Version July 2025
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.
Dosage guidance:
Safety: Dose-dependent QTc interval prolongation: Avoid use in patients with baseline QTc >450 msec or with risk factors for QTc prolongation. In patients with QTc >500 msec or QTc increase >60 msec on treatment, consider switching antipsychotics or lowering ziprasidone dose (Ref). Catatonia: Antipsychotics are not indicated for use in catatonia and may worsen psychosis and increase risk for neuroleptic malignant syndrome in patients with catatonia (Ref).
Clinical considerations: For treatment of psychiatric disorders, consult a psychiatry specialist for all management decisions; select antipsychotic carefully based on patient preference, clinical characteristics, history, comorbidities, and adverse effect profile (Ref).
Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia [labeled use], bipolar disorder [off-label use]), substance intoxication (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 (Ref). 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 meals (≥500 calories); 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 (Ref).
Note: For some patients, doses up to 240 mg/day may be necessary and tolerated (Ref). Combining with lithium or valproate for acute episode does not provide additional benefit (Ref).
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 (Ref).
Adjunctive with antimanic therapy:
Oral: 40 or 80 mg twice daily with meals (≥500 calories) (Ref).
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 (Ref).
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 (Ref). Reassess daily for continued need; consider discontinuation and/or taper as symptoms resolve, especially at transitions of care, to prevent unnecessary continuation of therapy (Ref). 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 (Ref).
Oral: 20 to 40 mg every 12 hours with meals (≥500 calories), if possible; maximum total daily dose: 80 mg (Ref).
Delusional infestation (delusional parasitosis) (off-label use): Oral: Initial: 20 mg twice daily with meals (≥500 calories); gradually increase every few weeks to lowest effective daily dose in range of 20 to 80 mg twice daily (Ref). After achieving adequate response, maintain for ≥1 to 12 months before attempting to taper (Ref).
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 (Ref).
Oral: Initial: 20 mg twice daily with meals (≥500 calories); 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 (Ref).
Schizophrenia:
Oral: Initial: 20 to 40 mg twice daily with meals (≥500 calories); because patients experiencing a first episode of psychosis will be more sensitive to adverse effects, administer 20 mg twice daily with meals as the initial dose. May increase daily dose based on response and tolerability in increments of 20 to 40 mg/day every ≥2 days. Monitor for akathisia, orthostatic hypotension, and sedation during titration. Usual daily dosage: 40 to 160 mg, in 2 divided doses; maximum dose: 160 mg/day (Ref).
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 (Ref).
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 (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Cyclodextrin is an excipient in the IM formulation; accumulation may occur with repeated doses in patients with kidney impairment, although the clinical significance is unclear (Ref).
Altered kidney function: IM, Oral: No dosage adjustment necessary for any degree of kidney impairment (Ref).
Hemodialysis, intermittent (thrice weekly): IM, Oral: Not dialyzable (Ref): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: IM, Oral: Unlikely to be significantly dialyzed (highly protein bound): No dosage adjustment necessary (Ref).
CRRT: IM, Oral: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): IM, Oral: No dosage adjustment necessary (Ref).
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.
Note: Avoid for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. If used, consider deprescribing attempts to assess continued need and/or lowest effective dose. Of note, use in certain indications may be appropriate (eg, schizophrenia, bipolar disorder) (Ref). For psychiatric disorders, consult a psychiatry specialist for all management decisions (Ref).
All indications: See adult dosing; dosages in the lower range of recommended adult dosing are generally sufficient. Titrate dosage slowly and monitor carefully.
(For additional information see "Ziprasidone: Pediatric drug information")
Agitation, acute: Limited data available:
Weight-directed dosing: Children ≥5 years and Adolescents: IM: 0.2 mg/kg/dose; maximum dose: 20 mg/dose; a retrospective review of 40 patients (age range: 5 to 18 years) presenting to the emergency department 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 (Ref).
Fixed dosing (Ref):
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) (Ref).
Autism spectrum disorders; irritability: Limited data available:
Children ≥6 years and Adolescents: Oral: Reported final daily dose range: 20 to 240 mg/day in divided doses twice daily; see the following for initial doses and titration reported (Ref).
A prospective, open-label study of 12 patients (12 to 18 years) used the following individually titrated doses (Ref):
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 of 98.7 ± 52 mg/day (1.7 ± 1.1 mg/kg/day); reported range: 20 to 240 mg/day (Ref). 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 (Ref).
Bipolar I disorder: Note: In June 2009, an FDA advisory panel advised that ziprasidone was 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 (Ref).
Fixed dosing: Limited data available (Ref): 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 (Ref).
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, attention-deficit/hyperactivity disorder, depression, conduct disorder) used the following weight-based dosing regimen (Ref):
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 (Ref).
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.
CNS depressive symptoms, including drowsiness and somnolence have been reported with ziprasidone and may cause nonadherence and impair physical and/or mental abilities resulting in subsequent falling and fracture, particularly in older adults.
Mechanism: Dose-related, related to the pharmacologic action; somnolence is believed to be due to histamine-1 receptor antagonism leading to potential CNS depressant effects (Ref).
Risk factors:
• Specific antipsychotic (ziprasidone is considered to be moderately sedating at usual therapeutic doses in comparison with other antipsychotics) (Ref)
• High doses (Ref)
• Concurrent administration with other CNS depressants (eg, benzodiazepines, antihistamines) (Ref)
Antipsychotics are associated with dyslipidemia in adult and pediatric patients, which is a component of the metabolic syndrome observed with this pharmacologic class. Of the second-generation antipsychotics, ziprasidone is associated with a low risk of causing lipid abnormalities; however, hypercholesterolemia has been observed (Ref).
Onset: Intermediate; increases in cholesterol have been reported within 2 to 4 weeks of antipsychotic initiation (Ref).
Risk factors:
• Schizophrenia (regardless of medication use) is associated with a higher rate of morbidity/mortality compared to the general population, primarily due to cardiovascular disease (Ref)
Ziprasidone may cause extrapyramidal reaction, also known as drug-induced movement disorders. Antipsychotics cause four main extrapyramidal symptoms (EPS): Acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia (Ref). EPS presenting as dysphagia, esophageal dysmotility, or aspiration have also been reported with antipsychotics, which may not be recognized as EPS (Ref).
Mechanism: EPS: Dose-related; due to antagonism of dopaminergic D2 receptors in nigrostriatal pathways (Ref). Tardive dyskinesia: Time-related (delayed); results from chronic exposure to D2 receptor antagonists leading to up-regulation of these receptors over time (Ref).
Onset:
Antipsychotics in general:
Acute dystonia: Rapid; in the majority of cases, dystonia usually occurs within the first 5 days after initiating antipsychotic therapy (even with the first dose, particularly in patients receiving parenteral antipsychotics) or a dosage increase (Ref).
Drug-induced parkinsonism: Varied; onset may be delayed from days to weeks, with 50% to 75% of cases occurring within 1 month and 90% within 3 months of antipsychotic initiation, a dosage increase, or a change in the medication regimen (such as adding another antipsychotic agent or discontinuing an anticholinergic medication) (Ref).
Akathisia: Varied; may begin within several days after antipsychotic initiation but usually increases with treatment duration, occurring within 1 month in up to 50% of cases, and within 3 months in 90% of cases (Ref).
Tardive dyskinesia: Delayed; symptoms usually appear after 1 to 2 years of continuous exposure to a D2 receptor antagonist and almost never before 3 months, with an insidious onset, evolving into a full syndrome over days and weeks, followed by symptom stabilization, and then a chronic waxing and waning of symptoms (Ref).
Esophageal dysfunction (associated with EPS): Varied; ranges from weeks to months following initiation (Ref).
Risk factors:
EPS (in general):
• Prior history of EPS (Ref)
• Higher doses (Ref)
• Younger age (in general, children and adolescents are usually at higher risk for EPS compared to adults) (Ref)
• Specific antipsychotic: Ziprasidone is usually associated with a low propensity to cause EPS compared to other antipsychotics (Ref)
Acute dystonia:
• Males (Ref)
• Young age (Ref)
Drug-induced parkinsonism:
• Females (Ref)
• Older patients (Ref)
Akathisia:
• Higher antipsychotic dosages (Ref)
• Polypharmacy (Ref)
• Mood disorders (Ref)
• Females (Ref)
• Older patients (Ref)
Tardive dyskinesia:
• Acute motor symptoms (eg, parkinsonism symptoms, Parkinson disease) (Ref)
• Age >55 years, females >55 years (Ref)
• Cognitive impairment (Ref)
• Concomitant treatment with anticholinergic medications (Ref)
• Diabetes (Ref)
• Diagnosis of schizophrenia or affective disorders (Ref)
• Females (Ref)
• Greater total antipsychotic exposure (especially first-generation antipsychotics) (Ref)
• History of EPS (Ref)
• Poor treatment response (Ref)
• Substance misuse or dependence (Ref)
• Race (White or African descent). Note: Although early literature supported race as a potential risk factor for tardive dyskinesia (Ref), newer studies have challenged this assertion (Ref).
Esophageal dysfunction (associated with EPS):
• Certain comorbidities such as neurologic degenerative disease, dementia, stroke, Parkinson disease, or myasthenia gravis (Ref)
• Adults >75 years of age (may be risk factor due to age-related muscle atrophy, cognitive impairment, reduced esophageal peristalsis) (Ref)
Agranulocytosis, leukopenia, and thrombocytopenia have been reported with ziprasidone. Neutropenia has been reported with other second-generation antipsychotics (Ref).
Onset: Varied; in general, drug-induced neutropenia usually manifests after 1 or 2 weeks of exposure and agranulocytosis usually appears 3 to 4 weeks following initiation of therapy; however, the onset may be insidious (Ref).
Risk factors:
• History of drug-induced leukopenia/neutropenia and preexisting low white blood cell count/absolute neutrophil count
• Older adults (Ref)
Antipsychotics are associated with hyperglycemia in adult and pediatric patients, to varying degrees, which is a component of the metabolic syndrome observed with the pharmacologic class (Ref). Ziprasidone is associated with a low risk of causing metabolic alterations in adult patients; however, glycemic abnormalities ranging from hyperglycemia to diabetes mellitus, and hyperglycemic hyperosmolar syndrome have been observed rarely (Ref).
Onset: Varied; with antipsychotics in general, new-onset diabetes has been observed within the first 3 months to a median onset of 3.9 years (Ref).
Risk factors:
Antipsychotics in general:
• African-American race (Ref)
• Males (Ref)
• Age <35 years (Ref)
• Preexisting obesity, poor exercise habits, or other risk factors for diabetes, including family history of diabetes (Ref)
• Exposure to other agents that also increase the risk of hyperglycemia (Ref)
• Specific antipsychotic: Ziprasidone is associated with a low to moderate risk of metabolic disturbances (Ref).
Ziprasidone is typically associated with a lower risk of causing significant effects on prolactin compared to other second-generation antipsychotics with a higher risk (such as risperidone), although there are case reports of hyperprolactinemia in adult and pediatric patients (Ref). Hyperprolactinemia may lead to gynecomastia, galactorrhea not associated with childbirth, amenorrhea, sexual disorder, and infertility (Ref). Although long-term effects of elevated prolactin levels have not been fully evaluated, some studies suggest a possible association between hyperprolactinemia and an increased risk for breast and/or pituitary tumors and osteopenia/osteoporosis (Ref).
Mechanism: Related to the pharmacologic action; antagonism of dopamine D2 receptors in the tuberoinfundibular dopaminergic pathway causes disinhibition of prolactin release resulting in hyperprolactinemia (Ref).
Onset: Varied; typically within a few weeks following initiation, but may also arise after long-term, stable use (Ref).
Risk factors:
• Specific antipsychotic: Ziprasidone is considered a prolactin-sparing antipsychotic with a low risk for hyperprolactinemia (Ref)
• Higher doses (Ref)
• Females (particularly those of reproductive age) (Ref)
Hypersensitivity reaction, including angioedema, skin rash, and urticaria, have been reported with ziprasidone. Drug reaction with eosinophilia and systemic symptoms (DRESS) and severe cutaneous adverse reactions (SCARs) (ie, Stevens-Johnson syndrome) have also been reported.
Mechanism: Hypersensitivity reactions: Delayed hypersensitivity reactions, including SCARs, are T-cell mediated (Ref).
Onset: Varied; in one case report, systemic hypersensitivity reaction with pruritic skin rash occurred 3 weeks following ziprasidone initiation; symptoms recurred 2 days after ziprasidone rechallenge (Ref). In another case report, urticaria and angioedema occurred 27 days and 30 days, respectively, following ziprasidone initiation (Ref).
Older adults with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to those treated with placebo. Although the causes of death were varied, most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature (Ref). In addition, an increased incidence of cerebrovascular effects, including fatalities, have been reported in placebo-controlled trials of other second-generation antipsychotics in older adults with dementia-related psychosis. Of note, ziprasidone is not approved for the treatment of dementia-related psychosis.
Mechanism: Unknown; possible mechanisms include arrhythmia, cardiac arrest, and extrapyramidal effects that may increase the risk of falls, aspirations, and pneumonia (Ref).
Risk factors:
• Dementia-related psychosis (eg, Lewy body dementia, Parkinson disease dementia)
• Higher antipsychotic dosage (Ref)
All antipsychotics have been associated with neuroleptic malignant syndrome (NMS), although the incidence is lower with second-generation (atypical) antipsychotics compared to first-generation (typical) antipsychotics. There are case reports of NMS with ziprasidone, including monotherapy (Ref).
Mechanism: Idiosyncratic; possibly due to a reduction in CNS dopaminergic tone, along with dysregulation of autonomic nervous system activity (Ref).
Onset: Varied; in general, most patients develop NMS within 2 weeks of antipsychotic initiation or dose increase. In some patients, prodromal symptoms emerge within an hour of initiation; once the syndrome starts, the full syndrome usually develops in 3 to 5 days (Ref). However, NMS may also occur months after stable antipsychotic therapy (Ref).
Risk factors:
Antipsychotics in general:
• Males (twice as likely to develop NMS compared to females) (Ref)
• Dehydration (Ref)
• High-dose antipsychotic treatment (Ref)
• Concomitant lithium or benzodiazepine (potential risk factors) (Ref)
• Catatonia (Ref)
• Polypharmacy (Ref)
• Pharmacokinetic interactions (Ref)
• IM administration (Ref)
• Rapid dosage escalation (Ref)
• Psychomotor agitation (Ref)
Ziprasidone may cause orthostatic hypotension (although at a lower prevalence compared to first-generation antipsychotics and certain second-generation antipsychotics, such as clozapine, risperidone, and quetiapine) and accompanying tachycardia, dizziness, and syncope in adults (Ref). Orthostatic hypotension may result in subsequent falls and fractures, particularly in older adults (Ref).
Mechanism: Related to pharmacologic action; orthostatic hypotension is thought to be due to alpha-1 adrenergic receptor antagonism (Ref).
Onset: Rapid; per manufacturer's labeling, orthostatic hypotension is most common during initial dose titration.
Risk factors:
• Known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities)
• Cerebrovascular disease
• Conditions which would predispose patients to hypotension (dehydration, hypovolemia, treatment with antihypertensive agents)
• Older adults
Ziprasidone is associated with prolonged QT interval on ECG in adult and pediatric patients, including reports of torsades de pointes (TdP), predominantly in the setting of multiple risk factors (Ref). Of the second-generation antipsychotics, ziprasidone is associated with a higher risk of QTc prolongation (Ref). In clinical trials, the average increase in QTc following oral ziprasidone was approximately 5 to 23 ms (Ref).
Mechanism: Dose-related; ziprasidone prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current (Ref), although other mechanisms may also be involved (Ref).
Risk factors:
Drug-induced QTc prolongation/TdP (in general):
• Females (Ref)
• Age >65 years (Ref)
• Structural heart disease (eg, history of myocardial infarction or heart failure with a reduced ejection fraction) (Ref)
• History of drug-induced TdP (Ref)
• Genetic defects of cardiac ion channels (Ref)
• Congenital long QT syndrome (Ref)
• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)
• Electrolyte disturbances (eg, hypokalemia, hypocalcemia, hypomagnesemia) (Ref)
• Bradycardia (Ref)
• Hepatic impairment (Ref)
• Kidney impairment (Ref)
• Coadministration of multiple medications (≥2) that prolong the QT interval or increase drug interactions that increase serum drug concentrations of QTc prolonging medications (Ref)
• Substance use (Ref)
Serotonin syndrome has been reported and typically occurs with coadministration of multiple serotonergic drugs but can occur following a single serotonergic agent at therapeutic doses (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).
Mechanism: Dose-related; overstimulation of serotonin receptors (5-HT2A) by serotonergic agents (Ref).
Onset: Rapid; in the majority of cases (74%), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref).
Risk factors:
• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism (eg, monoamine oxidase inhibitors [MAOIs]). Of note, concomitant use of some serotonergic agents, such as MAOIs, are contraindicated.
Antipsychotics may impair the body’s ability to regulate core body temperature, which may contribute to an elevation in core body temperature during predisposing conditions such as strenuous exercise or dehydration. Hypothermia has been reported with ziprasidone (Ref).
Mechanism: Non–dose-related; idiosyncratic. Exact mechanism is unknown; however, body temperature is regulated by the hypothalamus with involvement of the dopamine, serotonin, and norepinephrine neurotransmitters. D2 antagonism may cause an increase in body temperature, while 5-HT2A (serotonin) receptor antagonism may cause a decrease in body temperature. Of note, ziprasidone has stronger affinity for 5-HT2A receptors than for D2 receptors, suggesting that it is more likely to cause a reduction in body temperature than an increase. In addition, antagonism of peripheral alpha-1 adrenergic receptors has also been suggested as a factor in the hypothermic effect by inhibiting peripheral responses to cooling (Ref).
Onset: Hypothermia: Varied; antipsychotic-induced hypothermia cases indicate a typical onset in the period shortly after initiation of therapy or a dosage increase (first 7 to 10 days) (Ref).
Risk factors:
Heat stroke:
• Psychiatric illness (regardless of medication use) (Ref)
• Dehydration (Ref)
• Strenuous exercise (Ref)
• Heat exposure (Ref)
• Concomitant medications possessing anticholinergic effects (Ref)
Hypothermia:
• In general, predisposing risk factors include: Older adults, cerebrovascular accident, preexisting brain damage, hypothyroidism, malnutrition, shock, sepsis, adrenal insufficiency, diabetes, disability, burns, exfoliative dermatitis benzodiazepine use, alcohol intoxication, kidney or liver failure (Ref)
• Schizophrenia (regardless of antipsychotic use) (Ref)
Ziprasidone is associated with significant weight gain (increase of ≥7% from baseline) in adult and pediatric patients, which is a component of the metabolic syndrome observed with this pharmacologic class.
Mechanism: Multiple proposed mechanisms, including actions at serotonin, dopamine, histamine, and muscarinic receptors, with differing effects explained by differing affinity of antipsychotics at these receptors (Ref).
Onset: Varied; antipsychotic-induced weight gain usually occurs rapidly in the initial period following initiation, then gradually decreases and flattens over several months with patients continuing to gain weight in the long term (Ref).
Risk factors:
• Family history of obesity (Ref)
• Parental BMI (Ref)
• Children and adolescents (Ref)
• Rapid weight gain in the initial period: Younger age, lower baseline BMI, more robust response to antipsychotic, and increase in appetite; rapid weight gain of >5% in the first month has been observed as the best predictor for significant long-term weight gain (Ref)
• Duration of therapy (although weight gain plateaus, patients continue to gain weight over time) (Ref)
• Schizophrenia (regardless of medication) is associated with a higher prevalence of obesity compared to the general population due to components of the illness, such as negative symptoms, sedentary lifestyles, and unhealthy diets (Ref)
• Specific antipsychotic: Ziprasidone is considered to have a low propensity for causing weight gain; olanzapine and clozapine are associated with a high risk (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequencies represent oral administration in adults unless otherwise indicated.
>10%:
Endocrine & metabolic: Weight gain (4% to 16%) (table 1)
|
Drug (Ziprasidone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Ziprasidone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
4% |
2% |
60 to 80 mg twice daily |
Oral capsules |
Bipolar disorder |
388 |
451 |
|
2% |
2% |
20 to 40 mg twice daily |
Oral capsules |
Bipolar disorder |
295 |
451 |
|
16% |
4% |
80 mg twice daily |
Oral capsules |
Schizophrenia |
97 |
227 |
|
11% |
4% |
100 mg twice daily |
Oral capsules |
Schizophrenia |
74 |
227 |
|
10% |
4% |
40 mg twice daily |
Oral capsules |
Schizophrenia |
135 |
227 |
|
9% |
4% |
20 mg twice daily |
Oral capsules |
Schizophrenia |
167 |
227 |
|
7% |
4% |
60 mg twice daily |
Oral capsules |
Schizophrenia |
109 |
227 |
Gastrointestinal: Nausea (IM, oral: 8% to 12%)
Nervous system: Dizziness (IM, oral: 3% to 16%) (table 2), drowsiness (IM: 8% to 20%; oral: 14% to 31%) (table 3), extrapyramidal reaction (14% to 31%) (table 4), headache (IM, oral: 5% to 18%)
|
Drug (Ziprasidone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Ziprasidone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
10% |
N/A |
20 mg |
IM |
Agitation in schizophrenic patients |
41 |
N/A |
|
3% |
N/A |
10 mg |
IM |
Agitation in schizophrenic patients |
63 |
N/A |
|
16% |
7% |
40 to 80 mg twice daily |
Oral capsules |
Manic and mixed episodes associated with bipolar disorder |
279 |
136 |
|
8% |
6% |
N/A |
Oral capsules |
Schizophrenia |
702 |
273 |
|
Drug (Ziprasidone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Ziprasidone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
20% |
N/A |
20 mg |
IM |
Agitation in schizophrenic patients |
41 |
N/A |
|
8% |
N/A |
10 mg |
IM |
Agitation in schizophrenic patients |
63 |
N/A |
|
31% |
12% |
40 to 80 mg twice daily |
Oral capsules |
Manic and mixed episodes associated with bipolar disorder |
279 |
136 |
|
14% |
7% |
N/A |
Oral capsules |
Schizophrenia |
702 |
273 |
|
Drug (Ziprasidone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Ziprasidone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
31% |
12% |
40 to 80 mg twice daily |
Oral capsules |
Manic and mixed episodes associated with bipolar disorder |
279 |
136 |
|
14% |
8% |
N/A |
Oral capsules |
Schizophrenia |
702 |
273 |
1% to 10%:
Cardiovascular: Bradycardia (IM, oral: ≤2%), chest pain (3%), hypertension (3%), orthostatic hypotension (IM: 5%, oral: ≥1%), tachycardia (2%) (table 5)
|
Drug (Ziprasidone) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Ziprasidone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
2% |
1% |
Oral capsules |
Schizophrenia |
702 |
273 |
Dermatologic: Diaphoresis (IM: 2%), fungal dermatitis (2%), furunculosis (IM: 2%), skin photosensitivity (≥1%), skin rash (4% to 5%)
Gastrointestinal: Abdominal pain (IM: 2%; oral: ≥1%), anorexia (IM, oral: 2%), constipation (IM: 2%; oral: 9%), diarrhea (IM, oral: 3% to 5%), dyspepsia (IM, oral: 2% to 8%), dysphagia (2%) (table 6), rectal hemorrhage (IM, oral: ≤2%), sialorrhea (4%), vomiting (IM, oral: 3% to 5%), xerostomia (4% to 5%)
|
Drug (Ziprasidone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Ziprasidone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
2% |
0% |
40 to 80 mg twice daily |
Oral capsules |
Manic and mixed episodes associated with bipolar disorder |
279 |
136 |
Genitourinary: Dysmenorrhea (IM: 2%)
Hypersensitivity: Facial edema (≥1%), tongue edema (3%)
Local: Pain at injection site (IM: 7% to 8%)
Nervous system: Abnormal gait (≥1%), agitation (IM: 2%; oral: ≥1%), akathisia (IM: 2%; oral: 8% to 10%) (table 7), akinesia (≥1%), amnesia (≥1%), anxiety (5%), asthenia (5% to 6%), ataxia (≥1%), buccoglossal syndrome (≥1%), chills (≥1%), choreoathetosis (≥1%), cogwheel rigidity (≥1%), confusion (≥1%), delirium (≥1%), dysarthria (≥1%), falling (≥1%), hostility (≥1%), hypertonia (≥1%), hypoesthesia (2%), hypothermia (≥1%), hypotonia (≥1%), neuropathy (≥1%), paresthesia (IM: 2%; oral: ≥1%), personality disorder (IM: 2%), speech disturbance (IM, oral: 2%), tremor (≥1%), twitching (≥1%), vertigo (≥1%), withdrawal syndrome (≥1%)
|
Drug (Ziprasidone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Ziprasidone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
2% |
N/A |
10 mg |
IM |
Agitation in schizophrenic patients |
63 |
N/A |
|
10% |
5% |
40 to 80 mg twice daily |
Oral capsules |
Manic and mixed episodes associated with bipolar disorder |
279 |
136 |
|
8% |
7% |
N/A |
Oral capsules |
Schizophrenia |
702 |
273 |
Neuromuscular & skeletal: Dyskinesia (≥1%), dystonia (≥1%), hyperkinetic muscle activity (≥1%), hypokinesia (≥1%), myalgia (2%)
Ophthalmic: Diplopia (≥1%), oculogyric crisis (≥1%), visual disturbance (3% to 6%)
Renal: Flank pain (≥1%)
Respiratory: Dyspnea (2%), flu-like symptoms (≥1%), increased cough (3%), pharyngitis (3%), respiratory tract infection (8%), rhinitis (4%)
Miscellaneous: Fever (≥1%)
<1%:
Cardiovascular: Angina pectoris, atrial fibrillation, bundle branch block, cardiomegaly, deep vein thrombophlebitis, first-degree atrioventricular block, myocarditis, peripheral edema, phlebitis, pulmonary embolism, syncope, thrombophlebitis
Dermatologic: Alopecia, contact dermatitis, ecchymoses, eczema, exfoliative dermatitis, maculopapular rash, urticaria, vesicobullous dermatitis
Endocrine & metabolic: Albuminuria, amenorrhea, decreased glucose tolerance, dehydration, gynecomastia, heavy menstrual bleeding, hyperchloremia, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hyperthyroidism, hyperuricemia, hypocalcemia, hypochloremia, hypocholesterolemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypothyroidism, increased lactate dehydrogenase, increased thirst, ketosis, respiratory alkalosis, thyroiditis
Gastrointestinal: Fecal impaction, gingival hemorrhage, hematemesis, melena, oral leukoplakia, oral paresthesia
Genitourinary: Anorgasmia, ejaculatory disorder, erectile dysfunction, female sexual disorder, glycosuria, hematuria, lactation, male sexual disorder, nocturia, oliguria, polyuria, urinary retention, uterine hemorrhage, vaginal hemorrhage
Hematologic & oncologic: Anemia, basophilia, eosinophilia, hemophthalmos, hypochromic anemia, hypoproteinemia, leukocytosis, leukopenia, lymphadenopathy, lymphedema, lymphocytosis, monocytosis, polycythemia, thrombocytopenia, thrombocytosis
Hepatic: Cholestatic jaundice, hepatitis, hepatomegaly, increased gamma-glutamyl transferase, increased serum alkaline phosphatase, increased serum transaminases, jaundice, liver steatosis
Nervous system: Cerebral infarction, cerebrovascular accident, hyperreflexia, myoclonus, opisthotonus, paralysis, seizure, trismus
Neuromuscular & skeletal: Gout, increased creatine phosphokinase in blood specimen, myopathy, tenosynovitis, torticollis
Ophthalmic: Blepharitis, cataract, conjunctivitis, dry eye syndrome, keratitis, keratoconjunctivitis, nystagmus disorder, photophobia, visual field defect
Otic: Tinnitus
Renal: Increased blood urea nitrogen, increased serum creatinine
Respiratory: Epistaxis, hemoptysis, laryngismus, pneumonia
Frequency not defined: Neuromuscular & skeletal: Arthralgia
Postmarketing:
Cardiovascular: Prolonged QT interval on ECG (Atkinson 2022, Blair 2004, Camm 2012, Findling 2022), torsades de pointes (Heinrich 2006)
Dermatologic: Stevens-Johnson syndrome
Endocrine & metabolic: Diabetes mellitus (Greenberg 2007), galactorrhea not associated with childbirth (Raza 2010), hyperglycemic hyperosmolar syndrome (Létourneau 2011), hyperprolactinemia (Lusskin 2004)
Genitourinary: Priapism (Karamustafalioglu 2013), urinary incontinence
Hematologic & oncologic: Agranulocytosis (Montgomery 2006)
Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms (Chan 2015), hypersensitivity reaction (including allergic dermatitis, angioedema, orofacial edema) (Akkaya 2007), swollen tongue
Nervous system: Facial nerve paralysis, hypomania, insomnia, mania, neuroleptic malignant syndrome (Ozen 2007), serotonin syndrome (Lin 2010), somnambulism
Neuromuscular & skeletal: Lupus erythematous (including subacute cutaneous lupus erythematous) (Quintana Codina 2017, Swensen 2004), tardive dyskinesia (Ananth 2004)
Respiratory: Sleep apnea (obstructive) (Shirani 2011)
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; use of monoamine oxidase inhibitors (MAOIs) (concurrently or within 14 days of discontinuing the MAOI), including MAOIs such as linezolid and IV methylene blue.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• 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.
Disease-related concerns:
• Bariatric surgery: Presurgical assessment of the indication for use, symptoms, and goals of therapy should be documented to enable postsurgical assessment. Bariatric surgery diets commonly limit calories. Monitor weight closely postoperatively; if weight loss goals are not met or bariatric surgery diet limits meals to less than 500 calories, consider an alternative agent.
• 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.
• Hepatic impairment: Use with caution in patients with hepatic disease or 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. Older adult 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 a 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 (Wang 2016).
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).
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
Capsules (Geodon Oral)
20 mg (per each): $30.53
40 mg (per each): $30.53
60 mg (per each): $34.60
80 mg (per each): $37.05
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): $77.32
Solution (reconstituted) (Ziprasidone Mesylate Intramuscular)
20 mg (per each): $23.89 - $56.40
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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) (Ref). Swallow capsule whole; do not open, crush, or chew capsules.
Injection: For IM administration only.
Oral: Administer capsule with food (in adults, ≥500 calories) (Ref). Swallow capsule whole; do not open, crush, or chew capsules.
Parenteral: For IM use only; do not administer IV.
Hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
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 potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of stroke and a greater rate of cognitive decline and mortality in patients with dementia. Evidence also suggests there may be an increased risk of mortality with use independent of dementia. Avoid antipsychotics for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. 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. Use of antipsychotics may be appropriate for labeled indications including schizophrenia, bipolar disorder, Parkinson disease psychosis, adjunctive therapy in major depressive disorder, or for short-term use as an antiemetic (Beers Criteria [AGS 2023]).
Substrate of CYP1A2 (Minor), CYP3A4 (Major with inducers), CYP3A4 (Minor with inhibitors); 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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Agents With Seizure Threshold Lowering Potential: May increase adverse/toxic effects of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor
Amiodarone: QT-prolonging Miscellaneous Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may decrease therapeutic effects 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
Antidiabetic Agents: Hyperglycemia-Associated Agents may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Arsenic Trioxide: QT-prolonging Miscellaneous Agents (Highest Risk) may increase QTc-prolonging effects 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
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benzgalantamine-Galantamine: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects 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 increase hypotensive effects of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor
Bornaprine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, tardive dyskinesia symptoms may be potentiated. Risk C: Monitor
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase adverse/toxic effects of Antipsychotic Agents. Risk X: Avoid
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects 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 increase neuroexcitatory and/or seizure-potentiating effects of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cabergoline: May decrease therapeutic effects of Antipsychotic Agents. Risk X: Avoid
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Carbetocin: May increase QTc-prolonging effects 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
Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects 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 increase QTc-prolonging effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
ChlorproMAZINE: QT-prolonging Miscellaneous Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects 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: Ziprasidone may increase QTc-prolonging effects of Citalopram. Ziprasidone may increase serotonergic effects of Citalopram. This could result in serotonin syndrome. Risk X: Avoid
Clarithromycin: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Clarithromycin. Risk X: Avoid
Clofazimine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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
Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CloZAPine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Ziprasidone. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of Ziprasidone. Risk C: Monitor
Dabrafenib: May increase QTc-prolonging effects 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
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects 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 increase QTc-prolonging effects 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 increase QTc-prolonging effects 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 increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects 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 increase adverse/toxic effects of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Domperidone: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Domperidone. Risk X: Avoid
Donepezil: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
Dronedarone: QT-prolonging Miscellaneous Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Encorafenib: May increase QTc-prolonging effects of Ziprasidone. Encorafenib may decrease serum concentration of Ziprasidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation, ventricular arrhythmias, and decreased ziprasidone concentrations. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider Therapy Modification
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Entrectinib: May increase QTc-prolonging effects of QT-prolonging Agents (Highest Risk). Risk X: Avoid
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Etelcalcetide: May increase QTc-prolonging effects 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
Fenfluramine: May increase serotonergic effects of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Risk C: Monitor
Fexinidazole: May increase QTc-prolonging effects of QT-prolonging Agents (Highest Risk). Risk X: Avoid
Fingolimod: May increase QTc-prolonging effects 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
Flecainide: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Miscellaneous Agents (Highest Risk) may increase QTc-prolonging effects 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 increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects 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 increase QTc-prolonging effects 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 increase QTc-prolonging effects of Flupentixol. Risk X: Avoid
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
Gepirone: May increase serotonergic effects of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Risk C: Monitor
Gilteritinib: May increase QTc-prolonging effects 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 decrease therapeutic effects of Guanethidine. Risk C: Monitor
Halofantrine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
Huperzine A: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects 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 increase QTc-prolonging effects 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
Iloperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase adverse/toxic effects 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 increase adverse/toxic effects 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 increase adverse/toxic effects 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
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects 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
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Levofloxacin-Containing Products (Systemic): May increase QTc-prolonging effects 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 increase QTc-prolonging effects of Levoketoconazole. Risk X: Avoid
Linezolid: Ziprasidone may increase serotonergic effects of Linezolid. This could result in serotonin syndrome. Risk X: Avoid
Lithium: May increase neurotoxic effects of Antipsychotic Agents. Lithium may decrease serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Meglumine Antimoniate: May increase QTc-prolonging effects 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
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: Antipsychotic Agents may decrease therapeutic effects of Metergoline. Metergoline may decrease therapeutic effects of Antipsychotic Agents. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methadone: May increase QTc-prolonging effects 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 increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects 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
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methylene Blue: Ziprasidone may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid
Metoclopramide: May increase adverse/toxic effects of Antipsychotic Agents. Risk X: Avoid
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
MetyroSINE: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for extrapyramidal symptoms and excessive sedation may be increased. Risk C: Monitor
Midostaurin: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Monoamine Oxidase Inhibitors (Antidepressant): May increase serotonergic effects of Ziprasidone. This could result in serotonin syndrome. Risk X: Avoid
Monoamine Oxidase Inhibitors (Type B): Ziprasidone may increase serotonergic effects of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid
Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Moxifloxacin (Systemic). Risk X: Avoid
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nefazodone: Ziprasidone may increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Ziprasidone. Risk C: Monitor
Nilotinib: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Nilotinib. Risk X: Avoid
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Ondansetron: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects 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
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Osimertinib: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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
Oxitriptan: May increase serotonergic effects of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects 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 increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
Paliperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Papaverine: QT-prolonging Miscellaneous Agents (Highest Risk) may increase QTc-prolonging effects 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 increase CNS depressant effects of Paraldehyde. Risk X: Avoid
PAZOPanib: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of PAZOPanib. Risk X: Avoid
Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Pilsicainide: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid
Piperaquine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Piperaquine. Risk X: Avoid
Piribedil: Antipsychotic Agents may decrease therapeutic effects of Piribedil. Piribedil may decrease therapeutic effects 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
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor
Probucol: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Probucol. Risk X: Avoid
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Propafenone: May increase QTc-prolonging effects 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 increase QTc-prolonging effects 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 increase QTc-prolonging effects 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
QT-prolonging Agents (Indeterminate Risk - Caution): May increase QTc-prolonging effects 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
QT-prolonging Antidepressants (Moderate Risk): Ziprasidone may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of Ziprasidone. 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
QT-prolonging Class IA Antiarrhythmics (Highest Risk): May increase QTc-prolonging effects 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 increase QTc-prolonging effects 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 increase QTc-prolonging effects 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 increase QTc-prolonging effects 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 Miscellaneous Agents (Highest Risk): May increase QTc-prolonging effects 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
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May increase QTc-prolonging effects 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 increase QTc-prolonging effects 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 increase QTc-prolonging effects of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Risk X: Avoid
QUEtiapine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of QUEtiapine. Risk X: Avoid
Quinagolide: Antipsychotic Agents may decrease therapeutic effects of Quinagolide. Risk C: Monitor
QuiNINE: QT-prolonging Miscellaneous Agents (Highest Risk) may increase QTc-prolonging effects 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
Quizartinib: May increase QTc-prolonging effects 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
Ribociclib: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Ribociclib. Risk X: Avoid
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
RisperiDONE: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of RisperiDONE. QT-prolonging Agents (Highest Risk) may increase CNS depressant effects 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
Rivastigmine: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects 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
Serotonergic Agents (High Risk): Ziprasidone may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Serotonergic Agents (Moderate Risk, Miscellaneous): Ziprasidone may increase serotonergic effects of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Risk C: Monitor
Sertindole: May increase QTc-prolonging effects of QT-prolonging Agents (Highest Risk). Risk X: Avoid
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects 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
Sparfloxacin: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Sparfloxacin. Risk X: Avoid
St John's Wort: Ziprasidone may increase serotonergic effects of St John's Wort. This could result in serotonin syndrome. St John's Wort may decrease serum concentration of Ziprasidone. Risk C: Monitor
Sulpiride: Antipsychotic Agents may increase adverse/toxic effects of Sulpiride. Risk X: Avoid
SUNItinib: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase CNS depressant effects 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
Terbutaline: May increase QTc-prolonging effects 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
Tetrabenazine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for NMS and extrapyramidal symptoms may be increased. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Thioridazine: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects of Thioridazine. Risk X: Avoid
Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor
Toremifene: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Vemurafenib: QT-prolonging Agents (Highest Risk) may increase QTc-prolonging effects 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 increase CNS depressant effects 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
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. 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).
Evaluate pregnancy status and provide preconception counseling prior to initiating treatment in patients who could become pregnant (APA [Keepers 2020]; BAP [McAllister-Williams 2017]; CANMAT [Yatham 2018]). Patients effectively treated may continue their current antipsychotic medication when planning a pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]); the lowest effective dose and avoidance of polytherapy is recommended (BAP [Barnes 2020]; BAP [McAllister-Williams 2017]; CANMAT [Yatham 2018]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment and the risks of discontinuing antipsychotic therapy (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [Yatham 2018]).
Antipsychotic agents may be associated with sexual dysfunction. Some second generation (atypical) antipsychotics (SGAs) may cause hyperprolactinemia, resulting in menstrual disorders or impaired spermatogenesis. Consider changing to a medication that is prolactin-sparing in patients with clinical symptoms. Contraception should be provided if pregnancy is not desired as unintended pregnancies may occur when changing to a prolactin-sparing medication (APA [Keepers 2020]; BAP [McAllister-Williams 2017]).
Outcome data following exposure to second generation (atypical) antipsychotics (SGAs) as a class do not show a significant increased risk of major congenital malformations (BAP [Barnes 2020]); however, specific outcomes vary due to differences in study design (BAP [McAllister-Williams 2017]; Damkier 2018; Ellfolk 2021; Huybrechts 2016; Huybrechts 2023; Liu 2023; Terrana 2015; Viguera 2021; Wang 2021). Additional studies are needed for individual agents and specific outcomes (BAP [Barnes 2020]). Data related to the long-term effects of in utero antipsychotic exposure on infant neurodevelopment and behavior are limited (BAP [McAllister-Williams 2017]; Straub 2022; Swetlik 2024).
Antipsychotic use during the third trimester of pregnancy increases the risk for extrapyramidal symptoms and/or withdrawal symptoms in newborns following delivery (Viguera 2023). Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects may require prolonged hospitalization or resolve within hour or days without specific treatment. Tapering the dose late in pregnancy to reduce the risk of symptoms is not recommended (APA [Keepers 2020]).
Atypical antipsychotics are associated with metabolic changes and the risk varies by specific agent. Available studies that evaluated the risk of developing gestational diabetes mellitus (GDM) during antipsychotic therapy have conflicting results, possibly due to differences in study design (ACOG 2023; Uguz 2019). Pregnant patients with diabetes mellitus or GDM may continue antipsychotic treatment (ACOG 2023). Consider the metabolic risks of the specific antipsychotic if treatment is initiated for the first time during pregnancy (Heinonen 2022). Screening for GDM should continue as part of standard prenatal care; early screening is not needed due to psychiatric medication exposure (ACOG 2023; BAP [McAllister-Williams 2017]).
Untreated and undertreated mental health conditions are associated with adverse pregnancy and neonatal outcomes (ACOG 2023). Adverse obstetric and neonatal outcomes are associated with schizophrenia; however, comparisons between treated and untreated pregnancies are limited (BAP [McAllister-Williams 2017]). Untreated bipolar disorder is associated with fetal growth restriction, preterm birth, and adverse neurodevelopment, and may increase the risk of postpartum psychosis, worsening mood, and postpartum hospitalization. Discontinuing effective medications during pregnancy increases the risk of symptom relapse (ACOG 2023).
Patients effectively treated for schizophrenia or bipolar disorder pre-pregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; APA [Keeper 2020]). Second generation (atypical) antipsychotics (SGAs) are better tolerated and have fewer extrapyramidal adverse effects than first generation (typical) antipsychotics (ACOG 2023).
Management of mental health conditions should be made as part of a shared decision-making process (ACOG 2023; BAP [McAllister-Williams 2017]). Treatment should not be withheld or discontinued based only on pregnancy status. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Close monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
Data collection to monitor pregnancy and infant outcomes following exposure to psychiatric medications is ongoing. Encourage pregnant patients 45 years of age and younger with a history of psychiatric illness to enroll in the National Pregnancy Registry for Psychiatric Mediations (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/).
Ziprasidone is present in breast milk (Schlotterbeck 2009).
Data related to the presence of ziprasidone in breast milk are available from a case report. Ziprasidone was initiated 9 days postpartum and titrated to a dose of 80 mg twice daily over 4 days. Breast milk was sampled prior to the morning dose for 16 consecutive days. Ziprasidone was not detected in breast milk until day 10 of treatment (11 ng/mL) and was below the limit of quantification (<10 ng/mL) for the next 7 days. Authors of the study calculated the relative infant dose (RID) of ziprasidone to be 1.2% of the weight-adjusted maternal dose. The patient stopped breastfeeding at the start of treatment (Schlotterbeck 2009). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).
Outcome data following infant exposure to ziprasidone via breast milk are limited (Werremeyer 2009). Drowsiness, irritability, motor abnormalities, poor feeding, sedation, and slowed development has been reported in infants exposed to antipsychotics via breast milk. Monitor breastfed infants, especially those who are premature or of LBW, or when other sedative drugs are also prescribed (BAP [Barnes 2020]; BAP [McAllister-Williams 2017]).
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. When medications are used, the lowest effective dose and avoiding use of multiple medications is recommended. Consider sedative properties when initiating an antipsychotic medication for the first time postpartum (BAP [Barnes 2020]).
Capsule: Take with food (≥500 calories) (Lincoln 2010).
|
Frequency of Antipsychotic Monitoring for Ziprasidonea,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. | ||
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b ADA 2004; APA [Keepers 2020]; De Hert 2011; Gugger 2011; Jibson 2024; manufacturer's labeling. | ||
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c 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. | ||
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d 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. | ||
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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. |
|
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.c |
|
|
Fall risk |
Every visit |
|
|
Fasting plasma glucose/HbA1c |
4 months after initiation; annually |
Check more frequently than annually if abnormal. Follow diabetes guidelines. |
|
Lipid panel |
4 months after initiation; 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.d |
|
|
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 exposure (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: Hepatic impairment increases the AUC of ziprasidone.
