Medically reviewed on Nov 15, 2018

Pronunciation

(zi PRAS i done)

Index Terms

• Zeldox
• Ziprasidone HCl
• Ziprasidone Hydrochloride
• Ziprasidone Mesylate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Geodon: 20 mg, 40 mg, 60 mg, 80 mg

Generic: 20 mg, 40 mg, 60 mg, 80 mg

Solution Reconstituted, Intramuscular, as mesylate [strength expressed as base]:

Geodon: 20 mg (1 ea)

Brand Names: U.S.

• Geodon

Pharmacologic Category

• Second Generation (Atypical) Antipsychotic

Pharmacology

Ziprasidone is a benzylisothiazolylpiperazine antipsychotic. The exact mechanism of action is unknown. However, in vitro radioligand studies show that ziprasidone has high affinity for D₂, D₃, 5-HT_2A, 5-HT_1A, 5-HT_2C, 5-HT_1D, and alpha₁-adrenergic; moderate affinity for histamine H₁ receptors; and no appreciable affinity for alpha₂-adrenergic receptors, beta-adrenergic, 5-HT₃, 5-HT₄, cholinergic, mu, sigma, or benzodiazepine receptors. Ziprasidone functions as an antagonist at the D₂, 5-HT_2A, and 5-HT_1D receptors and as an agonist at the 5-HT_1A receptor. Ziprasidone moderately inhibits the reuptake of serotonin and norepinephrine.

Absorption

Well absorbed; administration with 500-calorie meals increases serum levels ~80% (Lincoln, 2010).

Distribution

V_d: 1.5 L/kg

Metabolism

Extensively hepatic, primarily chemical and enzymatic reductions via glutathione and aldehyde oxidase, respectively; less than ¹/₃ of total metabolism via CYP3A4 and CYP1A2 (minor)

Excretion

Feces (~66%; <4% of total dose as unchanged drug); urine (~20%; <1% of total dose as unchanged drug)

Clearance: Children: Mean: 11.5 to 13.1 mL/minute/kg (Sallee 2006); Adults: Mean: 7.5 mL/minute/kg

Time to Peak

Oral: Children: Mean: 5 to 5.5 hours (Sallee 2006); Adults: 6 to 8 hours

IM: ≤60 minutes

Half-Life Elimination

Oral: Mean terminal half-life:

Children: Mean: 3.3 to 4.1 hours (Sallee 2006)

Adults: 7 hours

IM: Mean half-life: 2 to 5 hours

Protein Binding

>99%, primarily to albumin and alpha-1 acid glycoprotein

Special Populations: Hepatic Function Impairment

Increases the AUC of ziprasidone.

Use: Labeled Indications

Treatment of schizophrenia; treatment of acute manic or mixed episodes associated with bipolar disorder with or without psychosis; maintenance treatment of bipolar disorder as an adjunct to lithium or valproate; acute agitation in patients with schizophrenia

Off Label Uses

Delusional infestation (also called delusional parasitosis)

Data from a limited number of patients studied in case reports suggest that ziprasidone may be beneficial for the treatment of delusional infestation (also called delusional parasitosis). Additional data may be necessary to further define the role of ziprasidone in this condition.

Major depressive disorder

Data from a double-blind, randomized, placebo-controlled trial support the use of adjunctive ziprasidone in the treatment of treatment-resistant major depressive disorder ^{[Papakostas 2015]}. Additional trials may be necessary to further define the role of ziprasidone in this condition.

Psychosis/agitation associated with dementia

Data from a limited number of patients in retrospective and open-label studies suggest that ziprasidone may be beneficial for the treatment of psychosis/agitation related to dementia ^{[Berkowitz 2003]}, ^{[Cole 2005]}, ^{[Rocha 2006]}. Additional data may be necessary to further define the role of ziprasidone in this condition.

Based on the American Psychiatric Association (APA) practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia, antipsychotics, such as ziprasidone, may be considered for the treatment of agitation and psychosis in certain patients; however, evidence for efficacy is modest and use should be limited to patients whose symptoms are dangerous, severe, or cause significant patient distress due to safety risks associated with antipsychotic use.

Contraindications

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

Dosing: Adult

Bipolar disorder (acute and maintenance as adjuncts to lithium or valproate): Oral: Initial: 40 mg twice daily; may increase to 60 or 80 mg twice daily on second day of treatment; subsequently adjust dose based on response and tolerability. Usual dosage: 40 to 80 mg twice daily.

Schizophrenia: Initial: 20 mg twice daily. Increase dose based on response and tolerability no more frequently than every 2 days; ordinarily patients should be observed for improvement over several weeks before adjusting the dose. Usual dosage: 40 to 100 mg twice daily. Note: Dosages up to 320 mg per day appear safe; however, there is no data suggesting improved efficacy at higher doses (APA 2004).

Acute agitation (schizophrenia): IM: 10 mg every 2 hours or 20 mg every 4 hours (maximum: 40 mg daily). Oral therapy should replace IM administration as soon as possible.

Delusional infestation (also called delusional parasitosis) (off-label use): Oral: 20 to 80 mg twice daily (De Berardis 2013; Freudenmann 2008). Additional data may be necessary to further define the role of ziprasidone in this condition.

Major depressive disorder (adjunct to antidepressants) (off-label use): Oral: Initial: 20 mg twice daily; may increase dose by 20 mg twice daily at weekly increments up to 80 mg twice daily based on response and tolerability. Average daily dose was 98 mg/day in the clinical trial (Papakostas 2015).

Discontinuation of therapy: American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (APA [Lehman 2004]; Cerovecki 2013; CPA [Addington 2005]; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months, and the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA [Addington 2005]). Continuing anti-parkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, 3 strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited, and results are conflicting (Cerovecki 2013; Remington 2005).

Dosing: Geriatric

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

Psychosis/agitation associated with dementia (off-label use): Oral: Initial: 20 to 40 mg daily, in 1 to 2 divided doses; increase total daily dose by 20 to 40 mg increments every 2 to 7 days; doses as high as 160 mg daily have been studied (Berkowitz 2003; Cole 2005; Rocha 2006). In patients without a clinically significant response after 4 weeks, taper and withdraw therapy. In patients with an adequate response, attempt to taper and withdraw therapy within 4 months, unless symptoms recurred with a previous taper attempt. Assess symptoms at least monthly during taper and for at least 4 months after withdrawal of therapy (APA [Reus 2016]).

Dosing: Renal Impairment

Oral: No dosage adjustment necessary.

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

Ziprasidone is not removed by hemodialysis.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, drug undergoes extensive hepatic metabolism and systemic exposure may be increased. Use with caution.

Reconstitution

Each vial should be reconstituted with 1.2 mL SWFI. Shake vigorously; will form a pale, pink solution containing 20 mg/mL ziprasidone.

Extemporaneously Prepared

A 2.5 mg/mL oral solution may be made with the injection. Use 8 vials of the 20 mg injectable powder. Add 1.2 mL of distilled water to each vial to make a 20 mg/mL solution. Once dissolved, transfer 7.5 mL to a calibrated bottle and add quantity of vehicle (Ora-Sweet®) sufficient to make 60 mL. Label "shake well" and "refrigerate". Stable for 14 days at room temperature or 42 days refrigerated (preferred).

Green K and Parish RC, "Stability of Ziprasidone Mesylate in an Extemporaneously Compounded Oral Solution," J Pediatr Pharmacol Ther, 2010, 15:138-41.

Administration

Oral: Administer with a meal containing at least 500 calories (Lincoln, 2010).

Injection: For IM administration only.

Dietary Considerations

Capsule: Take with food.

Storage

Capsule: Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F).

Vials for injection: Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Following reconstitution, injection may be stored at room temperature up to 24 hours or under refrigeration for up to 7 days. Protect from light.

Drug Interactions

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Amiodarone: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

Arsenic Trioxide: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Arsenic Trioxide. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Astemizole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Astemizole. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Bedaquiline: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Bedaquiline. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Bepridil: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Bepridil. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Monitor therapy

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Ziprasidone. Monitor therapy

Ceritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

ChlorproMAZINE: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of ChlorproMAZINE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Cisapride: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Cisapride. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Avoid combination

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Avoid combination

Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Delamanid: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Delamanid. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Avoid combination

Doxepin-Containing Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Doxepin-Containing Products. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dronedarone: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Dronedarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Droperidol: May enhance the QTc-prolonging effect of Ziprasidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Avoid combination

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Fluconazole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluconazole. Fluconazole may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

FLUoxetine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Avoid combination

Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gemifloxacin: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Monitor therapy

Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Haloperidol: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Ivosidenib: Ziprasidone may enhance the QTc-prolonging effect of Ivosidenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Levofloxacin-Containing Products (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Monitor therapy

Lofexidine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification

Methadone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Avoid combination

OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Ondansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Avoid combination

Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Avoid combination

Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination

Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Avoid combination

Propafenone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Dronedarone. Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Fluconazole; Nilotinib; Ribociclib. Consider therapy modification

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Exceptions: Clarithromycin. Avoid combination

QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Avoid combination

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

QuiNINE: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of QuiNINE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Avoid combination

RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sodium Stibogluconate: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sodium Stibogluconate. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Avoid combination

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Terfenadine: May enhance the QTc-prolonging effect of Ziprasidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

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

>10%:

Central nervous system: Drowsiness (oral and IM: 8% to 31%; may be dose-related), extrapyramidal reaction (oral: 1% to 31%), headache (oral and IM: 5% to 18%), dizziness (oral and IM: 3% to 16%; includes lightheadedness; may be dose-related)

Gastrointestinal: Nausea (oral and IM: 8% to 12%)

1% to 10%:

Cardiovascular: Orthostatic hypotension (IM: ≤5%, oral: ≥1%; may be dose-related), chest pain (3%), hypertension (oral and IM: 1% to 3%), tachycardia (1% to 2%), bradycardia (oral and IM: ≤2%), facial edema (≥1%), angina pectoris (≤1%), peripheral edema (≤1%)

Central nervous system: Akathisia (oral: 8% to 10%; IM: ≤2%), anxiety (oral: 5%; may be dose-related), hypoesthesia (1% to 2%), agitation (oral: ≥1%, IM: ≤2%), personality disorder (IM: ≤2%), speech disturbance (oral and IM: ≤2%), amnesia (≥1%), ataxia (≥1%), chills (≥1%), confusion (≥1%), delirium (≥1%), dystonia (≥1%; may be dose-related), falling (≥1%), flank pain (≥1%), hostility (≥1%), hypothermia (≥1%), vertigo (≥1%), withdrawal syndrome (≥1%), anorgasmia (≤1%), atrial fibrillation (≤1%), male sexual disorder (≤1%), paralysis (≤1%), insomnia

Dermatologic: Skin rash (1% to 5%; may be dose-related), fungal dermatitis (1% to 2%), diaphoresis (IM: ≤2%), furunculosis (IM: ≤2%), skin photosensitivity (≥1%), alopecia (≤1%), contact dermatitis (≤1%), ecchymoses (≤1%), eczema (≤1%), exfoliative dermatitis (≤1%), maculopapular rash (≤1%), urticaria (≤1%), vesiculobullous dermatitis (≤1%)

Endocrine & metabolic: Weight gain (4% to 16%), albuminuria (≤1%), amenorrhea (≤1%), dehydration (≤1%), glycosuria (≤1%), hypercholesterolemia (≤1%), hyperglycemia (≤1%), hypermenorrhea (≤1%), hypokalemia (≤1%), increased lactate dehydrogenase (≤1%), increased thirst (≤1%)

Gastrointestinal: Constipation (oral: 9%, IM: ≤2%), dyspepsia (oral: 8%, IM: 2% to 3%), vomiting (oral and IM: 1% to 5%), xerostomia (oral: 4% to 5%; may be dose-related), diarrhea (oral and IM: ≤5%), sialorrhea (4%; may be dose-related), abdominal pain (oral and IM: ≤2%), anorexia (oral and IM: ≤2%; may be dose-related), dysmenorrhea (IM: ≤2%), dysphagia (≤2%), buccoglossal syndrome (≥1%)

Genitourinary: Hematuria (≤1%), impotence (≤1%), lactation (female: ≤1%), priapism (IM: ≤1%), urinary retention (≤1%)

Hematologic & oncologic: Rectal hemorrhage (oral and IM: ≤2%), anemia (≤1%), eosinophilia (≤1%), leukocytosis (≤1%), leukopenia (≤1%), lymphadenopathy (≤1%)

Hepatic: Increased serum alkaline phosphatase (≤1%), increased serum transaminases (≤1%)

Hypersensitivity: Tongue edema (≤3%)

Local: Pain at injection site (IM: 7% to 8%)

Neuromuscular & skeletal: Weakness (oral: 5% to 6%; may be dose-related), myalgia (1% to 2%), paresthesia (oral and IM: ≤2%), abnormal gait (≥1%), akinesia (≥1%), choreoathetosis (≥1%), dysarthria (≥1%), dyskinesia (≥1%), hyperkinesia (≥1%), hypokinesia (≥1%), hypotonia (≥1%), neuropathy (≥1%), tremor (≥1%; may be dose-related), twitching (≥1%), cogwheel rigidity (oral: ≥1%), hypertonia (≥1%), increased creatine phosphokinase (≤1%), tenosynovitis (≤1%)

Ophthalmic: Visual disturbance (3% to 6%; may be dose-related), diplopia (≥1%), oculogyric crisis (≥1%), blepharitis (≤1%), cataract (≤1%), conjunctivitis (≤1%), photophobia (≤1%), xerophthalmia (≤1%)

Otic: Tinnitus (≤1%)

Renal: Polyuria (≤1%)

Respiratory: Respiratory tract infection (8%), rhinitis (oral: 4%), cough (3%), pharyngitis (3%), dyspnea (1% to 2%), flu-like symptoms (oral: ≥1%), epistaxis (≤1%), pneumonia (≤1%)

Miscellaneous: Accidental injury (4%), fever (≥1%), motor vehicle accident (≥1%)

<1%, postmarketing, and/or case reports: Agranulocytosis, angioedema, arthralgia, basophilia, bundle branch block, cardiomegaly, cerebral infarction, cerebrovascular accident, cholestatic jaundice, decreased glucose tolerance, deep vein thrombophlebitis, diabetic coma, DRESS syndrome, ejaculatory disorder, facial droop, fecal impaction, female sexual disorder, first degree atrioventricular block, galactorrhea, gingival hemorrhage, gout, granulocytopenia, gynecomastia, hematemesis, hemophthalmos, hemoptysis, hepatitis, hepatomegaly, hyperchloremia, hyperkalemia, hyperreflexia, hypersensitivity reaction (including allergic dermatitis, orofacial edema), hyperthyroidism, hyperuricemia, hypocalcemia, hypochloremia, hypocholesterolemia, hypochromic anemia, hypoglycemia, hypomagnesemia, hypomania, hyponatremia, hypoproteinemia, hypothyroidism, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased monocytes, increased serum creatinine, increased serum prolactin, jaundice, keratitis, keratoconjunctivitis, ketosis, laryngismus, liver steatosis, lymphedema, lymphocytosis, mania, melena, myocarditis, myoclonus, myopathy, neuroleptic malignant syndrome, neutropenia, nocturia, nystagmus, oliguria, opisthotonos, oral leukoplakia, oral paresthesia, phlebitis, polycythemia, prolonged Q-T interval on ECG, pulmonary embolism, respiratory alkalosis, seizure, serotonin syndrome (with or without serotonergic medications), sleep apnea syndrome (obstructive) (Health Canada 2016, Shirani 2011), Stevens-Johnson syndrome, swollen tongue, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, thrombophlebitis, thyroiditis, torsades de pointes, torticollis, trismus, urinary incontinence, vaginal hemorrhage, venous thromboembolism, visual field defect

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm³.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions: Cases of dermatologic reactions (including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported; may be fatal. Symptoms of DRESS include a combination of 3 or more of the following: severe skin eruption (rash or exfoliative dermatitis), fever, lymphadenopathy, eosinophilia and one or more systemic complications (eg, hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis). Discontinue use if DRESS or other severe cutaneous reactions are suspected.

• Dyslipidemia: Has been reported with atypical antipsychotics; risk profile may differ between agents.

• Esophageal dysmotility/Aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (ie, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).

• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk.

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

• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.

• Neuroleptic malignant syndrome (NMS): Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.

• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

• Priapism: Rare cases of priapism have been reported.

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

• Rash: Use has been associated with a fairly high incidence of rash (5%); discontinue if alternative etiology is not identified.

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

• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI.

Disease-related concerns:

• Cardiovascular disease: Use is contraindicated in patients with recent acute myocardial infarction (MI), QT prolongation, or uncompensated heart failure. Avoid use in patients with a history of cardiac arrhythmias; use with caution in patients with history of MI or unstable heart disease.

• Dementia: [US Boxed Warning]: Elderly patients with dementia-related behavioral disorders treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death (APA [Reus 2016]). Ziprasidone is not approved for the treatment of dementia-related psychosis.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

• Hepatic impairment: Use with caution in patients with hepatic disease or impairment.

• Renal impairment: Use the intramuscular formulation with caution in patients with renal impairment.

• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Dosage form specific issues:

• Intramuscular formulation: Use the intramuscular formulation with caution in patients with renal impairment; formulation contains cyclodextrin, an excipient which may accumulate in renal insufficiency, although the clinical significance of this finding is uncertain (Luke, 2010).

Other warnings/precautions:

• Discontinuation of therapy: When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or two episodes within 5 years (APA [Lehman 2004]).

Monitoring Parameters

Mental status; vital signs (as clinically indicated); blood pressure (baseline; repeat 3 months after antipsychotic initiation, then yearly); ECG (as clinically indicated); weight, height, BMI, waist circumference (baseline; repeat at 4, 8, and 12 weeks after initiating or changing therapy, then quarterly; consider switching to a different antipsychotic for a weight gain ≥5% of initial weight); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with pre-existing low WBC or history of drug-induced leukopenia/neutropenia); electrolytes (annually and as clinically indicated; perform baseline potassium and magnesium measurements in patients at risk for electrolyte disturbances and periodically monitor if diuretics are initiated during ziprasidone treatment); liver function (annually and as clinically indicated); personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease (baseline; repeat annually); fasting plasma glucose level/HbA_1c (baseline; repeat 3 months after starting antipsychotic, then yearly); fasting lipid panel (baseline; repeat 3 months after initiation of antipsychotic; if LDL level is normal repeat at 2-5 year intervals or more frequently if clinical indicated); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (at each visit for the first 12 weeks after the antipsychotic is initiated or until the dose is stable, then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 12 months; high-risk patients every 6 months); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004).

Pregnancy Risk Factor

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Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization. Ziprasidone may cause hyperprolactinemia, which may decrease reproductive function in both males and females.

The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to a typical antipsychotic that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008).

Healthcare providers are encouraged to enroll women 18-45 years of age exposed to ziprasidone during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388 or http://www.womensmentalhealth.org/pregnancyregistry).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, agitation, loss of strength and energy, nausea, vomiting, anxiety, constipation, diarrhea, dry mouth, headache, cough, or rhinorrhea. Have patient report immediately to prescriber signs of infection, signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, or vomiting), suicidal ideation, severe dizziness, passing out, tachycardia, bradycardia, behavioral changes, mood changes, change in balance, abnormal movements, twitching, dysphagia, difficulty speaking, difficulty focusing, seizures, vision changes, shortness of breath, swelling of arm or leg, excessive weight gain, enlarged breasts, sexual dysfunction, nipple discharge, amenorrhea, severe injection site irritation, priapism, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot), signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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