Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.
Note: Oral dose needs to be taken with a meal (≥500 calories) to be adequately absorbed (Gandelman 2009; Lincoln 2010). Safety: Dose-dependent QTc interval prolongation; consider monitoring ECG during therapy (baseline and after dose increases), particularly in patients with risk factors for QTc prolongation (eg, preexisting QT prolongation, other cardiovascular disease, uncorrected electrolyte abnormalities, concurrent use with other drugs that prolong QT interval) (Camm 2012; Shah 2014). Some experts recommend checking baseline ECG in patients with schizophrenia, regardless of risk factors (APA [Keepers 2020]).
Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia [labeled use], bipolar disorder [off-label use]), substance intoxications (off-label use), or other organic causes (off-label use) (alternative agent):
Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression. Other agents are used preferentially in agitation associated with certain intoxications (eg, anticholinergic substances, stimulants) or alcohol withdrawal. Depending on presentation, may combine with a benzodiazepine (Moore 2020; WFSBP [Hasan 2012]; Wilson 2012). For cooperative patients able to take oral medication, use an alternative antipsychotic that does not need to be taken with a meal.
IM: 10 mg every 2 hours or 20 mg every 4 hours (maximum: 40 mg/day). Oral therapy should replace IM administration as soon as possible.
Bipolar disorder:
Acute manic episodes with or without mixed features (labeled use) and acute hypomania, monotherapy (off-label use) (alternative agent):
Oral: Initial: 40 mg twice daily with meal; on day 2 of treatment, may increase to 60 or 80 mg twice daily; subsequently adjust dose based on response and tolerability. Usual dosage: 40 to 80 mg twice daily (CANMAT [Yatham 2018]; Stovall 2021; manufacturer's labeling).
Note: For some patients, doses up to 240 mg/day may be necessary and tolerated (Stovall 2021). Combining with lithium or valproate for acute episode does not provide additional benefit (Sachs 2012; Scherk 2007).
Maintenance treatment, monotherapy (off-label use) or adjunctive with antimanic therapy (labeled use):
Monotherapy: Oral: Continue dose that was used to achieve control of the acute episode (CANMAT [Yatham 2018]).
Adjunctive with antimanic therapy:
Oral: 40 or 80 mg twice daily with meal (manufacturer's labeling).
Note: Despite lack of added benefit for ziprasidone plus lithium or valproate in acute episodes, maintenance treatment with combination treatment may delay time to relapse (Bowden 2010; manufacturer's labeling).
Delirium in the ICU, hyperactive, treatment (alternative agent) (off-label use):
Note: Nonpharmacologic interventions and treatment of underlying conditions are initial steps to prevent and manage delirium. Antipsychotics may be used as short-term adjunctive treatment if distressing symptoms (eg, agitation, anxiety) are present (SCCM [Devlin 2018]). Reassess daily for continued need; consider discontinuation and/or taper as symptoms resolve, especially at transitions of care, to prevent unnecessary continuation of therapy (D’Angelo 2019; Marshall 2016; Tietze 2020). Although data are limited, some experts use the following:
IM: 10 mg, then may repeat every 2 hours if needed or 20 mg, then may repeat once in 4 hours if needed; maximum total daily dose: 40 mg (Tietze 2020).
Oral: 20 to 40 mg every 12 hours with meal, if possible; maximum total daily dose: 80 mg (Girard 2010; Tietze 2020).
Delusional infestation (delusional parasitosis) (off-label use): Oral: Initial: 20 mg twice daily with meal; gradually increase every few weeks to lowest effective daily dose in range of 20 to 80 mg twice daily (De Berardis 2013; Freudenmann 2008). After achieving adequate response, maintain for ≥1 to 3 months before attempting to taper and discontinue (Suh 2020).
Major depressive disorder, treatment resistant (unipolar, nonpsychotic) (adjunctive therapy with antidepressant) (alternative agent) (off-label use):
Note: Also can be used for initial treatment of major depression with psychotic features (ie, not necessarily treatment resistant) in combination with an antidepressant (Rothschild 2020).
Oral: Initial: 20 mg twice daily with meal; may increase daily dose based on response and tolerability in increments of 40 mg every week up to 160 mg/day in 2 divided doses (Dunner 2007; Papakostas 2015).
Schizophrenia:
Oral: Initial: 20 to 40 mg twice daily with meal; may increase dose based on response and tolerability every 2 days or more. Usual dosage: 20 to 80 mg twice daily; maximum dose: 80 mg twice daily (Stroup 2022; manufacturer's labeling).
Note: For IM administration in acute agitation associated with schizophrenia, refer to "Agitation/Aggression (Severe, Acute) Associated with Psychiatric Disorders, (eg, Schizophrenia [Labeled Use], Bipolar Disorder [Off-Label Use]), Substance Intoxications (Off-Label Use), or Other Organic Causes (Off-Label Use)."
Discontinuation of therapy : In the treatment of chronic psychiatric disease, switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (eg, over several weeks to months) is advised to detect a reemergence of symptoms and to avoid withdrawal reactions (ie, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2021).
Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2022).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Oral: No dosage adjustment necessary.
IM: No dosage adjustment necessary. Cyclodextrin, an excipient in the IM formulation, is cleared by renal filtration; use with caution.
Ziprasidone is not removed by hemodialysis.
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.
(For additional information see "Ziprasidone: Pediatric drug information")
Acute agitation (schizophrenia): Limited data available:
Weight-directed dosing: Children ≥5 years and Adolescents: IM: 0.2 mg/kg; maximum dose: 20 mg/dose; a retrospective review of 40 patients (age range: 5 to 18 years) presenting to the ED with acute agitation showed a significant (p=0.03) response with a mean initial single dose of 0.19 ± 0.1 mg/kg amongst responders compared to a mean initial dose of 0.13 ± 0.06 mg/kg in nonresponders (Nguyen 2018)
Fixed dosing (Barzman 2007; Khan 2006; Staller 2004):
Children 5 to 11 years: IM: 10 mg
Children ≥12 years and Adolescents: IM: 10 to 20 mg; one study (n=59; age range: 5 to 19 years) reported that 69% of 20 mg doses surpassed the desired calming therapeutic effect and caused varying degrees of sedation (4% of patients were unable to be aroused) (Barzman 2007)
Autistic disorders or Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS); irritability: Limited data available: Children ≥6 years and Adolescents: Oral: Reported final dose range: 20 to 240 mg/day divided twice daily; see the following for initial doses and titration reported (Dominick 2015; Malone 2007; McDougle 2002)
A prospective, open-labeled study of 12 patients (12 to 18 years) used the following individually titrated doses (Malone 2007):
Patient weight ≤35 kg: Initial: 20 mg every other day at bedtime for 2 doses; then increase dose in weekly increments based on clinical response and tolerability: Week 1: 10 mg twice daily (20 mg/day); Week 2: 20 mg twice daily (40 mg/day); Week 3: 40 mg twice daily (80 mg/day); Week 4: 80 mg twice daily (160 mg/day)
Patient weight >35 kg: Initial: 20 mg/day at bedtime for 3 doses; then increase dose in weekly increments based on clinical response and tolerability: Week 1: 20 mg twice daily (40 mg/day); Week 2: 40 mg twice daily (80 mg/day); Week 4: 80 mg twice daily (160 mg/day)
A retrospective trial evaluated 42 pediatric patients (mean age: 11.8 ± 3.9 years; range: 5.9 to 18.7 years) and reported treatment response in 40% of subjects based on improvement in Clinical Global Impressions-Improvement Scale (CGI-I) scores at a mean final dose: 98.7 ± 52 mg/day (1.7 ± 1.1 mg/kg/day), reported range: 20 to 240 mg/day (Dominick 2015). A case series of 12 patients (8 to 20 years) initiated therapy at 20 mg/day administered at bedtime and then increased by 10 to 20 mg/week divided twice daily based on clinical response and tolerability; final ziprasidone dosage ranged between 20 to 120 mg/day (mean: ~60 mg/day) divided twice daily (McDougle 2002).
Bipolar I disorder: Note: In June 2009, an FDA advisory panel advised that ziprasidone is effective in patients 10 to 17 years of age for the treatment of mixed and manic episodes of bipolar disorder, but did not conclude that it was safe due to large number of subjects lost to follow-up and ambiguity within QTc prolongation data. Since then, prescribing of ziprasidone has decreased similarly for pediatric and adult patients after the FDA non-approval (Wang 2016).
Fixed dosing: Limited data available (DelBello 2008a; DelBello 2008b; Elbe 2008; Findling 2008; Findling 2013; Mechcatie 2009): Children and Adolescents 10 to 17 years: Oral: Initial dose: 20 mg/day; titrate dose upwards as tolerated, using twice daily dosing over a 2-week period to the weight-based target range: 60 to 80 mg/day (weight <45 kg) divided into twice daily doses or 120 to 160 mg/day (weight ≥45 kg) divided into twice daily doses (Findling 2013).
Weight-directed dosing: Limited data available: Children ≥6 years and Adolescents: An open-label, 8-week study of 21 patients (6 to 17 years [mean: 10.3 years]) with bipolar disorder and comorbid conditions (eg, ADHD, depression, conduct disorder) used the following weight-based dosing regimen (Biederman 2007):
Initial dose: 1 mg/kg/day divided twice daily; increase to 1.5 mg/kg/day divided twice daily by Week 2 and increase to 2 mg/kg/day divided twice daily by Week 3 if tolerated; maximum dose: 160 mg/day; Note: Only 14 of the 21 patients completed the study; five dropped out due to lack of efficacy; two dropped out due to adverse reactions; patients experienced a high incidence of sedation (46%) and headaches (38%).
Tourette syndrome, tic disorder: Very limited data available: Children and Adolescents 7 to 16 years: Oral: Initial dose: 5 mg/day for 3 days then using twice daily dosing, titrate dose as tolerated up to 40 mg/day divided twice daily. Dosing is based on a double-blind, placebo-controlled pilot study (n=28), mean daily dose at the end of trial: 28.2 + 9.6 mg/day (Sallee 2000).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Oral: There are no pediatric-specific recommendations; based on experience in adult patients, no adjustment may be necessary
IM: There are no pediatric-specific recommendations; cyclodextrin, an excipient in the IM formulation, is cleared by renal filtration; use with caution
Ziprasidone is not removed by hemodialysis.
No dosage adjustment is recommended; however, drug undergoes extensive hepatic metabolism and systemic exposure may be increased. Use with caution.
Refer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Howard 2000).
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]:
Generic: 20 mg (1 ea)
Solution Reconstituted, Intramuscular, as mesylate [strength expressed as base, preservative free]:
Geodon: 20 mg (1 ea)
Generic: 20 mg (1 ea)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as hydrochloride:
Zeldox: 20 mg, 40 mg, 60 mg, 80 mg
Generic: 20 mg, 40 mg, 60 mg, 80 mg
Oral: Administer capsule with food (≥500 calories [Lincoln 2010]). Swallow capsule whole; do not open, crush, or chew capsules.
Injection: For IM administration only.
Oral: Administer capsule with food (in adults, ≥500 calories [Lincoln 2010]). Swallow capsule whole; do not open, crush, or chew capsules.
Parenteral: For IM use only; do not administer IV
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration. For IM preparation, double gloves, a protective gown, and ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator) are recommended. Double gloving and a protective gown are required during IM administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia, bipolar disorder), substance intoxications, or other organic causes (IM only): Treatment of acute agitation in patients with schizophrenia for whom treatment with ziprasidone is appropriate and who need IM antipsychotic medication for rapid control of agitation. May be used off label for the treatment of acute agitation associated with bipolar disorder (CANMAT [Yatham 2018]) and substance intoxication (Wilson 2012).
Bipolar disorder: Monotherapy for the acute treatment of manic episodes with or without mixed features associated with bipolar disorder; for the maintenance treatment of bipolar disorder (manic or mixed episodes) as monotherapy (off label) or as an adjunct to lithium or valproate. May be used off label for the treatment of hypomania (CANMAT [Yatham 2018]).
Schizophrenia: Treatment of schizophrenia.
Delirium in the ICU, hyperactive, treatment; Delusional infestation (delusional parasitosis); Major depressive disorder, treatment resistant (unipolar, nonpsychotic)
Ziprasidone may be confused with TraZODone
Beers Criteria: Antipsychotics are identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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 QT 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
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
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.
• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of olanzapine for the unapproved use in elderly patients with dementia-related psychosis.
• 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: Use has been associated with a fairly high incidence of rash and/or urticaria (5%) that was dose- and possibly duration-related; discontinue if alternative etiology is not identified. 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 three 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. Compared to other antipsychotics, the risk of dyslipidemia with ziprasidone is minimal to low (Solmi 2017).
• 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 [Keeper 2020]; 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.
• 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. Compared to other antipsychotics, the risk of hyperglycemia with ziprasidone is minimal to low (Solmi 2017).
• 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.
• 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. Compared to other antipsychotics, the risk of weight gain with ziprasidone is minimal to low (Solmi 2017).
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.
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, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).
In June 2009, an FDA advisory panel advised that ziprasidone is effective in patients 10 to 17 years of age for the treatment of mixed and manic episodes of bipolar disorder, but did not conclude that it was safe due to large number of subjects lost to follow-up and ambiguity within QTc prolongation data. Since then, prescribing of ziprasidone has decreased similarly for pediatric and adult patients after the FDA non-approval (Wang 2016). Observed QTc prolongation with ziprasidone was greater than with other atypical antipsychotic agents (eg, risperidone, olanzapine, quetiapine), but less than with thioridazine. A prospective study followed 20 children (mean age: 13.2 years) for an average of 4.6 months and reported significant QTc prolongation at relatively low ziprasidone doses (mean daily dose: 30 mg ± 13 mg/day); the authors suggest the effect is not dose dependent in children unlike adults and recommend reserving ziprasidone use as second- or third-line for patients at risk for QTc prolongation or when using doses >40 mg/day (Blair 2005); monitor ECG with use. Use with caution during diarrheal illnesses; monitor electrolytes closely, particularly potassium and magnesium (Blair 2004). May cause hyperprolactinemia; use with caution in children and adolescents; adverse effects due to increased prolactin concentrations have been observed; long-term effects on growth or sexual maturation have not been evaluated.
An increased risk for the development of type 2 diabetes mellitus (DM) was observed in pediatric patients 10 to 18 years receiving second-generation antipsychotics (SGA) at mean exposure duration of: 17.2 months. For patients initiated on SGA: 0.4% incidence with mean exposure at time type 2 DM diagnosed: 13.5 months; for SGA noniniators (patients receiving another agent prior to SGA initiation): 0.2% incidence with mean exposure at time of type 2 DM diagnosed: 14.6 months. Amongst specific SGAs, the risk was highest for aripiprazole (p=0.001) and ziprasidone (p=0.06) compared to risperidone as the reference group but not quetiapine or olanzapine (Rubin 2015).
Pediatric psychiatric disorders are frequently serious mental disorders which present with variable symptoms that do not always match adult diagnostic criteria. Conduct a thorough diagnostic evaluation and carefully consider risks of psychotropic medication before initiation in pediatric patients. Medication therapy for pediatric patients with bipolar disorder is indicated as part of a total treatment program that frequently includes educational, psychological, and social interventions. A systematic review and meta-analysis of trials (n=2,158, age range: 8 to 19 years old) reported inferior efficacy of ziprasidone compared to other agents (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, molindone) for youth with early-onset schizophrenia (Pagsberg 2017). Another systematic review evaluating the effect and safety of atypical antipsychotics for treatment of disruptive behavior disorders in children and youths noted a lack of evidence to support ziprasidone in children ≥5 years and youth and no evidence for children <5 years of age (Loy 2017).
Similar to adult experience, the American Academy of Child and Adolescent Psychiatry (AACAP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (AACAP [McClellan 2007]).
Substrate of CYP1A2 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Agents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: 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. Risk D: Consider therapy modification
Amisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral). 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 greater risk. Risk D: Consider therapy modification
Amphetamines: Antipsychotic Agents may enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: 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 avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification
Antipsychotic Agents: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
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. Risk D: 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. Risk D: Consider therapy modification
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: 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. Risk D: 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. Risk D: Consider therapy modification
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: 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 at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy
Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Carbetocin: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Risk X: Avoid combination
Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Risk X: 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. Risk D: Consider therapy modification
ClomiPRAMINE: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Ziprasidone. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ziprasidone. Risk C: Monitor therapy
Dabrafenib: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
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. Risk D: 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. Risk D: 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. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Risk X: 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. Risk D: 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. Risk C: 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. Risk D: 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. Risk X: 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. Risk D: Consider therapy modification
Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
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. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Etelcalcetide: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification
Fexinidazole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
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. Risk C: 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. Risk D: Consider therapy modification
Fluconazole: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluconazole. 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. Risk D: Consider therapy modification
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fluorouracil Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluorouracil Products. 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. Risk D: Consider therapy modification
Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Risk X: 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. Risk D: 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. Risk D: Consider therapy modification
Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modification
Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Iboga: 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. Risk D: Consider therapy modification
Imipramine: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification
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. Risk D: 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 antiseizure drugs. Risk D: 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 antiseizure drugs. Risk D: 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 antiseizure drugs. Risk D: Consider therapy modification
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Levoketoconazole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: 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. Risk D: Consider therapy modification
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Meglumine Antimoniate: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification
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. Risk D: 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. Risk D: 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: 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. Risk D: Consider therapy modification
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Risk X: Avoid combination
Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Risk X: 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. Risk D: Consider therapy modification
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: 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. Risk D: Consider therapy modification
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Oxytocin: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: Consider therapy modification
Pacritinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pacritinib. 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. Risk C: Monitor therapy
Papaverine: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Papaverine. 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. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
PAZOPanib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of PAZOPanib. Risk X: 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. Risk D: Consider therapy modification
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
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. Risk D: 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. Risk X: Avoid combination
Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Risk X: 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. Risk X: Avoid combination
Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Risk X: Avoid combination
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Propofol: May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk C: 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. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging 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. Risk D: 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. Risk D: Consider therapy modification
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate 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. Risk D: Consider therapy modification
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (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. Risk D: 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). Risk X: Avoid combination
QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Risk X: Avoid combination
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: 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. Risk D: Consider therapy modification
Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Risk X: 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. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combination
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Risk X: Avoid combination
Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: Avoid combination
SUNItinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of SUNItinib. 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. Risk D: Consider therapy modification
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. Risk D: 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. Risk D: Consider therapy modification
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Toremifene: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Toremifene. 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. Risk D: Consider therapy modification
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
Administration with a meal containing at least 500 calories increases serum levels ~80%. Management: Administer with a meal containing at least 500 calories (Lincoln 2010).
Ziprasidone may cause hyperprolactinemia, which may cause a reversible reduction of reproductive function in females.
If treatment is needed in a woman planning a pregnancy, use of an agent other than ziprasidone may be preferred (Grunze 2018; Larsen 2015).
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.
The American College of Obstetricians and Gynecologists 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 health care provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy are 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). If treatment is initiated during pregnancy, use of an agent other than ziprasidone may be preferred (Grunze 2018; Larsen 2015).
Health care providers are encouraged to enroll women 18 to 45 years of age exposed to ziprasidone during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388 or https://www.womensmentalhealth.org/pregnancyregistry).
Ziprasidone is present in breast milk (Schlotterbeck 2009).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Monitor infants exposed to ziprasidone via breast milk for excess sedation, irritability, poor feeding, and extrapyramidal symptoms. Until additional information is available, use of agents other than ziprasidone in breastfeeding women may be preferred (Larsen 2015).
Capsule: Take with food.
|
Frequency of Antipsychotic Monitoringa,b | ||
|---|---|---|
|
Monitoring parameter |
Frequency of monitoring |
Comments |
|
a For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected adverse reactions) in addition to the timeline. | ||
|
b ADA 2004; APA [Keepers 2020]; De Hert 2011; Gugger 2011; manufacturer's labeling. | ||
|
c Cardiac risk factors include congenital long QT syndrome, structural or functional cardiac disease, bradycardia, family history of sudden cardiac death. | ||
|
d Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic. | ||
|
e Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; past or current EPS. | ||
|
Adherence |
Every visit |
|
|
Blood chemistries (electrolytes, renal function, liver function, TSH) |
Annually |
Correct electrolyte imbalances (hypokalemia) prior to administration; may prolong QT interval |
|
CBC |
As clinically indicated |
Check frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia |
|
ECG |
As clinically indicated |
Check after significant dose increase or new QTc prolonging medication if there are cardiac risk factorsc |
|
Extrapyramidal symptoms |
Every visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high risk.d |
|
|
Fall risk |
Every visit |
|
|
Fasting plasma glucose/HbA1c |
12 weeks after initiation and dose change; annually |
Check more frequently than annually if abnormal. Follow diabetes guidelines. |
|
Lipid panel |
12 weeks after initiation and dose change; annually |
Check more frequently than annually if abnormal. Follow lipid guidelines. |
|
Mental status and alertness |
Every visit |
|
|
Metabolic syndrome history |
Annually |
Evaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease |
|
Prolactin |
Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported. |
Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejaculatory function |
|
Tardive dyskinesia |
Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high risk.e |
|
|
Vital signs (BP, orthostatics, temperature, pulse, signs of infection) |
Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change. |
|
|
Weight/Height/BMI |
8 and 12 weeks after initiation and dose change; quarterly |
Consider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome. Consider changing antipsychotic if BMI increases by ≥1 unit. Some experts recommend checking weight and height at every visit. |
Timing of serum samples: Draw trough just before next dose (Hiemke 2018).
Therapeutic reference range: 50 to 200 ng/mL (SI: 127.5 to 510 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations; however, therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).
Laboratory alert level: 400 ng/mL (SI: 1,020 nmol/L) (Hiemke 2018).
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.
Onset of action:
Agitation: IM: Initial effects within 15 minutes; adequate sedation within 30 minutes (Martel 2005).
Bipolar disorder, acute mania: Oral: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).
Major depressive disorder, unipolar: Oral: Initial effects may be observed within 1 week with continued improvements over 6 to 12 weeks (Wen 2014).
Schizophrenia: Oral: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).
Absorption: Well absorbed; administration with 500 calorie meals increases serum levels ~80% (Lincoln 2010).
Distribution: Vd: 1.5 L/kg.
Protein binding: >99%, primarily to albumin and alpha-1 acid glycoprotein.
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).
Bioavailability: Oral (with food): 60%; IM: 100%.
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.
Time to peak:
Oral: Children: Mean: 5 to 5.5 hours (Sallee 2006); Adults: 6 to 8 hours.
IM: ≤60 minutes.
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.
Hepatic function impairment: Increases the AUC of ziprasidone.
Capsules (Geodon Oral)
20 mg (per each): $25.40
40 mg (per each): $26.64
60 mg (per each): $30.82
80 mg (per each): $30.82
Capsules (Ziprasidone HCl Oral)
20 mg (per each): $8.00 - $8.96
40 mg (per each): $8.00 - $8.96
60 mg (per each): $9.83 - $10.88
80 mg (per each): $9.83 - $10.88
Solution (reconstituted) (Geodon Intramuscular)
20 mg (per each): $65.60
Solution (reconstituted) (Ziprasidone Mesylate Intramuscular)
20 mg (per each): $23.89 - $56.40
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