(zi PRAS i done)
- Ziprasidone HCl
- Ziprasidone Hydrochloride
- Ziprasidone Mesylate
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.
- Second Generation (Atypical) Antipsychotic
Ziprasidone is a benzylisothiazolylpiperazine antipsychotic. The exact mechanism of action is unknown. However, in vitro radioligand studies show that ziprasidone has high affinity for D2, D3, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT1D, and alpha1-adrenergic; moderate affinity for histamine H1 receptors; and no appreciable affinity for alpha2-adrenergic receptors, beta-adrenergic, 5-HT3, 5-HT4, cholinergic, mu, sigma, or benzodiazepine receptors. Ziprasidone functions as an antagonist at the D2, 5-HT2A, and 5-HT1D receptors and as an agonist at the 5-HT1A receptor. Ziprasidone moderately inhibits the reuptake of serotonin and norepinephrine.
Well absorbed; administration with 500-calorie meals increases serum levels ~80% (Lincoln, 2010).
Vd: 1.5 L/kg
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)
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
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
>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
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 QTc-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
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 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).
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.
Each vial should be reconstituted with 1.2 mL SWFI. Shake vigorously; will form a pale, pink solution containing 20 mg/mL ziprasidone.
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.
Oral: Administer with a meal containing at least 500 calories (Lincoln, 2010).
Injection: For IM administration only.
Capsule: Take with food.
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.
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
Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination
Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy
Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). 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
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
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination
Bilastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy
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
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
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
CarBAMazepine: May decrease the serum concentration of Ziprasidone. Monitor therapy
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
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
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
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification
FLUoxetine: May enhance the QTc-prolonging effect of Ziprasidone. Ziprasidone may enhance the serotonergic effect of FLUoxetine. This could result in serotonin syndrome. Avoid combination
Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination
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
Hydroxychloroquine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. 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
Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
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
MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination
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
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
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: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Promazine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy
Saquinavir: Ziprasidone may enhance the arrhythmogenic effect of Saquinavir. Avoid combination
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
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
Teneligliptin: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
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
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%).
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% (Limited to important or life-threatening): Agranulocytosis, 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, 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, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, thrombophlebitis, thyroiditis, torsade de pointes, torticollis, trismus, urinary incontinence, vaginal hemorrhage, visual field defect
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.
• 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; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease).
• 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 (torsade de pointes) and sudden death. Observed prolongation was greater than with other atypical antipsychotic agents (risperidone, olanzapine, quetiapine), but less than with thioridazine. Avoid hypokalemia, hypomagnesemia. Use caution in patients with bradycardia. Discontinue in patients found to have persistent QTc intervals >500 msec. Patients with symptoms of dizziness, palpitations, or syncope should receive further cardiac evaluation. Also see Contraindications.
• Rash: Use has been associated with a fairly high incidence of rash (5%); discontinue if alternative etiology is not identified.
• Sedation: Moderate to highly sedating, use with caution in disorders where CNS depression is a feature; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• 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.
• 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.
• Parkinson disease: Use with caution in patients with Parkinson disease; antipsychotics may aggravate the motor disturbances of Parkinson disease (APA [Lehman 2004]; APA [Reus 2016]).
• 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:
• Sedatives: CNS effects may be potentiated when used with other sedative drugs or ethanol.
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).
• 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]).
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/HbA1c (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
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).
• 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.
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- Drug class: atypical antipsychotics
Other brands: Geodon