receptors may explain the orthostatic hypotension observed with this drug.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
c-Fos immunohistochemistry was performed on paraformaldehyde-fixed cryosections of rat brains obtained, initially, from animals 2, 4, or 6 hr after oral administration of 10 mg/kg ziprasidone or vehicle and, subsequently, from animals 2 hr after oral administration of 1, 3, or 10 mg/kg ziprasidone or vehicle. The density of immunoreactive nuclei was assessed in pre-determined forebrain regions. Ziprasidone induced a time-dependent increase in the density of c-Fos-positive nuclei that was maximal at 2 hr. At the 2 hr time-point, c-Fos expression was significantly (p<0.05) elevated in the shell and core of the nucleus accumbens, lateral and medial caudate putamen, and lateral septum. At 4 hr post-dose, c-Fos expression was also significantly increased in the cingulate gyrus. Ziprasidone-induced c-Fos expression was dose-dependent with significant (p<0.05) c-Fos expression observed in the nucleus accumbens (shell and core) and caudate putamen (lateral and medial) at 3 and 10 mg/kg and in the lateral septum at 10 mg/kg. Increased c-Fos expression in the nucleus accumbens and lateral septum is considered to be predictive of activity against positive symptoms, in the caudate putamen of motor side effect liability, and in the cingulate gyrus of efficacy against negative symptoms. Thus, the observed pattern of c-Fos expression induced in rat brain by ziprasidone is consistent with its reported clinical effects...
Jennings CA et al; Psychopharmacology (Berl) 184 (1): 13-20 (2006)
... The mechanism of action for antipsychotics has not been fully elucidated, but the hypothermia induced by this class of medications is believed to be driven through the antagonism of the dopamine (D(1-4)) and 5-hydroxytryptamine-2 (5-HT2) receptors. It has been theorized that under normal conditions, there is a balance between dopamine acting to reduce the body temperature and 5-HT2 acting to elevate body temperature. Atypical antipsychotics, particularly ziprasidone, appear to have a higher affinity to antagonize the 5-HT2 receptor and less at the D(2) receptor, therefore creating an imbalance favoring the lowering of core body temperature. Other theories include the antagonism of alpha(1) receptors by these medications causing vasodilatation and shunting of blood to the skin causing profound heat loss. ...
Gibbons GM et al; Am J Emerg Med 26 (6): 737.e1-2 (2008)

5 Pharmacology

5.1 Therapeutic Uses (Complete)

Antipsychotic Agents; Dopamine Antagonists; Serotonin Antagonists
National Library of Medicine's Medical Subject Headings. Ziprasidone. Online file (MeSH, 2015). Available from, as of Septmeber 2, 2015: https://www.nlm.nih.gov/mesh/MBrowser.html
Ziprasidone is indicated for the treatment of schizophrenia. The efficacy of oral ziprasidone was established in four short-term (4- and 6-week) controlled trials of adult schizophrenic inpatients and in one maintenance trial of stable adult schizophrenic inpatients. /Included in US product label/
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Ziprasidone is indicated as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Efficacy was established in two 3-week monotherapy studies in adult patients /Included in US product label/
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Ziprasidone is indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder. Efficacy was established in a maintenance trial in adult patients. The efficacy of ziprasidone as monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials /Included in US product label/
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a

5.2 Drug Warnings (Complete)

/BOXED WARNING/ WARNING: 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. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Ziprasidone is not approved for the treatment of patients with Dementia-Related Psychosis.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Contraindications /include/ known history of QT prolongation (including congenital long QT syndrome), recent acute myocardial infarction, or uncompensated heart failure. Concomitant therapy with other drugs that prolong the QT interval. Known hypersensitivity to ziprasidone.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Analyses of seventeen placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6 - to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (ie, aripiprazole, olanzapine, quetiapine, risperidone) compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Prolongation of the QT interval can result in an occurrence of ventricular arrhythmias (eg, torsades de pointes) and/or sudden death. In one study, oral ziprasidone prolonged the QT interval on ECG by a mean of 9-14 msec more than that observed in patients receiving risperidone, olanzapine, quetiapine, or haloperidol, but approximately 14 msec less than that observed in patients receiving thioridazine. ... Patients at particular risk of torsades de pointes and/or sudden death include those with bradycardia, hypokalemia, or hypomagnesemia, those receiving concomitant therapy with other drugs that prolong the QTC interval, and those with congenital prolongation of QTC interval. The manufacturer states that ziprasidone should be avoided in patients with congenital prolongation of the QT interval or a history of cardiac arrhythmias and in those receiving concomitant therapy with other drugs that prolong the QTC interval.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Baseline serum potassium and magnesium concentrations should be determined in patients at risk for substantial electrolyte (ie, potassium, magnesium) disturbances, particularly those receiving concomitant diuretic therapy, and hypokalemia or hypomagnesemia should be corrected prior to initiating ziprasidone. Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (eg, Holter monitoring), is recommended during ziprasidone therapy in patients with symptoms that could indicate torsades de pointes (eg, dizziness, palpitations, syncope). Ziprasidone therapy should be discontinued if the QTC interval exceeds 500 msec.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including rare cases associated with ziprasidone therapy.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Because use of antipsychotic agents, including ziprasidone, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome. Chronic antipsychotic treatment generally should be reserved for patients with a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically. The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months. If signs and symptoms of tardive dyskinesia appear in a ziprasidone-treated patient, ziprasidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite presence of the syndrome.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies (which did not include ziprasidone) suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., clozapine, olanzapine, quetiapine, risperidone); it remains to be determined whether ziprasidone also is associated with this increased risk. Although there have been few reports of hyperglycemia or diabetes in patients receiving ziprasidone, it is not known whether the paucity of such reports is due to relatively limited experience with the drug. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While some evidence suggests that the risk for diabetes may be greater with some atypical antipsychotics (e.g., clozapine, olanzapine) than with others (e.g., aripiprazole, asenapine, iloperidone, lurasidone, quetiapine, risperidone, ziprasidone) in the class, available data are conflicting and insufficient to provide reliable estimates of relative risk associated with use of the various atypical antipsychotics. The manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment. Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing. In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
Rash and/or urticaria, possibly related to dose and/or duration of therapy, occurred in about 5% of patients in clinical studies and have necessitated discontinuance of the drug in about 17% of these patients. Several ziprasidone-treated patients with rash had signs and symptoms of associated systemic illness (e.g., elevated leukocyte count). Adjunctive treatment with antihistamines or corticosteroids and/or drug discontinuance may be required. Ziprasidone should be discontinued if an alternative etiology of rash cannot be identified.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
Orthostatic hypotension and associated adverse effects (e.g., dizziness, tachycardia, syncope) may occur during ziprasidone therapy in some patients, particularly during the initial dosage titration period, because of the drug's alpha1-adrenergic blocking activity. Syncope was reported in 0.6% of ziprasidone-treated patients in clinical studies. Ziprasidone should be used with particular caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
Seizures occurred in 0.4% of patients receiving ziprasidone in clinical trials. Ziprasidone should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia. Ziprasidone should be used with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer's dementia).
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
Suicide is an attendant risk with psychotic illness or bipolar disorder; high-risk patients should be closely supervised. Ziprasidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
Prolactin concentrations exceeding 22 ng/mL were reported in about 20% of patients receiving ziprasidone in phase II or III clinical studies compared with about 4, 46, or 89% of those receiving placebo, haloperidol, or risperidone, respectively.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
Median weight gain of 0.5 kg occurred in patients receiving ziprasidone compared with no median weight change in those receiving placebo. In clinical studies, ziprasidone reportedly caused less weight gain than clozapine, olanzapine, quetiapine, or risperidone.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2497
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.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
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.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
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, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Pharmacokinetics of oral ziprasidone hydrochloride (20 mg twice daily for 8 days) were similar between individuals with varying degrees of renal impairment and those with normal renal function, suggesting that dosage adjustment based on the degree of renal impairment is generally not necessary. Ziprasidone is not removed by hemodialysis. Ziprasidone for IM injection has not been systematically evaluated in patients with renal impairment. However, commercially available ziprasidone for injection, when reconstituted, contains methanesulfonic acid solubilized to sulfobutylether beta-cyclodextrin sodium, an excipient that is cleared by renal filtration. Therefore, IM ziprasidone should be used with caution in patients with renal impairment.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498
Adverse effects occurring in 5% or more of patients with schizophrenia receiving oral ziprasidone and at a frequency at least twice the that reported with placebo include somnolence and respiratory tract infection.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498
Adverse effects occurring in 5% or more of patients with schizophrenia receiving IM ziprasidone 10 or 20 mg and at a frequency at least twice that reported among those receiving IM ziprasidone 2 mg include somnolence, headache, and nausea.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498
Adverse effects occurring in 5% or more of patients with bipolar mania receiving oral ziprasidone and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, and vomiting.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2498
Adverse events /reported in post-marketing surveillance/ include rare occurrences of the following (no causal relationship with ziprasidone has been established): Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors); Digestive System Disorders: Swollen tongue; Nervous System Disorders: Facial droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Reproductive System and Breast Disorders: Galactorrhea, priapism; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash; Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg BID for 5 days in subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in AUC 0-12 of 13% and 34% in Childs-Pugh Class A and B, respectively, compared to a matched control group (n=14). A half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Not known whether ziprasidone is distributed into milk; use in nursing women is not recommended.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2496
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of March 30, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
According to premarketing studies, at least 1% of ziprasidone-treated patients exhibited hypertension; however, this figure is not necessarily attributable to the drug. A PubMed/MEDLINE search yielded no articles describing hypertension as a possible adverse event associated with oral ziprasidone therapy. We describe a 53-year-old African-American woman with hypertension and schizophrenia whose blood pressure increased during ziprasidone therapy. She experienced no similar blood pressure increases during therapy with four other atypical antipsychotics. Her mean systolic blood pressure during ziprasidone treatment (158 mm Hg) was significantly higher than before (141 mm Hg) and after (135 mm Hg) treatment. Also, her mean diastolic blood pressure during ziprasidone treatment (88 mm Hg) was significantly higher than after treatment (79 mm Hg). Linear regression analysis demonstrated that the patient's systolic blood pressure increased significantly with ziprasidone dose (regression coefficient [B] = 0.22 mm Hg x day/mg, 95% confidence interval 0.10-0.34, p=0.001). Thus, after adjusting for the effect of antihypertensive doses, an increase of 40 mg/day in ziprasidone yielded an increase of 8.8 mm Hg in systolic blood pressure. For unknown (perhaps genetic) reasons, this patient may have been particularly sensitive to ziprasidone. Clinicians prescribing ziprasidone in patients with hypertension should be aware that their hypertension could worsen with the addition of ziprasidone. If this occurs, replacement of ziprasidone with a different antipsychotic should be considered.
Villanueva N et al; Pharmacotherapy 26 (9): 1352-7 (2006)
... Psychiatric patients treated with atypical antipsychotic medications should be closely monitored for rhabdomyolysis during correction of hyponatremia, thus permitting prompt therapy to limit its complications.
Zaidi AN; Ann Pharmacother 39 (10): 1726-31 (2005)

5.3 Interactions (Complete)

In vivo studies have revealed an approximately 35% decrease in ziprasidone AUC by concomitantly administered carbamazepine, an approximately 35-40% increase in ziprasidone AUC by concomitantly administered ketoconazole, but no effect on ziprasidone's pharmacokinetics by cimetidine or antacid.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
Ziprasidone may antagonize the effects of levodopa and dopamine agonists.
NIH; DailyMed. Current Medication Information for Ziprasidone- ziprasidone hydrochloride capsule (Revised: December 2014). Available from, as of September 2, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=315e24c2-2f8c-47d9-b1b1-ce006646098a
... A 47-year-old white male with a history of schizoaffective disorder was admitted to the hospital due to an exacerbation of severe mania. He had been taking lithium 450 mg twice daily and divalproex sodium 750 mg/day. On hospital day 2, ziprasidone 80 mg twice daily was added, and as-needed doses of intramuscular ziprasidone 20 mg and lorazepam 2 mg were used for agitation. On day 6, the patient developed hyperthermia (39.4 degrees C), elevated creatine kinase 26,000 units/L and white blood cell (WBC) count (20.7 x 10(3)/uL), myoglobinuria, hypotension (68/40 mmHg), altered mental status, and tachypnea (28 breaths/min). This case is notable for the absence of muscle rigidity, which presents in greater than 90% of patients with NMS taking traditional antipsychotics. This case of ziprasidone- and lithium-induced NMS is of probable cause, as determined by the Naranjo probability scale. The patient presented with symptoms consistent with neuroleptic malignant syndrome 4 days after initiation of ziprasidone and lithium. ...
Borovicka MC et al; Ann Pharmacother 40 (1): 139-42 (2006)
In this study, /investigators/ determined if subacute administration of the atypical antipsychotic ziprasidone altered the toxic effects of cocaine in mice. Ziprasidone (4 mg/kg) or placebo was administered to the first two groups of CF-1 mice for 10 days and, then on day 10, an estimated LD50 dose of cocaine (102 mg/kg) was given to these mice. In a third group, in order to produce a ziprasidone withdrawal state, we administered ziprasidone for 10 days, followed by no treatment for 2 days before cocaine administration. There was no significant difference among the three groups in overall survival: 63% in the treatment group, 60% in the withdrawal group, and 80% in the placebo group. Survival time was significantly shorter for the withdrawal group than for the control group. /This/ study may have been limited by lower than expected serum ziprasidone concentrations and lower than expected lethality from cocaine. However, /these/ findings suggest that administration of an atypical antipsychotic for 10 days may increase the toxic effects of cocaine.
Heard K et bal; Hum Exp Toxicol. 2008 Jun;27(6):499-503 (2008)
... A 70-year-old male was initiated on quetiapine therapy for an acute exacerbation of chronic schizophrenia. The baseline electrocardiogram (ECG) showed a normal QT interval (QTc: 417 ms). In combination therapy of quetiapine and ziprasidone the patient developed suddenly cardiac arrhythmia with extrasystoles and the ECG revealed a prolonged QTc interval of 482 ms. After breaking off treatment with quetiapine and reduction of ziprasidone a normalized QT interval (QTc: 428 ms) was measured. /Investigators/ suppose a potential of pharmacokinetic interaction between quetiapine and ziprasidone because of the same metabolic pathway by CYP3A4. Combining treatment of quetiapine and ziprasidone is therefore contraindicated. ...
Minov C; Psychiatr Prax 31 (Suppl 1): S142-4 (2004)
... A 17-year-old male developed a widened QRS and a prolonged QTc interval following an overdose of ziprasidone and bupropion. He required hospital admission for aggressive cardiac monitoring and antidysrhythmic therapy, stabilizing to baseline by 80 hours postingestion. /Investigators/ present a case that underscores the potential cardiotoxicities of these medications. Ziprasidone and bupropion ingestion can be associated with cardiotoxicities that may require several days of aggressive cardiac monitoring and treatment.
Biswas AK et al; J Toxicol Clin Toxicol 41 (2): 101-4 (2003)

6 Environmental Fate & Exposure

6.1 Environmental Fate / Exposure Summary

Ziprasidone's production and administration as a medication may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.0X10-13 mm Hg at 25 °C indicates ziprasidone will exist solely in the particulate phase in the atmosphere. Particulate-phase ziprasidone will be removed from the atmosphere by wet and dry deposition. Ziprasidone contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, ziprasidone is expected to be immobile based upon an estimated Koc of 1.0X10+5. An estimated pKa of ziprasidone is 14.89, indicating that this compound will exist entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Ziprasidone is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, ziprasidone is expected to adsorb to suspended solids and sediment based upon the estimated Koc. The estimated pKa indicates ziprasidone will exist entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 110 suggests the potential for bioconcentration in aquatic organisms is high. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to ziprasidone may occur through inhalation and dermal contact with this compound at workplaces where ziprasidone is produced or used. Exposure to ziprasidone among the general population may be limited to those administered the drug, an antipsychotic. (SRC)

6.2 Probable Routes of Human Exposure (Complete)

Occupational exposure to ziprasidone may occur through inhalation and dermal contact with this compound at workplaces where ziprasidone is produced or used. Exposure to ziprasidone among the general population may be limited to those administered the drug, an antipsychotic. (SRC)

6.3 Artificial Pollution Sources (Complete)

Ziprasidone's production and adminitration as a medication(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1891 (2013)

6.4 Environmental Fate (Complete)

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+5(SRC), determined from a structure estimation method(2), indicates that ziprasidone is expected to be immobile in soil(SRC). An estimated pKa of ziprasidone of 14.89(3) indicates that this compound will exist entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Ziprasidone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 13, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) ChemSpider; Ziprasidone. (146939-27-7) CSID: 54841. London, UK: Royal Chemical Society. Available from, as of Feb 12, 2015: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+5(SRC), determined from a structure estimation method(2), indicates that ziprasidone is expected to adsorb to suspended solids and sediment(SRC). The estimated pKa of 14.89(3) indicates ziprasidone will exist entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. According to a classification scheme(4), an estimated BCF of 110(SRC), from an estimated log Kow of 3.60(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is highSRC). Biodegradation data in water were not available(SRC, 2015).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 13, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) ChemSpider; Ziprasidone. (146939-27-7) CSID: 54841. London, UK: Royal Chemical Society. Available from, as of Feb 12, 2015: https://www.chemspider.com/Search.aspx
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ziprasidone, which has an estimated vapor pressure of 1.0X10-13 mm at Hg 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ziprasidone may be removed from the air by wet and dry deposition(SRC). Ziprasidone contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 13, 2105: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

6.5 Environmental Abiotic Degradation (Complete)

Ziprasidone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Ziprasidone contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

6.6 Environmental Bioconcentration (Complete)

An estimated BCF of 110 was calculated in fish for ziprasidone(SRC), using n estimated log Kow of 3.60(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 13, 2105: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm/
(2) Franke C et al; Chemosphere 29: 1501-14 (1994)

6.7 Soil Adsorption / Mobility (Complete)

Using a structure estimation method based on molecular connectivity indices(1), the Koc of ziprasidone can be estimated to be 1.3X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that ziprasidone is expected to be immobile in soil. The estimated pKa value of ziprasidone is 14.89(3), indicating that this compound will exist entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 13, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) ChemSpider; Ziprasidone. (146939-27-7) CSID: 54841. London, UK: Royal Chemical Society. Available from, as of Feb 12, 2015: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

6.8 Volatilization from Water / Soil (Complete)

The estimated pKa of 14.89(1) indicates ziprasidone will exist entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process.Ziprasidone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-13 mm Hg(SRC), determined from a fragment constant method(2).
(1) ChemSpider; Ziprasidone. (146939-27-7) CSID: 54841. London, UK: Royal Chemical Society. Available from, as of Feb 12, 2015: https://www.chemspider.com/Search.aspx
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 13, 2105: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

6.9 Environmental Water Concentrations (Complete)

While data specific to ziprasidone were not located(SRC, 2015), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

7 Environmental Standards & Regulations

7.1 FDA Requirements (Complete)

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ziprasidone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ziprasidone hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 6, 2015: https://www.fda.gov/cder/ob/
The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ziprasidone mesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ziprasidone mesylate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 6, 2015: https://www.fda.gov/cder/ob/

8 Chemical / Physical Properties

8.1 Molecular Formula

C21-H21-Cl-N4-O-S
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1891

8.2 Molecular Weight

412.94
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1891

8.3 Other Experimental Properties (Complete)

White to slightly pink powder. MW: 467.41. Also prepared as the hemihydrate, mp >300 °C /Ziprasidone hydrochloride monohydrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1891

9 Chemical Safety & Handling

9.1 GHS Classification

Pictogram(s)
Flammable
Irritant
Health Hazard
Signal
Danger
GHS Hazard Statements

H225: Highly Flammable liquid and vapor [Danger Flammable liquids]

H315: Causes skin irritation [Warning Skin corrosion/irritation]

H360: May damage fertility or the unborn child [Danger Reproductive toxicity]

Precautionary Statement Codes

P203, P210, P233, P240, P241, P242, P243, P264, P280, P302+P352, P303+P361+P353, P318, P321, P332+P317, P362+P364, P370+P378, P403+P235, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

9.2 Flash Point

-2 °C (28 °F) - closed cup
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html

9.3 Fire Fighting Procedures (Complete)

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. Use water spray to cool unopened containers.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html
Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html

9.4 Hazardous Reactivities and Incompatibilities (Complete)

Incompatible materials: Alkali metals, Aluminum, Strong oxidizing agents, Bases, Amines, Magnesium, Strong acids and strong bases, Vinyl compounds
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html

9.5 Personal Protective Equipment (PPE) (Complete)

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Impervious clothing, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html
Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html

9.6 Preventive Measures (Complete)

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html
Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Use explosion-proof equipment.Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html

9.7 Stability / Shelf Life (Complete)

Stable under recommended storage conditions.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html

9.8 Storage Conditions (Complete)

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 °C; Storage class (TRGS 510): Flammable liquids
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html
Ziprasidone for Injection should be stored at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F) in dry form. Protect from light. Following reconstitution, ziprasidone for Injection can be stored, when protected from light, for up to 24 hours at 15-30 °C (59-86 °F) or up to 7 days refrigerated, 2-8 °C (36-46 °F).
US Natl Inst Health; DailyMed. Current Medication Information for GEODON (ziprasidone hydrochloride) capsule, GEODON (ziprasidone mesylate) injection, powder, lyophilized, for solution (September 2007). Available from, as of June 23, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=9532
Ziprasidone capsules should be stored at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F).
US Natl Inst Health; DailyMed. Current Medication Information for GEODON (ziprasidone hydrochloride) capsule, GEODON (ziprasidone mesylate) injection, powder, lyophilized, for solution (September 2007). Available from, as of June 23, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=9532

9.9 Cleanup Methods (Complete)

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.; Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations.
Sigma-Aldrich; Material Safety Data Sheet for Ziprasidone solution, Product Number: Z-002, Version 5.5 (Revision Date 02/10/2015). Available from, as of September 1, 2015: https://www.sigmaaldrich.com/safety-center.html

9.10 Disposal Methods (Complete)

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.
SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

10 Manufacturing / Use Information

10.1 Uses (Complete)

MEDICATION
Antipsychotic Agents; Dopamine Antagonists; Serotonin Antagonists
National Library of Medicine's Medical Subject Headings. Ziprasidone. Online file (MeSH, 2014). Available from, as of December 18, 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html

10.2 Manufacturers

Ziprasidone hydrochloride Distributors
Company
Roerig, A Division of Pfizer Inc
Address
New York, NY 10017
Company
Greenstone LLC
Address
Peapack, NJ 07977
Company
Apotex Corp
Address
Weston FL 33326
Company
Lupin Ltd for Bluepoint Laboratories
Address
Goa - 403 722 India
US Natl Inst Health; DailyMed. Current Medical Information. Available from, as of Feb 12, 2015: https://dailymed.nlm.nih.gov/dailymed/about.cfm
Pfizer Inc., 235 East 42nd St., New York, NY 10017-5755, (800) 438-1985 /Formulator/ /Hydrochloride; Mesylate/
Thomson Health Care Inc.; Physicians' Desk Reference 63 ed., Montvale, NJ 2009, p. 2520

10.3 Methods of Manufacturing (Complete)

Preparation: By refluxing 5-(2-chloroethyl)oxindole and N-(1,2-benzisothiazol-3-yl)piperazine with sodium carbonate and sodium iodide in methyl isobutyl ketone, followed by evaporation of the solvent and chromatography on silica gel with 4% methanol in methylene chloride. The salt is formed from the amine by addition of ether saturated with HCl gas.
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1516
Preparation: J. A. Lowe III, A. A. Nagel, European Patent Office patent 281309; eidem, United States of America patent 4831031 (1988, 1989 both to Pfizer).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1891

10.4 Formulations / Preparations (Complete)

Geodon is available in two routes of adminitration: orally in a capsule formulation of ziprasidone hydrochloride in 20 mg, 40 mg, 60 mg, and 80 mg concentrations; and an injection form of ziprasidone mesylate for intramuscular use only in a 20 mg of ziprasidone concentration.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2499

11 Laboratory Methods

11.1 Clinical Laboratory Methods (Complete)

HPLC determination in serum.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1891
Analyte: ziprasidone; matrix: blood (serum), feces, urine; procedure: high-performance liquid chromatography with mass spectrometry detection; limit of quantitation: 0.5 to 50 ng/mL
Prakash C et al; Drug Metab Dispos 25: 863-72 (1997). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)

12 Synonyms and Identifiers

Synonyms

146939-27-7

Ziprasidone

5-[2-[4-(1,2-benzisothiazol-3-yl)1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one

5-(2-(4-(1,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chlorooxindole

6-chloro-5-[2-[4-(9-thia-8-azabicyclo[4.3.0]nona-1,3,5,7-tetraen-7-yl) piperazin-1-yl]ethyl]-1,3-dihydroindol-2-one

UNII-6UKA5VEJ6X

2H-Indol-2-one, 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-

12.1 Substance Title

Ziprasidone

12.2 Associated Chemicals (Complete)

13 Administrative Information

13.1 Hazardous Substances DataBank Number

7745

13.2 Last Revision Date

20151019

13.3 Last Review Date

Reviewed by SRP on 5/14/2015

13.4 Update History

Complete Update on 2015-10-19, 0 fields added/edited/deleted

Complete Update on 2015-10-15, 0 fields added/edited/deleted

Complete Update on 2015-09-15, 46 fields added/edited/deleted

Complete Update on 2009-12-18, 25 fields added/edited/deleted

Created 20090413

CONTENTS