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ZIPRASIDONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ziprasidone is an atypical second generation antipsychotic that is chemically unrelated to phenothiazine or butyrophenone antipsychotics. It is a substituted benzisothiazoyl piperazine that exhibits potent and highly selective dopamine D2 and serotonin 5-HT2 receptor antagonistic activities. The exact mechanism of action of ziprasidone in bipolar disorder is unknown.

Specific Substances

    1) Ziprasidone mesylate (synonym)
    2) Ziprasidone hydrochloride (synonym)
    3) 5-(2-(4-(1,2-Benzisothiazol-3yl)-1-piperazinyl) ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one
    4) CP-88059
    5) CP-88,059-1
    6) Molecular formula: C21-H21-Cl-N4-O-S
    7) CAS 146939-27-7 (ziprasidone)
    8) CAS 138982-67-9 (ziprasidone hydrochloride)
    9) CAS 199191-69-0 (ziprasidone mesylate)

Available Forms Sources

    A) FORMS
    1) Ziprasidone is available as 20, 40, 60 or 80 mg oral capsules and 20 mg/mL single-use vials for intramuscular injection (Prod Info GEODON(R) intramuscular injection, 2015).
    B) USES
    1) Ziprasidone is approved for the treatment of schizophrenia and bipolar I disorder (monotherapy of acute manic or mixed episodes or as an adjunct to lithium or valproate) (Prod Info GEODON(R) intramuscular injection, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ziprasidone is approved for the treatment of schizophrenia and bipolar I disorder (monotherapy of acute manic or mixed episodes or as an adjunct to lithium or valproate).
    B) PHARMACOLOGY: Ziprasidone is an atypical second generation antipsychotic that is chemically unrelated to phenothiazine or butyrophenone antipsychotics. It is a substituted benzisothiazoyl piperazine that exhibits potent and highly selective dopamine D2 and serotonin 5-HT2 receptor antagonistic activities.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (5% or greater): Somnolence, dizziness, lightheadedness, asthenia, extrapyramidal symptoms (eg, hypertonia, dystonia, dyskinesia, hypokinesia, tremor), nausea, vomiting, constipation, dyspepsia, dry mouth, headache, abnormal vision. OTHER EFFECTS: Insomnia, agitation, anxiety, rash, urticaria, prolonged QT, torsades de pointes, hypotension, tachycardia, hypertension, oculogyric crisis, seizures, thrombocytopenia, leukopenia, elevated liver enzymes, neuroleptic malignant syndrome, and serotonin syndrome.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, somnolence, agitation, dizziness, slurred speech, extrapyramidal symptoms (eg, dystonia, akathisia, dyskinesia).
    2) SEVERE TOXICITY: Hypotension, hypertension, tachycardia, prolonged QRS and QTc intervals, torsades de pointes. Respiratory depression may occur following massive overdoses due to CNS depression.
    0.2.20) REPRODUCTIVE
    A) Ziprasidone is classified as FDA pregnancy category C. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. Developmental toxicity, including possible teratogenic effects, was reported in animal studies. It is not known whether ziprasidone or its metabolites are excreted in human milk.

Laboratory Monitoring

    A) Serum ziprasidone levels are not readily available at most facilities, and are not useful for guiding therapy after overdose.
    B) Monitor vital signs and mental status after significant overdose.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Monitor for CNS depression, seizures, and extrapyramidal reactions after significant overdose.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests in patients with respiratory depression.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Control agitation and confusion with benzodiazepines.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. If hypotension is unresponsive to IV fluids, agents with alpha adrenergic effects, such an norepinephrine or phenylephrine, may be preferred. Agents with beta adrenergic activity, such as epinephrine or dopamine, may worsen hypotension in the setting of ziprasidone-induced alpha blockade. Manage severe extrapyramidal symptoms with anticholinergics and/or benzodiazepines. Therapeutic doses of ziprasidone may cause prolongation of the QT interval. Concomitant use of ziprasidone and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities; overdrive pacing may be necessary. Treat QRS prolongation or ventricular dysrhythmias with sodium bicarbonate; use lidocaine if sodium bicarbonate is unsuccessful. Cardiovert unstable ventricular dysrhythmias. Although rare, treat neuroleptic malignant syndrome with benzodiazepines, bromocriptine, consider dantrolene, as well as cooling and supportive measures.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended due to the potential for somnolence, seizures and dystonic reaction.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with serious cardiac toxicity, coma or significant CNS or respiratory depression.
    E) ANTIDOTE
    1) None.
    F) HYPOTENSIVE EPISODE
    1) Administer IV fluids. In theory, agents with beta adrenergic activity, such as epinephrine or dopamine, may worsen hypotension in the setting of ziprasidone-induced alpha blockade. If hypotension is unresponsive to IV fluids, agents with alpha adrenergic effects, such an norepinephrine (0.1 to 0.2 mcg/kg/min, titrate as needed to desired response) or phenylephrine (100 to 180 mcg/min, titrate as needed to desired response), may be preferred.
    G) DYSTONIA
    1) ADULTS: Benztropine 1 to 2 mg IV or diphenhydramine 1 mg/kg/dose IV over 2 minutes. CHILDREN: Diphenhydramine 1 mg/kg/dose IV over 2 minutes (maximum 5 mg/kg/day or 50 mg/m(2)/day).
    H) CONDUCTION DISORDER OF THE HEART
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine. Because ziprasidone can cause Torsades de pointes and QTc prolongation, amiodarone should be used with caution.
    I) TORSADES DE POINTES
    1) Torsades de pointes may develop secondary to QTc prolongation. Treat torsade de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    J) SEIZURES
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    K) NEUROLEPTIC MALIGNANT SYNDROME
    1) Oral bromocriptine, benzodiazepines or oral or IV dantrolene in conjunction with cooling and other supportive measures.
    L) ENHANCED ELIMINATION
    1) Hemodialysis is not likely to be beneficial due to extensive protein binding and a volume of distribution of approximately 1.5 L/kg.
    M) PATIENT DISPOSITION
    1) HOME CRITERIA: Children less than 12 years of age who are naive to ziprasidone can be observed at home following an unintentional ingestion of less than 80 mg and are only experiencing mild sedation. All patients, 12 years of age or older, who are naive to ziprasidone, can be observed at home following an unintentional ingestion of 100 mg or less and are experiencing only mild sedation. All patients who are taking ziprasidone on a chronic basis can be observed at home if they have acutely ingested no more than 5 times their current single dose (not daily dose) of ziprasidone. Patients who have not developed signs or symptoms more than 6 hours after ingestion are unlikely to develop toxicity.
    2) OBSERVATION CRITERIA: Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility. Children less than 12 years of age who are naive to ziprasidone should be referred to a healthcare facility following an unintentional ingestion of 80 mg or more. All patients, 12 years of age or older, who are naive to ziprasidone should be referred to a healthcare facility following an unintentional ingestion of more than 100 mg. All patients who are taking ziprasidone on a chronic basis should be referred to a healthcare facility following an acute ingestion of more than 5 times their current single dose (not daily dose) of ziprasidone.
    3) ADMISSION CRITERIA: Patients with deliberate ingestions demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    N) PITFALLS
    1) When managing a suspected ziprasidone overdose, the possibility of coingestion of other CNS depressant or cardiotoxic agents should be determined.
    O) PHARMACOKINETICS
    1) ORAL: Absorption: rapid. Tmax: 2 to 6 hours postdose. Oral bioavailability: 60%. Protein binding: greater than 99%. Vd: 1.5 L/kg. Hepatic metabolism: extensive. Excretion: only less than 5% excreted as unchanged drug in urine and feces. Elimination half-life: about 7 hours following multiple therapeutic doses.
    2) INTRAMUSCULAR: Bioavailability: 100%. Peak serum concentrations typically occur at approximately 60 minutes or earlier following intramuscular administration. The mean half-life ranges from 2 to 5 hours .
    P) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose ingestions of other centrally acting agents (eg, tricyclic antidepressants, skeletal muscle relaxants) and agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), dystonia or dyskinesia (eg, antipsychotics, neuroleptics), and prolonged QT (eg, haloperidol, paliperidone).

Range Of Toxicity

    A) TOXICITY: SUMMARY: A dose of more than 80 mg is potentially toxic in a drug naive child less than 12 years old. A dose of more than 100 mg is potentially toxic in a drug naive child aged 12 years or greater. In children on chronic ziprasidone therapy an acute ingestion of more than 5 times their current single dose (not daily dose) is potentially toxic. ADULT: One patient developed extrapyramidal symptoms and only a modest increase in the QTc interval after ingesting 12.8 g of ziprasidone. An adult developed QTc prolongation and an episode of torsades de pointes after ingesting 6 g ziprasidone, ethanol and fluoxetine. PEDIATRIC: A 22-month-old girl developed somnolence, drooling, hypertension, and poor muscle tone after ingesting 800 mg of ziprasidone. She recovered following supportive care. A 30-month-old developed coma and respiratory depression after ingesting 40 mg of ziprasidone.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 20 to 80 mg orally twice daily. INTRAMUSCULAR: 10 mg every 2 hours or 20 mg every 4 hours intramuscularly up to a maximum dose of 40 mg daily. PEDIATRIC: The safety and efficacy of ziprasidone in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Ziprasidone is approved for the treatment of schizophrenia and bipolar I disorder (monotherapy of acute manic or mixed episodes or as an adjunct to lithium or valproate).
    B) PHARMACOLOGY: Ziprasidone is an atypical second generation antipsychotic that is chemically unrelated to phenothiazine or butyrophenone antipsychotics. It is a substituted benzisothiazoyl piperazine that exhibits potent and highly selective dopamine D2 and serotonin 5-HT2 receptor antagonistic activities.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (5% or greater): Somnolence, dizziness, lightheadedness, asthenia, extrapyramidal symptoms (eg, hypertonia, dystonia, dyskinesia, hypokinesia, tremor), nausea, vomiting, constipation, dyspepsia, dry mouth, headache, abnormal vision. OTHER EFFECTS: Insomnia, agitation, anxiety, rash, urticaria, prolonged QT, torsades de pointes, hypotension, tachycardia, hypertension, oculogyric crisis, seizures, thrombocytopenia, leukopenia, elevated liver enzymes, neuroleptic malignant syndrome, and serotonin syndrome.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, somnolence, agitation, dizziness, slurred speech, extrapyramidal symptoms (eg, dystonia, akathisia, dyskinesia).
    2) SEVERE TOXICITY: Hypotension, hypertension, tachycardia, prolonged QRS and QTc intervals, torsades de pointes. Respiratory depression may occur following massive overdoses due to CNS depression.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) HYPERTHERMIA
    a) Fever has been reported following therapy with ziprasidone (Prod Info GEODON(R) intramuscular injection, 2015).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) ABNORMAL VISION: The incidence of abnormal vision reported in short-term trials of patients with bipolar mania was 6% for ziprasidone hydrochloride-treated subjects (n=279) compared with 3% for placebo-treated patients (n=136) (Prod Info GEODON(R) intramuscular injection, 2015).
    2) OCULOGYRIC CRISIS developed in an 11-year-old boy after receiving ziprasidone 20 mg twice daily for the treatment of pervasive developmental disorder and psychotic symptoms. Six weeks following initiation of ziprasidone therapy, the child had a sudden onset of dystonic upward deviation of the eyes. Ziprasidone was discontinued and the patient was treated with oral diphenhydramine 50 mg every 4 hours. Symptoms subsided within 30 minutes of the first dose and completely resolved within 24 hours (Ramos et al, 2003).
    3) OCULOGYRIC CRISIS: A case report describes a 28-year-old woman who experienced oculogyric crisis following administration of ziprasidone (80 mg/day) for the treatment of schizophrenia. At 15 years of age, the patient was diagnosed with schizophrenia and was treated with haloperidol with poor response. At the age of 24 years, the patient developed upward deviation of the eyes and blepharospasm for 2 hours which occurred 2 to 3 times per week. She had no loss of consciousness, visual hallucinations, torticollis, or opisthotonus. Haloperidol was switched to ziprasidone 80 mg/day with no further occurrences for the next 7 months. However, this movement returned with a frequency of up to 3 episodes per month while on ziprasidone. An EEG revealed no epileptic issues. Clonazepam (1 mg/day) was then initiated with significant improvement in movement disorder, and she remained free of oculogyric crisis for 8 months. Three days upon discontinuation of clonazepam, movement disorder returned (Viana Bde et al, 2009).
    B) WITH POISONING/EXPOSURE
    1) MIOSIS: Pinpoint pupils unresponsive to naloxone developed in a 30-month-old girl who presented with profound mental status and respiratory depression after ingesting approximately 40 mg of ziprasidone. Following further supportive care, she recovered completely. The mechanism of miosis is unclear but is likely related to unopposed parasympathetic stimulation (Fasano et al, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) Ziprasidone can prolong the QTc and increase the risk of potentially fatal ventricular dysrhythmias ((Anon, 2000)). QT interval prolongation is dose-related. It is not yet known whether ziprasidone will cause torsades de pointes or increase the rate of sudden death. The manufacturer has issued a warning concerning possible QTc prolongation and risk of sudden death, particularly in patients taking other drugs known to prolong the QTc interval, in patients with congenital long QT syndrome, and in patients with a history of cardiac dysrhythmias (Prod Info GEODON(R) intramuscular injection, 2015).
    b) In clinical trials, ziprasidone increased the QTc interval, compared to placebo, by approximately 10 msec at the highest dose (160 mg) (Prod Info GEODON(R) intramuscular injection, 2015).
    c) The risk of QT prolongation and dysrhythmias are increased when potassium and magnesium levels are low. Other risk factors include bradycardia, concomitant use of other drugs that prolong QTc interval, and presence of congenital prolongation of the QT interval (Prod Info GEODON(R) intramuscular injection, 2015).
    d) Three case reports describe QTc prolongation following treatment with ziprasidone (Eker et al, 2009).
    1) The first patient, a 40-year-old man, was previously prescribed haloperidol (2.5 mg/day), quetiapine, and zuclopenthixol decanoate for psychotic disorder. Haloperidol was discontinued due to lack of effect and ziprasidone 80 mg/day was initiated, which was increased to 160 mg/day three weeks later. His psychotic symptoms improved. At 14 months into treatment with ziprasidone, his dose was increased to 240 mg/day to control psychotic exacerbation. Ten weeks following dose increase, an ECG revealed a QTc interval of 0.51 sec. Ziprasidone was decreased to 160 mg/day with initiation of haloperidol (5 mg/day) and biperiden (2 mg/day) to avoid exacerbation. QT prolongation at the subsequent 2, 16, and 20 weeks were 0.4 sec, 0.41 sec, and 0.35 sec, respectively (Eker et al, 2009).
    2) The second patient, a 27-year-old woman with schizophrenia previously taking haloperidol and quetiapine (1200 mg/day), was switched to ziprasidone 120 mg/day due to lack of effect. Within 3 days, her dose was increased to 160 mg/day. On day 25 of treatment, an ECG revealed a QTc interval of 0.44 sec. Her dose of ziprasidone and valproic acid were steadily increased to 240 mg/day and 750 mg/day, respectively. An ECG revealed a QTc interval of 0.51 sec. Her valproic acid dose remained the same, and ziprasidone was decreased to 160 mg/day. Following the ziprasidone dose decrease, ECG testing at the first and second week of dose reduction revealed a QTc intervals of 0.41 sec and 0.38 sec, respectively (Eker et al, 2009).
    3) Patient 3, a 45-year-old woman with schizophrenia, was previously prescribed quetiapine, amisulpride, haloperidol (5 mg/day), risperidone, venlafaxine (150 mg/day), lithium (900 mg/day), and bornaprine hydrochloride (16 mg/day). Haloperidol was switched to ziprasidone (80 mg/day) due to lack of effect. An ECG revealed a QTc interval of 0.4 sec. Two days later, ziprasidone was increased to 160 mg/day and on day 10, an ECG revealed an QTc interval of 0.48 sec. Ziprasidone was discontinued. Ten days later, another ECG revealed a QTc interval of 0.42 sec. All three cases demonstrated a temporal relationship between ziprasidone and QTc prolongation (Eker et al, 2009).
    2) WITH POISONING/EXPOSURE
    a) Prolongation of QRS and QTc intervals have been reported in overdose (Bryant et al, 2003).
    b) CASE REPORT/MIXED INGESTION: A 55-year-old woman with a history of bipolar disorder, anxiety, hepatitis C, alcohol abuse, hypothyroidism, pulmonary hypertension, and asthma, developed nausea and vomiting approximately 3 hours after ingesting 6 grams of ziprasidone and unknown quantities of 20-mg fluoxetine and 1-mg benztropine with a pint of rum. Several hours later, she presented to the ED with mydriasis and dry mouth. At this time, an ECG revealed a QTc of 529 msec. Approximately 4 hours later, she developed ventricular fibrillation and torsades de pointes. She returned to normal sinus rhythm following defibrillation. Laboratory analysis revealed magnesium 1.5 mg/dL (reference range, 1.8 to 2.5 mg/dL); phosphorous 2.4 mg/dL (reference range, 2.5 to 4.6 mg/dL), and potassium 3.7 mg/dL (reference range, 3.6 to 5.1 mg/dL). These values normalized after electrolytes supplementation. The QTc on day 1 and 4 were 612 msec (maximum value) and 497 msec, respectively (Alipour et al, 2010).
    c) OBSERVATIONAL STUDY: A prospective observational study by four regional poison centers was conducted in part to determine the incidence and severity of QTc prolongation. Of the 56 cases (ziprasidone alone or coingestant not known to prolong the QTc interval) reported, only one case of QTc interval prolongation greater than 0.500 second occurred in an adult following an ingestion of ziprasidone and methylphenidate. Seven individuals had a QTc of 0.450 to 0.500 second. In all 8 cases, the effect was noted within 12 hours (range 0.75 to 12 hours) of ingestion, and had begun to normalize or narrow within 6 hours (Klein-Schwartz et al, 2007).
    d) CASE REPORT/MIXED INGESTION: A 30-year-old woman with a history of mental retardation and depression, intentionally ingested ziprasidone, amantadine and ibuprofen and was found unresponsive. An ECG obtained approximately 3 hours after exposure showed slight bradycardia (55 bpm) and a prolonged QT of 800 ms with a QTc of 770 ms. Eight hours after arrival, the patient lost consciousness and developed a wide complex tachydysrhythmia requiring defibrillation. She was successfully resuscitated and started on an infusion of magnesium. Despite intensive supportive care, the patient continued to have episodes of sustained ventricular tachycardia until her QTc shortened to less than 500 ms. Although the patient was hemodynamically stable, she died on hospital day 10 due to numerous nosocomial complications (ie, urosepsis, DIC, and pulmonary embolism) (Manini et al, 2007).
    e) CASE REPORT/MIXED INGESTION: A 17-year-old man was reported on ECG to have a widened QRS complex (200 msec) and prolonged QTc interval (480 msec) 2.5 hours following an intentional multi-drug overdose (2400 mg ziprasidone and between 2250-3000 mg bupropion SR). Initial ECG in the ED 1 hour postingestion was normal. The patient was somnolent and his condition deteriorated requiring intubation and supportive care. By 80 hours postingestion his QTc normalized around 440 msec (Biswas et al, 2003).
    f) CASE SERIES/MIXED INGESTION: Prolonged QTc interval was reported in 3 of 3 cases of ziprasidone overdose, including one case where a 50-year-old woman presented to the ED with somnolence and a QTc of 638 msec after ingesting 1760 mg ziprasidone and 1000 mg quetiapine tablets. The patient was admitted to the ICU for supportive care. Her QTc interval decreased and her mental status improved over the course of the next several hours(Bryant et al, 2003).
    g) CASE REPORT: A mild delay in intraventricular conduction (QRS duration - 111 msec), QT interval (395 msec) and QTc interval (445 msec) was seen on ECG in a 38-year-old woman following an ingestion of 4020 mg ziprasidone. Mild hypotension (99/34 mm Hg), diarrhea and urinary retention were also reported. The patient recovered after a 14-hour period (House, 2002).
    h) CASE REPORT: Four and one-half hours following an overdose of 3120 mg of ziprasidone a 50-year-old man was shown to have minimal QT prolongation (QT/QTc 430/490 msec) and nonspecific flattening of the T wave on ECG. No dysrhythmias were recorded. Results of a CBC were normal. Changes in QT were maximal at 6 hours after exposure. The patient fully recovered following charcoal decontamination and supportive care (Burton et al, 2000).
    i) CASE REPORT: A 57-year-old woman developed a QTc of 457 ms 12 hours after ingesting 4440 mg of ziprasidone. She recovered following supportive care (Prieto et al, 2005).
    B) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 28-year-old woman with systemic lupus erythematosus, mood disorder, and borderline personality disorder, taking multiple medications, including lithium and ziprasidone, developed an episode of asymptomatic nonsustained polymorphic ventricular tachycardia which was preceded by a prolonged QT interval of 560 msec. Although the authors noted multiple factors may have played a role in the development of torsades in this patient with a complicated psychiatric history, a causal relationship between ziprasidone and torsades and repolarization abnormalities was strongly suggested by development of QTc prolongation when the patient was challenged on 2 separate occasions with ziprasidone. A shortening of the QT interval was also observed when ziprasidone was discontinued (Heinrich et al, 2006).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT/MIXED INGESTION: A 55-year-old woman with a history of bipolar disorder, anxiety, hepatitis C, alcohol abuse, hypothyroidism, pulmonary hypertension, and asthma, developed nausea and vomiting approximately 3 hours after ingesting 6 grams of ziprasidone and unknown quantities of 20-mg fluoxetine and 1-mg benztropine with a pint of rum. Several hours later, she presented to the ED with mydriasis and dry mouth. At this time, an ECG revealed a QTc of 529 msec. Approximately 4 hours later, she developed ventricular fibrillation and torsades de pointes. She returned to normal sinus rhythm following defibrillation. Laboratory analysis revealed magnesium 1.5 mg/dL (reference range, 1.8 to 2.5 mg/dL); phosphorous 2.4 mg/dL (reference range, 2.5 to 4.6 mg/dL), and potassium 3.7 mg/dL (reference range, 3.6 to 5.1 mg/dL). These values normalized after electrolytes supplementation. The QTc on day 1 and 4 were 612 msec (maximum value) and 497 msec, respectively (Alipour et al, 2010).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Postural hypotension (incidence unknown) has been reported in clinical trials following therapeutic doses (Prod Info GEODON(R) intramuscular injection, 2015; Citrome, 1997).
    2) WITH POISONING/EXPOSURE
    a) Significant hypotension may occur following severe ziprasidone poisoning due to its alpha-1 adrenergic antagonist properties (Prod Info GEODON(R) intramuscular injection, 2015).
    b) CASE SERIES: In a study of 433 ziprasidone exposure cases, hypotension was reported in 9 (2.1%) patients. The ingested dose was known in 191 of the cases, with a mean dose of 666 mg (range 6 to 11,200 mg) (Forrester, 2008).
    c) In a retrospective study of ziprasidone overdoses by the California Poison Control System, mild hypotension (90/60 mmHg) was reported in 1 of 26 adults (4%) (Lackey et al, 2002).
    d) CASE REPORT: Mild hypotension developed in a 22-year-old man after ingesting ziprasidone (4480 mg) and clomethiazole (20 or 25 of 192 mg capsules) (Gomez-Criado et al, 2005).
    D) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported with therapeutic use of ziprasidone (Prod Info GEODON(R) intramuscular injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia is an expected overdose effect as a result of exaggeration of the drug's pharmacological effects, which includes alpha-1-receptor blockade causing orthostasis and reflex tachycardia. In clinical trials ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute (Prod Info Geodon(TM), ziprasidone hydrochloride, 2002).
    b) CASE REPORT: Tachycardia (140 beats/min) developed in a 30-month-old girl who presented with profound mental status and respiratory depression, and miosis after ingesting approximately 40 mg of ziprasidone. She was treated with 2 doses of 0.4 mg of intravenous naloxone, but her neurologic status did not improve. Following further supportive care, she gradually recovered (Fasano et al, 2009).
    c) CASE SERIES: In a study of 433 ziprasidone exposure cases, tachycardia was reported in 33 (7.6%) patients. The ingested dose was known in 191 of the cases, with a mean dose of 666 mg (range 6 to 11,200 mg) (Forrester, 2008).
    d) CASE REPORT: Hypertension (220/140 mmHg) and tachycardia (110 bpm) occurred 72 hours after a 57-year-old woman ingested 4440 mg of ziprasidone. She recovered following supportive care (Prieto et al, 2005).
    e) OBSERVATIONAL STUDY: In a prospective observational study conducted by four regional poison centers, tachycardia occurred in 10 (37.0%) of 26 cases of ziprasidone only exposures (Klein-Schwartz et al, 2007).
    f) In a retrospective study of ziprasidone overdoses by the California Poison Control System, mild tachycardia (100 to 120 bpm) was reported in 8 of 26 adults (31%) and in 1 of 7 (14%) pediatric patients (Lackey et al, 2002; Lackey et al, 2002a).
    E) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported with therapeutic use of ziprasidone (Prod Info GEODON(R) intramuscular injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Transitory hypertension has been reported following overdoses, which resolved spontaneously (MacVane & Baumann, 2009; Prieto et al, 2005; Prod Info Geodon(TM), ziprasidone hydrochloride, 2002; Burton et al, 2000).
    b) CASE SERIES: In a study of 433 ziprasidone exposure cases, hypertension was reported in 15 (3.5%) patients. The ingested dose was known in 191 of the cases, with a mean dose of 666 mg (range 6 to 11,200 mg) (Forrester, 2008).
    c) CASE REPORT: Hypertension (220/140 mmHg) and tachycardia (110 bpm) occurred 72 hours after a 57-year-old woman ingested 4440 mg of ziprasidone. She recovered following supportive care (Prieto et al, 2005).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression may occur following massive overdoses, accompanying CNS depressive effects. Airway management may be necessary following massive overdoses (Prod Info Geodon(TM), ziprasidone hydrochloride, 2002).
    b) CASE REPORT: A 30-month-old girl developed coma with pinpoint pupils, tachycardia, and respiratory depression after ingesting approximately 40 mg of ziprasidone. She was treated with 2 doses of 0.4 mg of intravenous naloxone, but her neurologic status did not improve. Following further supportive care, she gradually recovered (Fasano et al, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Somnolence (up to 20% of patients) and headache (up to 30% of patients) have been reported in clinical trials (Prod Info GEODON(R) intramuscular injection, 2015; Brown et al, 1999; Citrome, 1997; Reeves & Harrigan, 1996; Kerwin & Taylor, 1996); somnolence may be dose-dependent (Sallee et al, 2000). Less commonly reported are dizziness (up to 16% of patients), light-headedness, insomnia, agitation, anxiety, and asthenia (Prod Info GEODON(R) oral capsules, intramuscular injection, 2010; Citrome, 1997; Reeves & Harrigan, 1996). Somnolence may be due to antagonism of histamine H1 receptors (Prod Info Geodon(TM), ziprasidone hydrochloride, 2002).
    2) WITH POISONING/EXPOSURE
    a) SOMNOLENCE/DROWSINESS
    1) CNS depression may occur in severe poisonings.
    2) CASE REPORT: A 22-month-old girl developed somnolence, drooling, and poor muscle tone after ingesting 800 mg of ziprasidone. She recovered following supportive care (MacVane & Baumann, 2009).
    3) CASE REPORT: A 30-month-old girl developed coma with miosis, tachycardia and respiratory depression after ingesting approximately 40 mg of ziprasidone. She was treated with 2 doses of 0.4 mg of intravenous naloxone, but her neurologic status did not improve. Following further supportive care, she gradually recovered (Fasano et al, 2009).
    4) CASE SERIES: In a study of 433 ziprasidone exposure cases, drowsiness, agitation, dizziness, and slurred speech were reported in 126 (29.1%), 19 (4.4%), 11 (2.5%), and 5 (1.2%) patients, respectively. The ingested dose was known in 191 of the cases, with a mean dose of 666 mg (range 6 to 11,200 mg) (Forrester, 2008).
    5) OBSERVATIONAL STUDY: In a prospective observational study conducted by four regional poison centers, lethargy/drowsiness was the most commonly reported clinical effect in ziprasidone only exposures. Of the 27 cases, 14 (51.9%) reported this symptom (Klein-Schwartz et al, 2007).
    6) CASE REPORT: A 50-year-old man was reported to be drowsy and have slurred speech approximately 4.5 hours after a 3120 mg ziprasidone overdose (Burton et al, 2000).
    7) CASE REPORT: The only symptoms reported following an overdose of 3240 mg were minimal sedation, slurring of speech and transitory hypertension (Prod Info GEODON(R) intramuscular injection, 2015). Another patient experienced drowsiness, anxiety, and a mild distal tremor (lasting a week) after ingesting 4440 mg of ziprasidone (Prieto et al, 2005).
    8) In 12-month retrospective reviews of adult (n=26) and pediatric (n=7) ingestions of ziprasidone reported to the California Poison Control System, somnolence was reported in 19 of 26 adults (73%) and 4 of 7 pediatric patients (57%). The mean amount ingested in adults was 720 mg (range of 180 to 4020 mg) and 156 mg (range of 60 to 360 mg) in pediatric patients. No serious effects occurred in either group (Lackey et al, 2002; Lackey et al, 2002a).
    9) Three cases of acute ziprasidone overdoses (780 to 4480 mg) resulted in only mild symptoms (mild drowsiness [n=3], tremor and anxiety [n=1]) . In 2 cases, excess doses of benzodiazepines and/or other hypnotics and sedatives were also taken (Gomez-Criado et al, 2005).
    B) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, extrapyramidal effects have been relatively uncommon; akathisia most frequent (up to 14% of patients). Incidence of parkinsonian symptoms, dystonia, hypertonia: 0% to 6% (relative to placebo) (Prod Info GEODON(R) intramuscular injection, 2015; Reeves & Harrigan, 1996; Harrigan & Morrissey, 1996; Kerwin & Taylor, 1996; Citrome, 1997).
    b) The incidence of extrapyramidal symptoms (EPS) reported in short-term trials of patients with bipolar mania was 31% for ziprasidone hydrochloride-treated subjects (n=279) compared with 12% for placebo-treated patients (n=136) (Prod Info GEODON(R) intramuscular injection, 2015).
    c) Hypertonia occurred at a frequency of less than 10% in bipolar mania trials and less than 5% in schizophrenia trials. Hypertonia was frequently (occurred in at least 1 of 100 people) observed during premarketing schizophrenia clinical trials (n=3834) at multiple doses greater than 4 mg/day (Prod Info GEODON(R) intramuscular injection, 2015).
    d) CASE REPORT: A 50-year-old woman who was taking ziprasidone 80 mg/day for 4 months presented with involuntary neck movements. Ziprasidone was gradually discontinued in 20-mg/day increments over 4 days. However, her symptoms persisted and became worse. She was initiated on clonazepam 12.5 mg/day which was titrated to 150 mg/day, but there was no improvement. Patient and family history showed no serious diseases. Physical examination revealed neck extension and head tilt caused by patterned, repetitive and spasmodic contraction of her neck muscles. Brain and cervical MRI and other biochemical tests were all normal. A diagnosis of tardive cervical dystonia with torticollis was made after ruling out causes of secondary dystonia and family history of dystonia. She was treated with botulinum toxin type A injections in 4 muscles of her neck and spinal area. The treatment was repeated 4 times at 1-month intervals. The patient experienced a significant improvement in neck pain and head deviation after the fourth injection with no recurrence of tardive symptoms after 5 months of follow-up (Kutlu et al, 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a study of 433 ziprasidone exposure cases, dystonia was reported in 17 (3.9%) patients. The ingested dose was known in 191 of the cases, with a mean dose of 666 mg (range 6 to 11,200 mg) (Forrester, 2008).
    b) CASE REPORT: A 19-year-old woman with chronic paranoid schizophrenia developed pronounced extrapyramidal symptoms, including cogwheeling and stiffness, and marked akathisia after ingesting 12,800 mg of ziprasidone. Following supportive care, her symptoms improved without further sequelae (Arbuck, 2005).
    C) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Dose-related akathisia was reported in an adolescent taking 40 mg/day. The akathisia resolved after a dose reduction of ziprasidone (Sallee et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) Although not reported yet after overdose, tardive dyskinesia may develop, especially in the elderly. Patients at highest risk are those on chronic therapy with a high total cumulative dose (Prod Info Geodon(TM), ziprasidone hydrochloride, 2002).
    D) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) The use of antipsychotic drugs, such as ziprasidone hydrochloride, has been associated with the development of neuroleptic malignant syndrome. Signs and symptoms include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability, elevated creatinine phosphokinase, myoglobinuria, and acute renal failure (Prod Info GEODON(R) intramuscular injection, 2015).
    b) Neuroleptic malignant syndrome (NMS) developed in a 49-year-old woman after receiving ziprasidone (20 to 60 mg twice daily) for the treatment of recurrent psychotic depression. Symptoms included agitation, disorganized thoughts, sweating, tachycardia, hypertension, elevated liver enzymes, and hyponatremia. Although there was no evidence of fever or muscle rigidity, a diagnosis of rhabdomyolysis secondary to NMS was made. All medications were stopped and the symptoms resolved over the next 6 days following aggressive treatment including intravenous hydration and electrolyte replacement (Murty et al, 2002).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures were reported in 0.4% of patients treated with ziprasidone during clinical trials (Prod Info GEODON(R) intramuscular injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Although not yet reported following ziprasidone overdose, it is possible that seizures may occur, particularly in conditions that lower the seizure threshold (Prod Info GEODON(R) intramuscular injection, 2015).
    F) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A patient developed coma after ingesting an unknown quantity of ziprasidone. After 8 hours of supportive care, the patient recovered (LoVecchio et al, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Constipation, dyspepsia, nausea, vomiting (constipation appears most common effect) has been reported in clinical trials (Prod Info GEODON(R) intramuscular injection, 2015; Harrigan & Morrissey, 1996; Kerwin & Taylor, 1996; Reeves & Harrigan, 1996).
    b) Anticholinergic effects, consisting of decreased bowel sounds, constipation and dry mouth, are common adverse effects of ziprasidone therapy. These effects are dose-related and may be anticipated following overdose (Prod Info Geodon(TM), ziprasidone hydrochloride, 2002).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea has been reported following ziprasidone overdose (House, 2002).
    b) CASE SERIES: In a study of 433 ziprasidone exposure cases, nausea and vomiting were reported in 9 (2.1%) and 9 (2.1%) patients, respectively. The ingested dose was known in 191 of the cases, with a mean dose of 666 mg (range 6 to 11,200 mg) (Forrester, 2008).
    c) CASE REPORT/MIXED INGESTION: Nausea, vomiting, and dry mouth developed in a woman who ingested 6 grams of ziprasidone and unknown quantities of 20-mg fluoxetine and 1-mg benztropine with a pint of rum (Alipour et al, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Rises in liver enzymes (occasional; have not been clinically significant) have been reported in clinical trials (Brown et al, 1999; Citrome, 1997; Kerwin & Taylor, 1996). No cases of overt hepatotoxicity have been reported.
    b) Two patients in a clinical trial of ziprasidone were discontinued because of abnormal laboratory results. One patient had elevated gamma-glutamyl transpeptidase (GGT) and serum alanine aminotransferase (ALT) after 7 days of treatment with ziprasidone 10 mg/day, and one patient showed elevations of both serum aspartate aminotransferase (AST) and ALT after 8 days of treatment with ziprasidone 40 mg/day. Both patients had elevated GGT values at baseline. At follow-up, all values had returned or were returning to normal (Goff et al, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) Urinary retention has been reported following ziprasidone overdose (House, 2002).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) LACK OF EFFECT: Unlike clozapine, a related antipsychotic drug, ziprasidone has not been shown in preclinical trials to cause any significant leukopenia or agranulocytosis (Harrigan & Morrissey, 1996; Citrome, 1997).
    b) Thrombocytopenia and leukopenia were reported have been reported infrequently in patients who received oral ziprasidone hydrochloride during premarketing schizophrenia clinical trials (n=3834) at multiple doses greater than 4 mg/day (Prod Info GEODON(R) intramuscular injection, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Development of a dose-dependent rash and/or urticaria was reported in about 5% of patients during premarketing trials with ziprasidone hydrochloride and was one of the more common reasons given for study dropouts (Prod Info GEODON(R) intramuscular injection, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERPROLACTINEMIA
    1) WITH THERAPEUTIC USE
    a) Prolactin level may increase with increasing dose, although increases are usually small and are seen mainly with higher doses (Kerwin & Taylor, 1996); elevations are also transient, returning to baseline within 12 hours of ziprasidone administration (Miceli et al, 2000a; Goff et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 57-year-old woman developed elevated prolactin levels (9.70 ng/mL) after ingesting 4440 mg of ziprasidone (Prieto et al, 2005).

Reproductive

    3.20.1) SUMMARY
    A) Ziprasidone is classified as FDA pregnancy category C. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. Developmental toxicity, including possible teratogenic effects, was reported in animal studies. It is not known whether ziprasidone or its metabolites are excreted in human milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Developmental toxicity, including possible teratogenic effects, was reported in animal studies. In rabbits, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney changes) were observed at 3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m(2) basis in pregnant animals during organogenesis. In rats, embryofetal toxicity was observed following doses up to 8 times the MRHD on a mg/m(2) basis, but no evidence of teratogenicity was noted (Prod Info GEODON(R) intramuscular injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ziprasidone has been classified as FDA pregnancy category C (Prod Info GEODON(R) intramuscular injection, 2015).
    B) RISK SUMMARY
    1) There are no adequate and well-controlled studies in pregnant women. Administer ziprasidone to a pregnant woman only if the potential benefit outweighs the potential risk to the fetus (Prod Info GEODON(R) intramuscular injection, 2015).
    C) EXTRAPYRAMIDAL AND/OR WITHDRAWAL SYMPTOMS
    1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info GEODON(R) intramuscular injection, 2015).
    D) ANIMAL STUDIES
    1) During animal studies there was an increased in the number of pups born stillborn and a decrease in postnatal survival through the first 4 days of lactation among the offspring of female rats treated during gestation and lactation at doses of 0.5 times the MRHD on a mg/m(2) basis or greater. In addition, developmental delays and neurobehavioral functional impairment were observed in offsprings at doses of 0.2 times the MRHD on a mg/m(2) basis or greater. A no-effect level was not determined for any of these events (Prod Info GEODON(R) intramuscular injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether ziprasidone or its metabolites are excreted in human milk. It is recommended that women should not breastfeed during ziprasidone therapy (Prod Info GEODON(R) intramuscular injection, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Time to copulation was increased in Sprague-Dawley rats administered ziprasidone at doses of 0.5 to 8 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m(2) basis in 2 fertility and early embryonic development studies. Doses 8 times the MRHD on a mg/m(2) basis also reduced fertility in females. In a 6-month study in male rats given 10 times the MRHD on a mg/m(2) basis, there were no treatment-related findings observed in the testes (Prod Info GEODON(R) intramuscular injection, 2015).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) RATS/MICE - Following chronic ziprasidone daily feedings of up to 5 times the recommended human dose, no evidence of increased incidence of tumors, compared to controls, was seen in rats or male mice. There were dose-related increases in incidences of pituitary gland adenoma and carcinoma, and mammary gland adenocarcinoma at all doses tested in female mice. These changes are considered to be prolactin-mediated. The relevance for human risk is unknown (Prod Info Geodon(TM), ziprasidone hydrochloride, 2002).

Genotoxicity

    A) A reproducible mutagenic response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation has been reported. Positive results were reported in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes (Prod Info Geodon(TM), ziprasidone hydrochloride, 2002).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum ziprasidone levels are not readily available at most facilities, and are not useful for guiding therapy after overdose.
    B) Monitor vital signs and mental status after significant overdose.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Monitor for CNS depression, seizures, and extrapyramidal reactions after significant overdose.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests in patients with respiratory depression.

Methods

    A) CHROMATOGRAPHY
    1) A description of a new membrane solid phase extraction (SPE) in 96-well microtiter plate format for the automated analysis of ziprasidone in biological fluids is given. A very rapid processing speed complements the high-throughput speed of contemporary high performance liquid chromatography mass spectrometry (HPLC/MS) analysis (Janiszewski et al, 1997).
    2) Prakash et al (1997) described a representative reversed-phase HPLC/MS/MS system, using ion spray, for showing the metabolite profiles of ziprasidone in biologic fluids. The ion spray interface was operated at 6000 V, and the mass spectrometer was operated in the positive ion mode (Prakash et al, 1997).
    3) A high-sensitivity assay for ziprasidone with solid-phase extraction and narrow-bore high-performance liquid chromatography was developed and validated for quantitation of the drug in human serum. A standard curve range of 1 to 250 ng/mL was reported. This validated method is highly sensitive, accurate and precise (Janiszewski et al, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with deliberate ingestions demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children less than 12 years of age who are naive to ziprasidone can be observed at home following an unintentional ingestion of less than 80 mg and are only experiencing mild sedation. All patients, 12 years of age or older, who are naive to ziprasidone, can be observed at home following an unintentional ingestion of 100 mg or less and are experiencing only mild sedation. All patients who are taking ziprasidone on a chronic basis can be observed at home if they have acutely ingested no more than 5 times their current single dose (not daily dose) of ziprasidone. Patients who have not developed signs or symptoms more than 6 hours after ingestion are unlikely to develop toxicity (Cobaugh et al, 2007).
    B) Lo Vecchio et al (2005) suggested that low-dose inadvertent ingestions may be monitored at home with close follow-up (LoVecchio et al, 2005).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility. Children less than 12 years of age who are naive to ziprasidone should be referred to a healthcare facility following an unintentional ingestion of 80 mg or more. All patients, 12 years of age or older, who are naive to ziprasidone should be referred to a healthcare facility following an unintentional ingestion of more than 100 mg. All patients who are taking ziprasidone on a chronic basis should be referred to a healthcare facility following an acute ingestion of more than 5 times their current single dose (not daily dose) of ziprasidone (Cobaugh et al, 2007).

Monitoring

    A) Serum ziprasidone levels are not readily available at most facilities, and are not useful for guiding therapy after overdose.
    B) Monitor vital signs and mental status after significant overdose.
    C) Obtain an ECG and institute continuous cardiac monitoring.
    D) Monitor for CNS depression, seizures, and extrapyramidal reactions after significant overdose.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests in patients with respiratory depression.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended due to the potential for somnolence, seizures and dystonic reaction.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) It is anticipated that activated charcoal would be effective if given soon after the overdose. Rapid absorption of the drug occurs, with peak plasma concentrations occurring 4 to 6 hours after ingestion (Burton et al, 2000).
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Serum ziprasidone levels are not readily available at most facilities, and are not useful for guiding therapy after overdose.
    2) Monitor vital signs and mental status after significant overdose.
    3) Obtain an ECG and institute continuous cardiac monitoring.
    4) Monitor for CNS depression, seizures, and extrapyramidal reactions after significant overdose.
    5) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests in patients with respiratory depression.
    B) HYPOTENSIVE EPISODE
    1) Administer IV fluids and keep the patient supine. In theory, agents with beta adrenergic activity such as epinephrine or dopamine may worsen hypotension in the setting of ziprasidone-induced alpha blockade. If hypotension is unresponsive to IV fluids, agents with alpha adrenergic effects such as norepinephrine or phenylephrine may be preferred.
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    3) Phenylephrine hydrochloride injection is indicated for the treatment of vascular failure in shock, shocklike states, and drug-induced hypotension or hypersensitivity (Prod Info phenylephrine hcl injection, 1%, 2005).
    a) DOSE: initial, 100 to 180 mcg/min continuous IV infusion; once blood pressure is stabilized, decrease rate to 40 to 60 mcg/min to maintain blood pressure (Prod Info phenylephrine hcl injection, 1%, 2005)
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    9) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    10) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    11) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    12) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    13) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    14) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    15) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    E) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    F) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    G) CONDUCTION DISORDER OF THE HEART
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias. In patients unresponsive to bicarbonate, consider lidocaine. Because ziprasidone can cause Torsades de pointes and QTc prolongation amiodarone should be used with caution.
    2) SERUM ALKALINIZATION
    a) Administer sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg by intravenous bolus, repeated as needed. Maintain arterial pH between 7.45 and 7.55. Monitor serial ECGs and arterial blood gases frequently.
    3) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    H) NEUROLEPTIC MALIGNANT SYNDROME
    1) May be successfully managed diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992).
    a) BENZODIAZEPINES: In conjunction with cooling measures and supportive care, initial management of NMS should include administration of intravenous benzodiazepines for muscle relaxation (Goldfrank et al, 2002) Benzodiazepines may also be helpful in controlling agitation or reversal of catatonia (Caroff & Mann, 1993; Gratz et al, 1992).
    1) DIAZEPAM DOSE: 3 to 5 mg intravenous bolus to slow push initially, followed by 1 to 2.5 mg intravenously in 10 minutes.
    b) BROMOCRIPTINE DOSE: 5 mg 3 times a day orally (Mueller et al, 1983).
    c) DANTROLENE LOADING DOSE: 2.5 mg/kg, to a maximum of 10 mg/kg intravenously (Barkin, 1992).
    d) DANTROLENE MAINTENANCE DOSE: 2.5 mg/kg intravenously every 6 hours (Barkin, 1992); 1 mg/kg orally every 12 hours, up to 50 mg/dose has also been successful (May et al, 1983).
    1) EFFICACY: Variable; often ineffective as a sole agent. Most efficacious in reducing rigidity and the fever that may be produced at a muscular level; will not always resolve mental status changes or psychotic symptoms that probably are more central in origin. Efficacy may be improved if given with a dopamine agonist (Granato et al, 1983; Blue et al, 1986; May et al, 1983).
    2) Some studies report NO beneficial effects and suggest that dantrolene might even worsen the course of NMS (Rosebush & Stewart, 1989) (Rosebush et al, 1991a).
    e) NON-PHARMACOLOGIC METHODS: Rapid cooling, hydration, and serial assessment of respiratory, cardiovascular, renal and neurologic function, and fluid status are used in conjunction with drug therapy and discontinuation of the antipsychotic agent (Knight & Roberts, 1986).
    2) In a review of 67 case reports of neuroleptic malignant syndrome, the onset of clinical response was shorter after treatment with DANTROLENE (mean 1.15 days) or BROMOCRIPTINE (1.03 days) than with supportive measures alone (6.8 days).
    a) The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).
    3) The intravenous administration of dopamine has also been reported to be effective in two case reports (Ungvari, 1987; Ryken & Merrell, 1989).
    4) RETROSPECTIVE STUDY: A study comparing 438 untreated patients with neuroleptic malignant syndrome and 196 treated cases found that administration of dantrolene, bromocriptine, or amantadine significantly reduced the death rate in these cases (Sakkas et al, 1991).
    a) Death rate of untreated cases was 21%; administration of dantrolene alone (no dosage reported) decreased death rate to 8.6% (n=58); with bromocriptine alone death rate was 7.8% (n=51); and with amantadine alone death rate was 5.9% (n=17).
    b) In combination with other drugs, each of these drugs significantly decreased the NMS-related death rate, although the decrease was slightly less than for single administrations.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Methods such as forced diuresis, hemodialysis, hemoperfusion, and exchange transfusion are NOT LIKELY to be of benefit in treating ziprasidone overdose due to extensive protein binding (99%) and volume of distribution of approximately 1.5 L/kg (Prod Info GEODON(R) intramuscular injection, 2015; Aweeka et al, 2000).

Abstracts

Case Reports

    A) ADULT
    1) A 50-year-old man presented to the ED 4.5 hours after taking 3120 mg of ziprasidone (52 60-mg tablets). No concomitant drugs nor alcohol were ingested. Glasgow Coma Scale (3) score was 15; blood pressure was 200/95 mm Hg (which decreased to 160/80 mm Hg within 1.5 hours); pulse ranged between 70 and 90; the patient was slightly drowsy with slurred speech. Admission ECG revealed minimal QTc prolongation (QT/QTc 430/490 msec) and nonspecific flattening of T-wave. CBC was within normal limits. Change in ECG was maximal at 6 hours postingestion, correlating with peak drug plasma level. ECG then returned to normal. Treatment following the initial ECG included a normal saline infusion, 10 mg metoclopramide, and 50 mg oral charcoal and 150 mL sorbitol given 5 hours postingestion. No dysrhythmias were noted on serial ECGs, and only transient QTc change occurred; no hemodynamic abnormalities were reported. The patient remained in the ED for 13 hours for observation before being discharged (Burton et al, 2000).

Range Of Toxicity

Summary

    A) TOXICITY: SUMMARY: A dose of more than 80 mg is potentially toxic in a drug naive child less than 12 years old. A dose of more than 100 mg is potentially toxic in a drug naive child aged 12 years or greater. In children on chronic ziprasidone therapy an acute ingestion of more than 5 times their current single dose (not daily dose) is potentially toxic. ADULT: One patient developed extrapyramidal symptoms and only a modest increase in the QTc interval after ingesting 12.8 g of ziprasidone. An adult developed QTc prolongation and an episode of torsades de pointes after ingesting 6 g ziprasidone, ethanol and fluoxetine. PEDIATRIC: A 22-month-old girl developed somnolence, drooling, hypertension, and poor muscle tone after ingesting 800 mg of ziprasidone. She recovered following supportive care. A 30-month-old developed coma and respiratory depression after ingesting 40 mg of ziprasidone.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 20 to 80 mg orally twice daily. INTRAMUSCULAR: 10 mg every 2 hours or 20 mg every 4 hours intramuscularly up to a maximum dose of 40 mg daily. PEDIATRIC: The safety and efficacy of ziprasidone in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) BIPOLAR I DISORDER
    1) ACUTE TREATMENT
    a) INITIAL: The recommended initial dose is 40 mg oral twice daily and increased to 60 mg to 80 mg orally twice daily on the second day of treatment (Prod Info GEODON(R) intramuscular injection, 2014; Prod Info GEODON(R) oral capsules, 2014; Prod Info GEODON(R) oral suspension, 2009).
    b) MAINTENANCE: After the second day of treatment, the recommended dose range is 40 mg to 80 mg orally twice daily (Prod Info GEODON(R) intramuscular injection, 2014; Prod Info GEODON(R) oral capsules, 2014; Prod Info GEODON(R) oral suspension, 2009).
    2) MAINTENANCE TREATMENT
    a) When administered concurrently with lithium or valproate, the recommended maintenance dose is 40 mg to 80 mg orally twice daily (Prod Info GEODON(R) intramuscular injection, 2014; Prod Info GEODON(R) oral capsules, 2014).
    B) SCHIZOPHRENIA
    1) ORAL
    a) INITIAL DOSE: The recommended dose initial dose is 20 mg to 80 mg orally twice daily (Prod Info GEODON(R) oral suspension, 2009). Doses above 80 mg orally twice daily are generally not recommended; doses above 100 mg orally twice daily have not been systematically evaluated (Prod Info GEODON(R) intramuscular injection, 2014; Prod Info GEODON(R) oral capsules, 2014).
    b) MAINTENANCE DOSE: The recommended maintenance dose range is 20 mg to 80 mg orally twice daily (Prod Info GEODON(R) oral suspension, 2009). In clinical studies, no additional benefits were noted for doses greater than 20 mg orally twice daily (Prod Info GEODON(R) intramuscular injection, 2014; Prod Info GEODON(R) oral capsules, 2014).
    2) INTRAMUSCULAR
    a) The recommended dose is 10 mg to 20 mg IM, up to a maximum of 40 mg/day. Doses of 10 mg IM may be administered every 2 hours; 20 mg doses IM may be administered every 4 hours. IM administration for more than 3 consecutive days has not been studied (Prod Info GEODON(R) intramuscular injection, 2014; Prod Info GEODON(R) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of ziprasidone in pediatric patients have not been established (Prod Info GEODON(R) intramuscular injection, 2014; Prod Info GEODON(R) oral capsules, 2014; Prod Info GEODON(R) oral suspension, 2009).

Maximum Tolerated Exposure

    A) SUMMARY
    1) A dose of more than 80 mg is potentially toxic in a drug naive child less than 12 years old. A dose of more than 100 mg is potentially toxic in a drug naive child aged 12 years or greater. In children on chronic ziprasidone therapy an acute ingestion of more than 5 times their current single dose (not daily dose) is potentially toxic.(Cobaugh et al, 2007).
    2) In a study of 433 ziprasidone exposure cases (adults and children), neurological (eg, drowsiness, agitation, dystonia), cardiovascular (eg, tachycardia, hypertension, hypotension), and gastrointestinal (eg, nausea, vomiting) symptoms were reported in 41.8%, 13%, and 4.6% of patients, respectively. The ingested dose was known in 191 of the cases, with a mean dose of 666 mg (range 6 to 11,200 mg) (Forrester, 2008).
    3) Clinical events that have been reported with ziprasidone overdose have included extrapyramidal symptoms, somnolence, tremor and anxiety (Prod Info GEODON(R) intramuscular injection, 2015).
    B) ADULT
    1) CASE REPORT: A 19-year-old woman with chronic paranoid schizophrenia developed pronounced extrapyramidal symptoms, including cogwheeling and stiffness, and marked akathisia after ingesting 12,800 mg of ziprasidone. Following supportive care, her symptoms improved without further sequelae (Arbuck, 2005).
    2) CASE REPORT/MIXED INGESTION: A 55-year-old woman with a history of bipolar disorder, anxiety, hepatitis C, alcohol abuse, hypothyroidism, pulmonary hypertension, and asthma, developed nausea, vomiting, mydriasis, dry mouth, prolonged QTc, and torsades de pointes after ingesting 6 grams of ziprasidone and unknown quantities of 20-mg fluoxetine and 1-mg benztropine with a pint of rum. Following supportive care, she recovered completely (Alipour et al, 2010).
    3) Following an acute ingestion of 4020 mg ziprasidone, a 38-year-old woman alternated between agitation and drowsiness, developed a prolonged QTc interval of 445 msec and mild hypotension. All symptoms resolved after 14 hours (House, 2002).
    4) Four and one-half hours following an overdose of 3120 mg of ziprasidone a 50-year-old man was shown to have minimal QT prolongation (QT/QTc 430/490 msec) and nonspecific flattening of the T wave on ECG. No dysrhythmias were recorded. Results of a CBC were normal. Changes in QTc were maximal at 6 hours post-overdose. Recovery was complete (Burton et al, 2000).
    5) Following an acute overdose of 3240 mg, minimal sedation, slurred speech and transitory hypertension (200/95) were the only events reported in one adult (Prod Info GEODON(R) intramuscular injection, 2015).
    6) A retrospective study of adult ziprasidone overdoses (n=26) conducted by the California Poison Control System reported the following outcomes: no effect in 7 patients (27%), minor effects (somnolence) in 17 patients (65%), and moderate effects (mild hypotension or tachycardia) in 2 patients (8%). Amounts ingested ranged from 180 to 4020 mg (mean 720 mg). No serious effects were reported (Lackey et al, 2002).
    7) Four cases of acute ziprasidone overdoses (780 to 4480 mg) resulted in only mild symptoms. In 2 cases, excess doses of benzodiazepines and/or other hypnotics and sedative were taken. One patient was asymptomatic after ingesting 1120 mg of ziprasidone. Mild drowsiness (n=3), tremor and anxiety (n=1), and mild hypotension (n=1) were also reported. No cardiac adverse effects were observed (Gomez-Criado et al, 2005).
    8) A 57-year-old woman developed drowsiness, anxiety, a distal tremor, and a prolonged QTc (457.20 ms 12 hours post-ingestion) after ingesting 4440 mg of ziprasidone. In addition, she developed hypertension (220/140 mmHg) and tachycardia (110 bpm) 72 hours after the ingestion. She recovered following supportive care (Prieto et al, 2005).
    C) PEDIATRIC
    1) CASE REPORT: A 22-month-old girl developed somnolence, drooling, hypertension (140/90 mmHg), and poor muscle tone after ingesting 800 mg of ziprasidone. She recovered following supportive care (MacVane & Baumann, 2009).
    2) A 30-month-old girl developed coma with pinpoint pupils, tachycardia, and respiratory depression after ingesting approximately 40 mg of ziprasidone. She was treated with 2 doses of 0.4 mg of IV naloxone, but her neurologic status did not improve. Following further supportive care, she gradually recovered (Fasano et al, 2009).
    3) A small 12 month retrospective evaluation of pediatric ziprasidone overdoses (n=7) by the California Poison Control System reported favorable outcomes following overdoses of 60 to 360 mg (mean 156 mg). No effects were seen in 3 cases (43%), minor effects (somnolence) in 3 cases (43%), and a moderate effect (mild tachycardia) in 1 case (14%) (Lackey et al, 2002a).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) A serum concentration of 2 mg/L was reported in a 30-month-old girl who developed coma with pinpoint pupils, tachycardia, and respiratory depression after ingesting approximately 40 mg of ziprasidone. She was treated with 2 doses of 0.4 mg of intravenous naloxone, but her neurologic status did not improve. Following further supportive care, she gradually recovered (Fasano et al, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Atypical antipsychotic (benzisothiazoyl piperazine derivative); serotonin (5HT)-2A/dopamine D2 antagonist. Also a 5HT-1A agonist (property may confer greater protection against adverse extrapyramidal effects). High in vitro binding affinity for dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A and 5HT1D and alpha1-adrenergic receptors and moderate affinity for the histamine H1 receptor. Ziprasidone functions as an antagonist at the D2, 5HT2A, and 5HT1D receptors, and as an agonist at the 5HT1A receptor. NO appreciable affinity has been shown for the cholinergic muscarinic receptor (Prod Info GEODON(R) intramuscular injection, 2015; Sprouse et al, 1999; Kerwin & Taylor, 1996; Fischman et al, 1996; Owens, 1996; Schotte et al, 1996; Pickar, 1995; Lieberman, 1993; Bench et al, 1993).
    1) Ziprasidone inhibits serotonin neuronal firing, which is a dose-dependent response, with complete inhibition at the highest doses tested (Sprouse et al, 1999). Ziprasidone appears to be a centrally acting 5-HT1A agonist, unlike clozapine and olanzapine.
    B) Modest-to-low affinity for alpha-1, H1 receptors (Kerwin & Taylor, 1996). Inhibits norepinephrine reuptake (Pickar, 1995; Seeger et al, 1995).
    C) In vitro: ratio of 5HT-2A/dopamine D2 receptor affinity greater than clozapine (2-fold), haloperidol (680-fold) (Seeger et al, 1995).

Toxicologic Mechanism

    A) SOMNOLENCE may be explained by antagonism of histamine H1 receptors by ziprasidone (Prod Info GEODON(R) intramuscular injection, 2015).
    B) ORTHOSTATIC HYPOTENSION may be explained by antagonism of adrenergic alpha-1 receptors by ziprasidone (Prod Info GEODON(R) intramuscular injection, 2015).

Physicochemical

Physical Characteristics

    A) Ziprasidone hydrochloride monohydrate is a white to slightly pink powder (Prod Info GEODON(R) intramuscular injection, 2015).

Molecular Weight

    A) 467.42 (ziprasidone hydrochloride monohydrate) (Prod Info GEODON(R) intramuscular injection, 2015)
    B) 563.09 (ziprasidone mesylate trihydrate for injection) (Prod Info GEODON(R) intramuscular injection, 2015)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
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