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    Serotonin-Dopamine Antagonist (SDA) Antipsychotics

    BOXED WARNING

    Dementia, geriatric, stroke

    Given the greater incidence of concomitant chronic illness and other conditions vs. younger adults, geriatric patients should generally be started on lower doses of oral ziprasidone followed by careful dosage titration and close observation. Intramuscular ziprasidone injections have not been specifically evaluated in geriatric patients.[28233] Antipsychotics do not have approval for the treatment of dementia-related psychosis in geriatric patients. All atypical antipsychotics include a boxed warning in the product labels indicating that increased death rates (1.6 to 1.7 times that of placebo) have been noted in this patient population with use. Death typically occurred due to heart failure, sudden death, or infections (primarily pneumonia). Of 17 placebo-controlled trials (n = 5,106) performed with olanzapine, aripiprazole, risperidone, or quetiapine in geriatric patients with dementia-related psychosis, 15 showed numerical increases in mortality in the drug-treated group vs. with placebo. During a placebo-controlled trial, elderly patients with dementia who were randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of cerebrovascular adverse reactions, including stroke, fatal stroke, and transient ischemic attack.[28233] According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients, and use should be avoided except for treating schizophrenia or bipolar disorder, and for short-term use as antiemetics during chemotherapy. Avoidance of ziprasidone is recommended in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: Parkinson's disease (symptom exacerbation), delirium (possible new-onset or worsening delirium), and dementia (adverse CNS effects). There is an increased risk of stroke and a greater rate of cognitive decline and mortality in persons with dementia receiving antipsychotics, and the Beers expert panel recommends avoiding antipsychotics to treat delirium- or dementia-related behavioral problems unless non-pharmacological options have failed or are not possible and the patient is a substantial threat to self or others. The Panel recommends avoiding antipsychotics in elderly patients with a history of falls or fractures unless safer alternatives are not available. Antipsychotics can cause ataxia, impaired psychomotor function, syncope, and falls; if an antipsychotic must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. Because antipsychotics can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions, sodium levels should be closely monitored when starting or changing dosages of antipsychotics in older adults.[60515] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). An antipsychotic should generally be used only for the conditions listed in the guidelines (e.g., schizophrenia, mood disorder, Tourette's disorder) and that meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for use. There is an increased risk of morbidity and mortality in elderly patients treated with antipsychotics for dementia-related psychosis. Therefore, identify and address all possible causes of behavioral or psychological symptoms of dementia (BPSD) before considering an antipsychotic. To initiate antipsychotic therapy, behavioral symptoms must be a danger to self or others and are either 1) due to mania or psychosis or 2) the plan of care includes documentation of attempted behavioral interventions (except in an emergency). Limit emergency treatment to 7 days or less with evaluation and documentation within 7 days which identifies and addresses contributors/causes. For acute conditions persisting beyond 7 days, pertinent non-pharmacologic interventions must be attempted, unless clinically contraindicated, and documented. Treatment of non-acute, chronic, or prolonged BPSD must meet all of the OBRA criteria for BPSD treatment and include monitoring that ensures the behavioral symptoms are not due to a treatable or correctable medical condition, are not due to correctable environmental or treatable psychological stressors alone, and provides clearly documented evidence of persistence. The LTCF must evaluate the appropriateness of the antipsychotic during or within 2 weeks of admission for a newly admitted resident on an antipsychotic. In all cases, the lowest possible dose and shortest duration should be prescribed. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Monitoring of antipsychotics should include evaluation of ongoing effectiveness, the rationale for use, and potential adverse effects (e.g., anticholinergic effects, neurological symptoms, metabolic syndrome, cardiac effects). Antipsychotics are subject to periodic review for effectiveness, necessity, and the potential for gradual dose reduction (GDR) or discontinuation. Refer to the OBRA guidelines for complete information.[60742]

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and parenteral atypical antipsychotic; has a potential for QT prolongation
    Used orally in adults for schizophrenia, as monotherapy for acute mania or mixed episodes of bipolar I disorder, and as an adjunct to lithium or valproate for maintenance treatment of bipolar I disorder; IM injection is used for acute agitation in adults with schizophrenia
    As with all antipsychotics, boxed warning for increased mortality risk in elderly patients with dementia-related psychosis

    COMMON BRAND NAMES

    Geodon

    HOW SUPPLIED

    Geodon Intramuscular Inj Pwd F/Sol: 20mg
    Geodon/Ziprasidone/Ziprasidone Hydrochloride Oral Cap: 20mg, 40mg, 60mg, 80mg

    DOSAGE & INDICATIONS

    For the treatment of schizophrenia.
    Oral dosage
    Adults

    Initially, 20 mg PO twice daily with food. Increase as needed at intervals of 2 days or more. Ordinarily observe patient for several weeks before upward dosage adjustment. Usual Max: 80 mg PO twice per day. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage.

    For the treatment of bipolar disorder (bipolar I disorder), including monotherapy treatment of mania or mixed episodes and as an adjunct to lithium or valproate in maintenance therapy.
    Oral dosage
    Adults

    FOR ACUTE MANIA OR MIXED EPISODES AS MONOTHERAPY: Initially, 40 mg PO twice daily with food. On day 2 of treatment, increase to 60 or 80 mg PO twice a day. Thereafter, adjust dose based on tolerability and efficacy within the range 40 to 80 mg PO twice a day. In flexible-dose clinical trials, the mean daily dose administered was approximately 120 mg/day. Clinical trial results, based on the Mania Rating Scale, demonstrated that patients improved with ziprasidone (vs. placebo) by the second day and reached statistical significance by day 21. At endpoint, the reduction in scores was -12.4 and -7.8 for ziprasidone- and placebo-treated groups, respectively. Trials lasted for only 3 weeks, although it is generally agreed that longer-term therapy is required for maintenance of bipolar disorder. MAINTENANCE TREATMENT AS AN ADJUNCT TO LITHIUM OR VALPROATE: Continue at the same dose on which the patient was initially stabilized, within the range of 40 to 80 mg PO twice daily. Efficacy of ziprasidone as an adjunct to lithium or valproate was established in one maintenance trial in adult patients. Periodically re-evaluate the need for continued treatment.

    For the treatment of acute agitation associated with schizophrenia or other psychiatric illness† associated with acute agitation.
    Intramuscular dosage (injection solution; Geodon injection)
    Adults

    10 to 20 mg IM per dose. Doses of 10 mg IM may be given every 2 hours as needed; doses of 20 mg IM may be administered every 4 hours as needed. Max: 40 mg/day IM. Do not administer IM dosage for more than 3 consecutive days. Convert to oral therapy as soon as possible if long term treatment is indicated. There is no experience in administering IM ziprasidone to patients already receiving oral ziprasidone; co-administration is NOT recommended. A reduction in anxiety usually occurs within 15 minutes of an IM dose, with improvement sustained for 4 hours or more after administration. An open-label, pilot study suggests the transition from IM to oral dosing on days 4 to 5 of treatment is well tolerated; no EPS symptoms, acute dystonia, or serious adverse events were reported. While FDA-approved for use in acute agitation due to schizophrenia, use for patients with other acute agitation (i.e., schizoaffective or bipolar disorder) is common in acute settings. Newer antipsychotics which have shown efficacy in treating acute agitation secondary to psychiatric disorders are preferential in emergency use to conventional antipsychotics.

    Geriatric Adults†

    Not FDA approved, safety and efficacy have not been established in controlled clinical trials. Off-label use has been reported in the literature, using the same dosing as for younger adults: 10 to 20 mg IM per dose. Doses of 10 mg IM may be given every 2 hours as needed; doses of 20 mg IM may be administered every 4 hours as needed. Max: 40 mg/day IM. Do not give via IM route for more than 3 consecutive days. Convert to oral therapy as soon as possible if long term treatment is indicated. There is no experience in administering IM ziprasidone to patients already receiving oral ziprasidone and co-use is NOT recommended. Newer antipsychotics which have shown efficacy in treating acute agitation secondary to psychiatric disorders are preferential in emergency use to conventional antipsychotics.

    Children† and Adolescents† 12 years and older

    Not FDA approved, safety and efficacy have not been established in controlled clinical trials. Data are limited; controlled studies are needed. Off-label use has been reported as effective but is reserved for when non-pharmacologic treatment fails or oral treatment is refused. Suggested dosing: 10 mg IM per dose (12 to 16 years), and 10 mg to 20 mg IM per dose (more than 16 years). Sedation appears to be common. Convert to oral therapy as soon as possible if long term treatment is indicated.

    For the treatment of Tourette's syndrome†.
    Oral dosage
    Children and Adolescents 7 years and older

    Initially, 5 mg PO once daily for 3 days, increased thereafter in divided doses as tolerated. Max: 20 mg PO twice daily. At the end of a 56-day pilot study (n = 28), the mean daily dose of ziprasidone was 28.2 +/- 9.6 mg/day (0.64 +/- 0.24 mg/kg/day).

    For the treatment of severe behavioral or psychological symptoms of dementia† (BPSD)†.
    Oral dosage
    Geriatric Adults

    Dosage not established. According to the Agency for Healthcare Research and Quality (AHRQ) atypical antipsychotic review in 2011, ziprasidone had not been studied as an off-label treatment for behavioral disturbances associated with dementia. Antipsychotics are not FDA-approved for the treatment of behavioral problems associated with dementia and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility (LTCF) residents with dementia-related behavioral symptoms. Specific criteria for treatment must be met, and adherence to daily dose thresholds for each antipsychotic is required, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. No OBRA Max ziprasidone dosing guidance is available due to lack of safety and efficacy data in these patients. For all antipsychotics, the facility must attempt a gradual dose reduction (GDR) in 2 separate quarters, at least 1 month apart, within the first year of admission to the facility or after the facility has initiated an antipsychotic, unless clinically contraindicated. After the first year, a GDR must be attempted annually unless clinically contraindicated. The GDR may be considered clinically contraindicated if the target symptoms returned or worsened after the most recent GDR attempt within the facility and the physician has documented justification for why attempting additional dose reductions at that time would likely impair the resident's function or increase distressed behavior.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    160 mg/day PO or 40 mg/day IM.

    Geriatric

    160 mg/day PO. 40 mg/day IM is suggested from off-label use.

    Adolescents

    More than 16 years: 40 mg/day PO per Tourette's off-label use. 20 mg/dose IM for acute agitation off-label use has been suggested.
    13 to 16 years: 40 mg/day PO per Tourette's off-label use. 10 mg/dose IM for acute agitation off-label use has been suggested.

    Children

    12 years: 40 mg/day PO per Tourette's off-label use. 10 mg/dose IM for acute agitation off-label use has been suggested.
    7 to 11 years: 40 mg/day PO per Tourette's off-label use. Safety and efficacy have not been established for IM dosing.
    6 years or less: Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The AUC and half-life of ziprasidone have been increased after oral administration in those with cirrhosis; however, the manufacturer does not require oral dosage adjustments in patients with hepatic impairment. Intramuscular ziprasidone has not been evaluated in patients with hepatic dysfunction.

    Renal Impairment

    Dosage adjustments are not required in patients with renal impairment; however, intramuscular ziprasidone has not been systematically evaluated in patients with renal impairment. Because the cyclodextrin excipient in the intramuscular formulation is cleared by renal filtration, this dosage form should be administered with caution to patients with impaired renal function.
     
    Intermittent hemodialysis
    Ziprasidone is not removed by hemodialysis.

    ADMINISTRATION

    Oral Administration

    Administer capsules whole with plenty of fluid and at roughly the same times each day. Administer with food to ensure adequate absorption.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution affords a colorless to pale pink color upon dilution.

    Intramuscular Administration

    For administration by the intramuscular (IM) route only; do not administer intravenously.
    Do not mix with other drugs (i.e., in the same syringe).
    Ziprasidone injection requires reconstitution prior to administration.
     
    Reconstitution of vial:
    Using aseptic technique, add 1.2 mL of Sterile Water for Injection, USP to the single-dose vial and shake vigorously until all the drug is dissolved. The resulting solution contains ziprasidone 20 mg/mL.
    The solution contains no preservative or bacteriostatic agents; therefore, any remaining solution from a partially used vial should be discarded.
    Do not mix with any other medicinal products or solvents other than Sterile Water for Injection (SWI).
    Storage of reconstituted vial: Following reconstitution, the unused vial can be stored, protected from light, for up to 24 hours at 15 to 30 degrees C (59 to 86 degrees F). Alternatively, may store for up to 7 days refrigerated and protected from light at 2 to 8 degrees C (36 to 46 degrees F).
     
    Intramuscular (IM) injection:
    Inject ziprasidone slowly and deeply into a large muscle (i.e., upper outer quadrant of the gluteus maximus or lateral part of the thigh).
    If possible, keep patient in a recumbent position for at least 30 minutes following injection to minimize any potential hypotensive effects.

    STORAGE

    Geodon:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Serious rash

    Ziprasidone is contraindicated in those with hypersensitivity to ziprasidone or any of its ingredients. Ziprasidone has been associated with serious rash and related cutaneous conditions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a rare but potentially fatal syndrome characterized by symptoms such as rash, fever, lymphadenopathy, eosinophilia, and organ involvement. Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with ziprasidone exposure. Severe cutaneous adverse reactions are sometimes fatal. Discontinue ziprasidone immediately if severe cutaneous adverse reactions or DRESS are suspected. Patients should be advised to promptly report symptoms of rash, swollen lymph nodes and/or fever.

    Agranulocytosis, leukopenia, neutropenia

    Hematologic effects including leukopenia, neutropenia, and agranulocytosis have been associated with antipsychotic use. A history of drug-induced leukopenia or neutropenia or a pre-existing low white blood cell (WBC) count may increase the likelihood of developing hematologic effects during treatment with an antipsychotic medication like ziprasidone. Patients with a history of clinically significant low WBC count or drug-induced leukopenia/neutropenia should have frequent assessment of complete blood count (CBC) with differential during the first few months of treatment. Discontinuation of ziprasidone should be considered if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Patients with clinically significant neutropenia should be closely monitored for fever and infection, and appropriate medical intervention should be instituted if necessary. Ziprasidone should be discontinued in patients with severe neutropenia (ANC less than 1,000/mm3); ongoing medical care is recommended until the symptoms resolve.

    Acute myocardial infarction, alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cerebrovascular disease, coronary artery disease, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, orthostatic hypotension, QT prolongation, thyroid disease, torsade de pointes

    Clinical trial data indicate that ziprasidone causes QT prolongation; therefore, the drug is contraindicated in patients with a known history of QT prolongation (including congenital long QT syndrome). Ziprasidone is also contraindicated in patients with a recent acute myocardial infarction or uncompensated heart failure. Torsade de pointes has rarely been reported during post-marketing use of the drug. Given the potential for QT prolongation, ziprasidone is contraindicated for use with other drugs that cause QT prolongation. Use ziprasidone with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Baseline magnesium and potassium levels are recommended for high-risk patients, with periodic monitoring as clinically indicated. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Ziprasidone should be discontinued in any patient with persistent QT interval measurements greater than 500 msec. Prescribers should evaluate symptoms of dizziness, syncope, or palpitations that occur with ziprasidone treatment. Ziprasidone may induce tachycardia and/or orthostatic hypotension and may potentiate hypotension caused by hypovolemia, the presence of antihypertensive drugs, or a dehydrated state. Orthostatic hypotension or syncope is most likely to occur during the dosage titration phase. Therefore, a low initial dosage should be used, followed by gradual dosage titration, in patients with potential risk factors for hypotension. Orthostatic hypotension could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate orthostasis. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Due to the potential orthostatic effects of ziprasidone, caution is recommended in patients with cerebrovascular disease.

    Renal failure, renal impairment

    Ziprasidone is not extensively excreted by the kidney. However, intramuscular ziprasidone injections have not been evaluated in patients with renal impairment or renal failure and the cyclodextrin excipient in the injection is cleared by renal filtration; the injection should be administered with caution to patients with impaired renal function.

    Tardive dyskinesia

    Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Periodic evaluation for movement disorders is recommended (e.g., AIMS). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the initiation of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotics differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotics administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may even arise after drug discontinuation. The syndrome may remit, partially or completely, if the antipsychotic is withdrawn. Antipsychotics may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotics, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic therapy, the smallest dose and the shortest duration producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear, ziprasidone discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

    Ambient temperature increase, dehydration, hyperthermia, hypothermia, strenuous exercise

    Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving ziprasidone should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases.

    Hepatic disease

    Ziprasidone is extensively metabolized in the liver. An increase in AUC and half-life has been observed in patients with cirrhosis. Although specific guidelines for dosage adjustments in those with hepatic disease have not been recommended, initiate therapy with caution and titrate upward slowly while monitoring liver function tests (LFTs). Intramuscular ziprasidone injections have not been evaluated in patients with impaired liver function.

    CNS depression, coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Ziprasidone has the potential to impair cognitive and motor skills. The sedative effects of ziprasidone may be most evident in the initial days of treatment. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness, until they know how ziprasidone affects their cognition. Somnolence from antipsychotic use could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate somnolence. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Because ziprasidone may cause CNS depression, it is not recommended for use in those with severe CNS depression. Given the primary CNS effects of ziprasidone, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should be advised to avoid use of alcoholic beverages.

    Dysphagia

    Patients with dysphagia or those at risk for aspiration pneumonia should be closely monitored while receiving ziprasidone. The use of antipsychotics has been associated with esophageal dysmotility and aspiration of gastric contents which may increase the incidence of aspiration pneumonia in certain patient populations, such as patients with advanced Alzheimer's disease.

    Diabetes mellitus, hyperglycemia, obesity

    Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been a few cases of hyperglycemia and diabetes reported during treatment with ziprasidone; however, no reports of diabetes mellitus requiring emergency treatment have been reported. It is not known if this lower incidence of reports is due to a lower risk with ziprasidone, due to fewer patients treated with ziprasidone, or some other cause. In epidemiological studies and case reports, atypical antipsychotics have been associated with elevations in blood glucose, decreased insulin sensitivity, and precipitation or unmasking of diabetes mellitus in susceptible patients (see Adverse Reactions). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with pre-existing diabetes mellitus should monitor their blood glucose levels and watch for signs of excessive urination, thirst, weakness and hunger while taking atypical antipsychotics. Additionally, the clinician should regularly monitor the patient for worsening of glucose control. Patients with risk factors for diabetes, such as obesity or a family history of diabetes should undergo fasting glucose testing at baseline and periodically throughout treatment. Patients developing signs or symptoms suggestive of diabetes while receiving an atypical antipsychotic should be tested for diabetes. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

    Seizure disorder, seizures

    The manufacturer reports that during pre-marketing studies, 0.4% of ziprasidone-treated patients developed seizures, however, confounding factors may have contributed to the occurrence of seizures in many of these cases. Ziprasidone should be used cautiously in those patients with a history of seizure disorder or with conditions that potentially lower the seizure threshold. The continuation of adequate anticonvulsant therapy should prevent an increase in seizure frequency during ziprasidone treatment. If ziprasidone therapy is needed, it should be initiated with a low dosage and titrated upward slowly to the desired clinical effect.

    Suicidal ideation

    Suicidal ideation is inherent in schizophrenia. Ziprasidone should be used with caution in these patients because of the possibility of suicide. Close monitoring of the schizophrenic patient is essential during the initial stages of therapy. Ziprasidone should be prescribed in the smallest quantity consistent with good management in order to reduce the risk of overdose.

    Neurological disease, Parkinson's disease

    Antipsychotics can cause motor and sensory instability, which may lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Ziprasidone should be used cautiously in patients with Parkinson's disease. Central blockade of dopamine (D2) receptors may dramatically worsen the extrapyramidal symptoms of Parkinson's disease. If treatment with an antipsychotic is indicated, however, atypical antipsychotics (like ziprasidone) are preferable to conventional antipsychotics due to a lower likelihood of symptom exacerbation from extrapyramidal effects.

    Dementia, geriatric, stroke

    Given the greater incidence of concomitant chronic illness and other conditions vs. younger adults, geriatric patients should generally be started on lower doses of oral ziprasidone followed by careful dosage titration and close observation. Intramuscular ziprasidone injections have not been specifically evaluated in geriatric patients.[28233] Antipsychotics do not have approval for the treatment of dementia-related psychosis in geriatric patients. All atypical antipsychotics include a boxed warning in the product labels indicating that increased death rates (1.6 to 1.7 times that of placebo) have been noted in this patient population with use. Death typically occurred due to heart failure, sudden death, or infections (primarily pneumonia). Of 17 placebo-controlled trials (n = 5,106) performed with olanzapine, aripiprazole, risperidone, or quetiapine in geriatric patients with dementia-related psychosis, 15 showed numerical increases in mortality in the drug-treated group vs. with placebo. During a placebo-controlled trial, elderly patients with dementia who were randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of cerebrovascular adverse reactions, including stroke, fatal stroke, and transient ischemic attack.[28233] According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients, and use should be avoided except for treating schizophrenia or bipolar disorder, and for short-term use as antiemetics during chemotherapy. Avoidance of ziprasidone is recommended in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: Parkinson's disease (symptom exacerbation), delirium (possible new-onset or worsening delirium), and dementia (adverse CNS effects). There is an increased risk of stroke and a greater rate of cognitive decline and mortality in persons with dementia receiving antipsychotics, and the Beers expert panel recommends avoiding antipsychotics to treat delirium- or dementia-related behavioral problems unless non-pharmacological options have failed or are not possible and the patient is a substantial threat to self or others. The Panel recommends avoiding antipsychotics in elderly patients with a history of falls or fractures unless safer alternatives are not available. Antipsychotics can cause ataxia, impaired psychomotor function, syncope, and falls; if an antipsychotic must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. Because antipsychotics can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions, sodium levels should be closely monitored when starting or changing dosages of antipsychotics in older adults.[60515] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). An antipsychotic should generally be used only for the conditions listed in the guidelines (e.g., schizophrenia, mood disorder, Tourette's disorder) and that meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for use. There is an increased risk of morbidity and mortality in elderly patients treated with antipsychotics for dementia-related psychosis. Therefore, identify and address all possible causes of behavioral or psychological symptoms of dementia (BPSD) before considering an antipsychotic. To initiate antipsychotic therapy, behavioral symptoms must be a danger to self or others and are either 1) due to mania or psychosis or 2) the plan of care includes documentation of attempted behavioral interventions (except in an emergency). Limit emergency treatment to 7 days or less with evaluation and documentation within 7 days which identifies and addresses contributors/causes. For acute conditions persisting beyond 7 days, pertinent non-pharmacologic interventions must be attempted, unless clinically contraindicated, and documented. Treatment of non-acute, chronic, or prolonged BPSD must meet all of the OBRA criteria for BPSD treatment and include monitoring that ensures the behavioral symptoms are not due to a treatable or correctable medical condition, are not due to correctable environmental or treatable psychological stressors alone, and provides clearly documented evidence of persistence. The LTCF must evaluate the appropriateness of the antipsychotic during or within 2 weeks of admission for a newly admitted resident on an antipsychotic. In all cases, the lowest possible dose and shortest duration should be prescribed. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Monitoring of antipsychotics should include evaluation of ongoing effectiveness, the rationale for use, and potential adverse effects (e.g., anticholinergic effects, neurological symptoms, metabolic syndrome, cardiac effects). Antipsychotics are subject to periodic review for effectiveness, necessity, and the potential for gradual dose reduction (GDR) or discontinuation. Refer to the OBRA guidelines for complete information.[60742]

    Sunlight (UV) exposure

    Photosensitivity reactions (1%) have been reported during clinical trials with ziprasidone. Patients should be warned either to keep out of the sun or to use effective sunscreens (SPF 15+) on exposed areas of the body. Patients should avoid undue sunlight (UV) exposure and the use of tanning beds.

    Breast cancer, hyperprolactinemia, infertility

    Similar to other antipsychotics, ziprasidone can cause hyperprolactinemia, likely due to central dopamine D2 antagonism.Although endocrine disturbances such as galactorrhea, amenorrhea, gynecomastia, impotence and infertility have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Chronic hyperprolactinemia when associated with hypogonadism may lead to decreased bone density (osteopenia). Some human breast cancers may be prolactin-dependent and therefore most antipsychotics should be used cautiously in those who have a history of breast cancer; mammary gland neoplasia was noted in mice during animal studies of ziprasidone, but not in rats and the clinical implications for humans are unclear.

    Neonates, pregnancy, pregnancy testing

    Ziprasidone should be used during pregnancy only if the benefits outweigh the potential risks to the fetus. Although the effects in pregnant women are unknown, animals studies indicate that ziprasidone may cause fetal structural abnormalities, decreased fetal weight, delayed skeletal ossification, and decreased postnatal survival. Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity and have ranged from self-limited to those requiring intensive care unit support and prolonged hospitalization. Neonates exhibiting signs or symptoms of extrapyramidal effects or withdrawal should be carefully monitored. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotic agents and requires further investigation. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential prior to initiation of an antipsychotic. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388. It is not known if antipsychotics, through their effect on prolactin, would affect labor or obstetric delivery.

    Breast-feeding

    According to the manufacturer, it is not known if ziprasidone or its metabolites are excreted in breast milk and it is recommended that women receiving ziprasidone should not breast-feed. However, in one case report, the use of ziprasidone 160 mg/day for one week resulted in a milk to plasma ratio of 0.06 and a relative infant dose of 1.2%. In a separate case, no adverse effects on the growth and development occurred in one nursing infant after maternal use of ziprasidone 40 mg/day for 6 months during breast-feeding. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. There is very limited experience with ziprasidone during breast-feeding; other agents may be preferred especially while nursing a newborn or preterm infant. Alternate medications for consideration include atypical agents such as olanzapine or quetiapine. Data related to the safety of antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    Safety and efficacy of ziprasidone use in children and adolescents under the age of 18 years have not been established. Limited data exist regarding the off-label use of oral ziprasidone in pediatric patients 7 years of age or older, and the use of IM ziprasidone for acute agitation secondary to psychiatric disorders in adolescents. Routine cardiovascular monitoring has been suggested for any children receiving certain psychotropic medications due to the potential of these agents to produce adverse cardiac effects. Monitor the electrocardiogram (ECG) in children taking ziprasidone. Avoid use of this drug in children who have known cardiac conduction defects or congenital heart disease (i.e. congenital long QT syndrome). There is no known use of ziprasidone in infants. Additionally, adverse effects have been reported after delivery in newborns exposed to antipsychotics during the third trimester; these effects have varied in severity ranging from self-limited to requiring intensive care unit stays and prolonged hospitalization.

    Abrupt discontinuation

    Abrupt discontinuation of ziprasidone is not recommended, unless required by the patient's medical condition. Otherwise discontinuation should usually occur via a gradual 1—2 week reduction in dosage. Patients should be carefully observed for the recurrence of psychotic symptoms during drug discontinuation.

    Priapism

    Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. One case of priapism was reported during pre-marketing evaluation of ziprasidone. Priapism requires medical treatment and severe cases may require surgical intervention. Advise male patients to seek medical intervention if they experience a prolonged or painful erection lasting more than 4 hours. The patient should call their healthcare provider or go to the nearest emergency room right away if this occurs.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 3.0-6.0
    bradycardia / Rapid / 0-2.0
    exfoliative dermatitis / Delayed / 0.1-1.0
    muscle paralysis / Delayed / 0.1-1.0
    atrial fibrillation / Early / 0.1-1.0
    seizures / Delayed / 0.4-0.4
    myocarditis / Delayed / 0-0.1
    torticollis / Delayed / 0-0.1
    hematemesis / Delayed / 0-0.1
    AV block / Early / 0-0.1
    stroke / Early / 0-0.1
    pulmonary embolism / Delayed / 0-0.1
    laryngospasm / Rapid / 0-0.1
    oliguria / Early / 0-0.1
    keratitis / Delayed / 0-0.1
    ocular hemorrhage / Delayed / 0-0.1
    keratoconjunctivitis / Early / 0-0.1
    hyperkalemia / Delayed / 0-0.1
    akinesia / Delayed / 1.0
    tardive dyskinesia / Delayed / 1.0
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    pericarditis / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    water intoxication / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    akathisia / Delayed / 0-10.0
    constipation / Delayed / 0-9.0
    chest pain (unspecified) / Early / 3.0-3.0
    sinus tachycardia / Rapid / 2.0-2.0
    dysphagia / Delayed / 0.1-2.0
    atopic dermatitis / Delayed / 0.1-1.0
    eosinophilia / Delayed / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    contact dermatitis / Delayed / 0.1-1.0
    psychosis / Early / 0-1.0
    peripheral vasodilation / Rapid / 0-1.0
    angina / Early / 0.1-1.0
    galactorrhea / Delayed / 0.1-1.0
    priapism / Early / 0-1.0
    ejaculation dysfunction / Delayed / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    glycosuria / Early / 0.1-1.0
    blepharitis / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    cataracts / Delayed / 0.1-1.0
    synovitis / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    peripheral edema / Delayed / 0.1-1.0
    hepatitis / Delayed / 0-0.1
    trismus / Delayed / 0-0.1
    myoclonia / Delayed / 0-0.1
    nystagmus / Delayed / 0-0.1
    hyperreflexia / Delayed / 0-0.1
    melena / Delayed / 0-0.1
    phlebitis / Rapid / 0-0.1
    bundle-branch block / Early / 0-0.1
    hemoptysis / Delayed / 0-0.1
    vaginal bleeding / Delayed / 0-0.1
    myopathy / Delayed / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    thrombocytopenia / Delayed / 0-0.1
    polycythemia / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    hyperthyroidism / Delayed / 0-0.1
    hypocalcemia / Delayed / 0-0.1
    hyperchloremia / Delayed / 0-0.1
    hypomagnesemia / Delayed / 0-0.1
    hyperuricemia / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    gout / Delayed / 0-0.1
    hypochloremia / Delayed / 0-0.1
    hepatomegaly / Delayed / 0-0.1
    steatosis / Delayed / 0-0.1
    jaundice / Delayed / 0-0.1
    hyponatremia / Delayed / 0-0.1
    dyskinesia / Delayed / 1.0
    choreoathetosis / Delayed / 1.0
    pseudoparkinsonism / Delayed / 1.0
    dystonic reaction / Delayed / 1.0
    hypertonia / Delayed / 1.0
    delirium / Early / 1.0
    hostility / Early / 1.0
    amnesia / Delayed / 1.0
    confusion / Early / 1.0
    hypotonia / Delayed / 1.0
    ataxia / Delayed / 1.0
    peripheral neuropathy / Delayed / 1.0
    withdrawal / Early / 1.0
    hypertension / Early / 1.0
    orthostatic hypotension / Delayed / 1.0
    dyspnea / Early / 1.0
    dysarthria / Delayed / 1.0
    flank pain / Delayed / 1.0
    bullous rash / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    mania / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hyperthermia / Delayed / Incidence not known

    Mild

    drowsiness / Early / 8.0-31.0
    insomnia / Early / 0-30.0
    weight gain / Delayed / 2.4-20.0
    headache / Early / 3.0-18.0
    dizziness / Early / 3.0-16.0
    nausea / Early / 4.0-12.0
    injection site reaction / Rapid / 7.0-9.0
    dyspepsia / Early / 1.0-8.0
    infection / Delayed / 0.1-8.0
    asthenia / Delayed / 2.0-6.0
    rash / Early / 3.0-5.0
    anxiety / Delayed / 0-5.0
    vomiting / Early / 0-5.0
    xerostomia / Early / 0-5.0
    diarrhea / Early / 0-5.0
    hypersalivation / Early / 4.0-4.0
    rhinitis / Early / 0-4.0
    pharyngitis / Delayed / 3.0-3.0
    cough / Delayed / 3.0-3.0
    hyperhidrosis / Delayed / 0-2.0
    agitation / Early / 0-2.0
    paresthesias / Delayed / 0-2.0
    anorexia / Delayed / 0-2.0
    dysmenorrhea / Delayed / 0-2.0
    maculopapular rash / Early / 0.1-1.0
    vesicular rash / Delayed / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    orgasm dysfunction / Delayed / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    polyuria / Early / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    back pain / Delayed / 0-1.0
    leukocytosis / Delayed / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    polydipsia / Early / 0.1-1.0
    gynecomastia / Delayed / 0-0.1
    nocturia / Early / 0-0.1
    tremor / Early / 1.0
    hyperkinesis / Delayed / 1.0
    vertigo / Early / 1.0
    abdominal pain / Early / 1.0
    photosensitivity / Delayed / 1.0
    influenza / Delayed / 1.0
    fever / Early / 1.0
    diplopia / Early / 1.0
    myalgia / Early / 1.0
    chills / Rapid / 1.0
    hypothermia / Delayed / 1.0
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Concomitant use of ziprasidone and abarelix should be avoided due to the potential for additive QT prolongation. Abarelix can cause QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
    Acarbose: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Acetaminophen; Butalbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Acetaminophen; Butalbital; Caffeine: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of dihydrocodeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Dihydrocodeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Acetaminophen; Codeine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Drugs that can cause CNS depression, including dichloralphenazone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness if used concomitantly with atypical antipsychotics.
    Acetaminophen; Diphenhydramine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Acetaminophen; Oxycodone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including oxycodone.
    Acetaminophen; Pentazocine: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
    Acetaminophen; Propoxyphene: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including propoxyphene.
    Acetaminophen; Tramadol: (Moderate) Concurrent use of tramadol and ziprasidone should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and ziprasidone.
    Albiglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Albuterol: (Minor) Use these drugs together with caution. Beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Albuterol; Ipratropium: (Minor) Use these drugs together with caution. Beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psyhcotropic activity. Use with caution.
    Alfentanil: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including alfentanil.
    Alfuzosin: (Major) Concomitant use of ziprasidone and alfuzosin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
    Aliskiren; Amlodipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Alogliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alogliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alogliptin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alpha-glucosidase Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alprazolam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Amiloride: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amiodarone: (Severe) Concomitant use of ziprasidone and class III antiarrhythmics, such as amiodarone, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class III antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Amitriptyline: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant. (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amlodipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amlodipine; Atorvastatin: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amlodipine; Benazepril: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amlodipine; Olmesartan: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amlodipine; Telmisartan: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amlodipine; Valsartan: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Amobarbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Amoxapine: (Moderate) Use caution during co-administration of amoxapine and ziprasidone. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. CNS effects, orthostatic hypotension, anticholinergic effects, and lowering of seizure threshold are potential problems with the combined use of amoxapine and antipsychotics.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Concomitant use of ziprasidone and clarithromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of ziprasidone and clarithromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amphetamine: (Major) Ziprasidone should be used cautiously with drugs that are known to lower seizure threshold such as amphetamine or dextroamphetamine. Also, ziprasidone has a risk for QT prolongation, and amphetamines can potentially sensitize the myocardium.
    Amphetamine; Dextroamphetamine Salts: (Major) Ziprasidone should be used cautiously with drugs that are known to lower seizure threshold such as amphetamine or dextroamphetamine. Also, ziprasidone has a risk for QT prolongation, and amphetamines can potentially sensitize the myocardium.
    Amphetamine; Dextroamphetamine: (Major) Ziprasidone should be used cautiously with drugs that are known to lower seizure threshold such as amphetamine or dextroamphetamine. Also, ziprasidone has a risk for QT prolongation, and amphetamines can potentially sensitize the myocardium.
    Anagrelide: (Major) Avoid use of anagrelide with other drugs that prolong the QT interval, such as ziprasidone. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy.
    Angiotensin II receptor antagonists: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Angiotensin-converting enzyme inhibitors: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Apalutamide: (Moderate) Monitor for decreased efficacy of ziprasidone if coadministration with apalutamide is necessary. Ziprasidone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ziprasidone exposure by 35%.
    Apomorphine: (Major) Concomitant use of ziprasidone and apomorphine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Limited data indicate that QT prolongation is possible with apomorphine administration; however, the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In addition, the benefits and risks of a dopamine antagonist, such as ziprasidone, in Parkinson's patients should be considered since dopamine antagonists may exacerbate Parkinson's symptoms thereby reducing the effectiveness of agents used to treat Parkinson's disease, such as apomorphine.
    Aprepitant, Fosaprepitant: (Major) Use caution if ziprasidone and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ziprasidone-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ziprasidone is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ziprasidone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Major) Concomitant use of ziprasidone and aripiprazole should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Arsenic Trioxide: (Severe) Ziprasidone is contraindicated for use with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including arsenic trioxide. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block, and a TdP-type ventricular arrhythmia, which can be fatal.
    Artemether; Lumefantrine: (Major) Concomitant use of ziprasidone and artemether; lumefantrine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Artemether; lumefantrine is associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Major) The alpha-adrenergic effects of epinephrine, and possibly of other adrenergic agonists, can be blocked during concurrent administration of ziprasidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of ziprasidone. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with alpha-1 antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.
    Asenapine: (Major) Concomitant use of ziprasidone and asenapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect. In addition, coadministration of ziprasidone with other antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of dihydrocodeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Dihydrocodeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Aspirin, ASA; Carisoprodol: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including carisoprodol.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including carisoprodol.
    Aspirin, ASA; Oxycodone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including oxycodone.
    Atazanavir: (Major) Avoid coadministration when possible. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of ziprasidone and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and ziprasidone. Downward dosage adjustment of ziprasidone may be necessary.
    Atazanavir; Cobicistat: (Major) Avoid coadministration when possible. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of ziprasidone and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and ziprasidone. Downward dosage adjustment of ziprasidone may be necessary. (Moderate) The plasma concentrations of ziprasidone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
    Atomoxetine: (Major) Concomitant use of ziprasidone and atomoxetine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Difenoxin: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including diphenoxylate/difenoxin.
    Atropine; Diphenoxylate: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including diphenoxylate/difenoxin.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Azithromycin: (Major) Concomitant use of ziprasidone and azithromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation and TdP have been spontaneously reported during azithromycin postmarketing surveillance.
    Baclofen: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including baclofen.
    Barbiturates: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Bedaquiline: (Severe) Due to the potential for torsade de pointes (TdP), concurrent use of bedaquiline with ziprasidone is contraindicated. Prolongation of the QT interval is known to occur with both drugs, and coadministration may result in additive QT prolongation. Ziprasidone is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, such as bedaquiline.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Belladonna; Opium: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including opium.
    Benzodiazepines: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Benzphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Bepridil: (Severe) Bepridil is associated with a well-established risk of QT prolongation and torsade de pointes (TdP) and was contraindicated for use with any drugs that prolong the QT interval due to the risk of TdP, including ziprasidone. Bepridil is no longer commerically available.
    Beta-adrenergic blockers: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of ziprasidone and metronidazole should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of ziprasidone and metronidazole should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering ziprasidone with boceprevir due to an increased potential for ziprasidone-related adverse events. If ziprasidone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ziprasidone. Ziprasidone is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated ziprasidone plasma concentrations.
    Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as ziprasidone. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
    Bromocriptine: (Moderate) The prolactin-lowering effect of bromocriptine at the anterior pituitary may be antagonized by medications that increase prolactin levels, such as the atypical antipsychotics. The atypical antipsychotics elevate prolactin to various degrees. Like other drugs that antagonize dopamine D2 receptors, the elevation in prolactin from atypical antipsychotics can persist during chronic administration. Monitor the patient for reduced response to bromocriptine. Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. If bromocriptine is taken for diabetes, monitor for worsening glycemic control.
    Brompheniramine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Brompheniramine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Buprenorphine: (Major) Concomitant use of ziprasidone and buprenorphine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The prescribing information for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Buprenorphine; Naloxone: (Major) Concomitant use of ziprasidone and buprenorphine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The prescribing information for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Buspirone: (Moderate) The combination of buspirone and CNS depressants like the antipsychotics can increase the risk for drowsiness, sedation, and dizziness.
    Butabarbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other central nervous system (CNS) depressants, such as ziprasidone, can potentiate the effects of butorphanol and may lead to additive CNS or respiratory depression. Prior to concurrent use of butorphanol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, a reduced dosage of butorphanol and/or ziprasidone may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Cabergoline: (Major) The prolactin-lowering effect of cabergoline may be antagonized by antipsychotic medications that increase prolactin levels. In addition, cabergoline, which is a dopamine agonist, may diminish the effectiveness of dopamine antagonists such as the antipsychotics. In general, however, atypical antipsychotics like ziprasidone are less likely to interfere with these therapies than traditional antipsychotic agents.
    Canagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Canagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and atypical antipsychotics. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including metaxalone.
    Carbamazepine: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone. Decreased anticonvulsant efficacy is a possibility when some antipsychotic or antidepressant agents are administered to patients with a seizure disorder, because some of these drugs lower the seizure threshold. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted when carbamazepine is used with ziprasidone.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbidopa; Levodopa: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. In general, however, the 'atypical antipsychotics' are less likely to interfere with these therapies than traditional antipsychotic agents (e.g., phenothiazines). Antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. In general, experts consider quetiapine the atypical antipsychotic of choice in Parkinson's patients due to a lower incidence of extrapyramidal symptoms, although the choice of antipsychotic medication must always be made on a case-by-case decision.
    Carbidopa; Levodopa; Entacapone: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. In general, however, the 'atypical antipsychotics' are less likely to interfere with these therapies than traditional antipsychotic agents (e.g., phenothiazines). Antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. In general, experts consider quetiapine the atypical antipsychotic of choice in Parkinson's patients due to a lower incidence of extrapyramidal symptoms, although the choice of antipsychotic medication must always be made on a case-by-case decision. (Major) Atypical antipsychotics are central dopamine antagonists and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of atypical antipsychotics, additive drowsiness may occur with Parkinson's treatments like entacapone or tolcapone. In general, atypical antipsychotics are less likely to interfere with these therapies than traditional antipsychotic agents.
    Carbinoxamine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbinoxamine; Phenylephrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carbinoxamine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Carisoprodol: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including carisoprodol.
    Ceritinib: (Major) Concomitant use of ziprasidone and ceritinib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Concentration-dependent QT prolongation has been reported with ceritinib. Conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients taking medications known to prolong the QTc interval. Hold ceritinib therapy in patients who develop a QTc greater than 500 milliseconds on at least 2 separate ECGs; additionally, a ceritinib dosage adjustment and/or therapy discontinuation may be necessary. Permanently discontinue ceritinib therapy in patients who develop QT prolongation with torsade de pointes, polymorphic ventricular tachycardia, or other serious arrhythmias.
    Cetrorelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorcyclizine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlordiazepoxide: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Chlordiazepoxide; Clidinium: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Chloroquine: (Major) Concomitant use of ziprasidone and chloroquine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Chloroquine is associated with an increased risk of QT prolongation and TdP; fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpheniramine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Codeine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Dextromethorphan: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of dihydrocodeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of dihydrocodeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Dihydrocodeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of dihydrocodeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of dihydrocodeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Dihydrocodeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Phenylephrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Chlorpromazine: (Severe) Concomitant use of ziprasidone and chlorpromazine is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Chlorthalidone; Clonidine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Chlorzoxazone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including chlorzoxazone.
    Ciprofloxacin: (Major) Concomitant use of ziprasidone and ciprofloxacin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Cisapride has a well-established potential for QT prolongation and torsade de pointes (TdP). Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including cisapride. Ziprasidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Citalopram: (Major) Concomitant use of ziprasidone and citalopram should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer of citalopram, citalopram should not be used in patients who are taking other drugs that prolong the QTc interval. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Clarithromycin: (Major) Concomitant use of ziprasidone and clarithromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Clemastine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Clobazam: (Moderate) Benzodiazepines such as clobazam should be combined cautiously with antipsychotics because of the potential for additive CNS depressant effects, and reduced effectiveness of clobazam as an anticonvulsant due to the possible lowering of the seizure threshold by antipsychotics.
    Clomipramine: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clonazepam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Clonidine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Clorazepate: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Clozapine: (Major) Concomitant use of ziprasidone and clozapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. At elevated serum concentrations, clozapine may produce clinically significant prolongation of the QTc interval. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Cobicistat: (Moderate) The plasma concentrations of ziprasidone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of ziprasidone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of ziprasidone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
    Cocaine: (Moderate) Ziprasidone should be used cautiously with drugs that are known to lower seizure threshold such as cocaine. Also, ziprasidone has a risk for QT prolongation, and cocaine, if absorbed systemically, can sensitize the myocardium.
    Codeine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Codeine; Guaifenesin: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Concomitant use of ziprasidone and promethazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of typical adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Codeine; Promethazine: (Major) Concomitant use of codeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Codeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Codeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Concomitant use of ziprasidone and promethazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of typical adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    COMT inhibitors: (Major) Atypical antipsychotics are central dopamine antagonists and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of atypical antipsychotics, additive drowsiness may occur with Parkinson's treatments like entacapone or tolcapone. In general, atypical antipsychotics are less likely to interfere with these therapies than traditional antipsychotic agents.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ziprasidone, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ziprasidone. Treatment with ziprasidone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Concomitant use of ziprasidone and crizotinib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Crizotinib has been associated with concentration-dependent QT prolongation. Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with other drugs known to prolong the QT interval. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.
    Cyclobenzaprine: (Major) Concomitant use of ziprasidone and cyclobenzaprine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Cyclobenzaprine is associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose.
    Cyproheptadine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Danazol: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of ziprasidone. Patients receiving ziprasidone should be closely monitored for toxicity if danazol is added to therapy.
    Dantrolene: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including dantrolene.
    Dapagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Dapagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Dapagliflozin; Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Darunavir: (Major) The plasma concentrations of ziprasidone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Major) The plasma concentrations of ziprasidone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate. (Moderate) The plasma concentrations of ziprasidone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) The plasma concentrations of ziprasidone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate. (Moderate) The plasma concentrations of ziprasidone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of ziprasidone and ritonavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. The use of ritonavir could result in QT prolongation. In addition, the plasma concentrations of ziprasidone may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor and ziprasidone is a partial CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of ziprasidone by about 35 to 40%.
    Dasatinib: (Major) Concomitant use of ziprasidone and dasatinib should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Major) Concomitant use of ziprasidone and degarelix should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QTc prolongation has been reported with the use of degarelix.
    Desipramine: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Concomitant use of ziprasidone and deutetrabenazine should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Clinically relevant QTc prolongation may occur with deutetrabenazine. Additionally, deutetrabenazine is a reversible, dopamine-depleting drug, and ziprasidone is a dopamine antagonist. The risk for parkinsonism, neuroleptic malignant syndrome (NMS), and akathisia may be increased with concomitant administration. Concurrent use of deutetrabenazine and drugs that cause CNS depression, such as ziprasidone, may have additive effects and worsen drowsiness or sedation.
    Dexchlorpheniramine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Dexmethylphenidate: (Moderate) Atypical antipsychotics and dexmethylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Dexmethylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of dexmethylphenidate.
    Dextroamphetamine: (Major) Ziprasidone should be used cautiously with drugs that are known to lower seizure threshold such as amphetamine or dextroamphetamine. Also, ziprasidone has a risk for QT prolongation, and amphetamines can potentially sensitize the myocardium.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Dextromethorphan; Promethazine: (Moderate) Concomitant use of ziprasidone and promethazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of typical adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Dextromethorphan; Quinidine: (Severe) Concomitant use of ziprasidone and class 1A antiarrhythmics, such as quinidine, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class 1A antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Diazepam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of dihydrocodeine with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression, and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of dihydrocodeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Dihydrocodeine should be used in reduced dosages if used concurrently with a CNS depressant. Also, consider using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Dihydrocodeine and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Diltiazem: (Major) Diltiazem may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes. In addition, additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Dimenhydrinate: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Diphenhydramine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Diphenhydramine; Ibuprofen: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Diphenhydramine; Naproxen: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Diphenhydramine; Phenylephrine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Disopyramide: (Severe) Concomitant use of ziprasidone and class 1A antiarrhythmics, such as disopyramide, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class 1A antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Dofetilide: (Severe) Concomitant use of ziprasidone and class III antiarrhythmics, such as dofetilide, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class III antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Dolasetron: (Severe) Concomitant use of ziprasidone and dolasetron is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Concomitant use of ziprasidone and rilpivirine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) Concomitant use of ziprasidone and donepezil should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Donepezil; Memantine: (Major) Concomitant use of ziprasidone and donepezil should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Dopamine: (Moderate) The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of ziprasidone.
    Doxazosin: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Doxepin: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Doxylamine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Doxylamine; Pyridoxine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Dronabinol: (Moderate) Drugs that can cause CNS depression such as dronabinol, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Dronedarone: (Severe) Coadministration of ziprasidone and dronedarone is contraindicated since there is an increased risk for QT prolongation and torsade de pointes (TdP). Dronedarone is contraindicated for concomitant use with drugs that prolong the QT interval and might increase the risk of TdP. Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including dronedarone. Dronedarone induces a moderate (average of about 10 milliseconds but much greater effects have been observed) prolongation of the QTc (Bazett). Ziprasidone has been associated with a possible risk for QT prolongation and/or TdP.
    Droperidol: (Severe) Concomitant use of ziprasidone and droperidol is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Droperidol administration is associated with an established risk for QT prolongation and TdP. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    Dulaglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Efavirenz: (Major) Concomitant use of ziprasidone and efavirenz should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when coadministering with a drug with a known risk of TdP.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Concomitant use of ziprasidone and efavirenz should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when coadministering with a drug with a known risk of TdP.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of ziprasidone and efavirenz should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when coadministering with a drug with a known risk of TdP.
    Elbasvir; Grazoprevir: (Major) Administering ziprasidone with grazoprevir may result in elevated ziprasidone plasma concentrations. Ziprasidone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Concomitant use of ziprasidone and eliglustat should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Empagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Empagliflozin; Linagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Empagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concomitant use of ziprasidone and rilpivirine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Concomitant use of ziprasidone and rilpivirine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Enalapril; Felodipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Encorafenib: (Major) Avoid coadministration of encorafenib and ziprasidone due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
    Enflurane: (Major) Concomitant use of ziprasidone and enflurane should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Halogenated anesthetics, such as enflurane, can prolong the QT interval.
    Entacapone: (Major) Atypical antipsychotics are central dopamine antagonists and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of atypical antipsychotics, additive drowsiness may occur with Parkinson's treatments like entacapone or tolcapone. In general, atypical antipsychotics are less likely to interfere with these therapies than traditional antipsychotic agents.
    Epinephrine: (Major) The alpha-adrenergic effects of epinephrine, and possibly of other adrenergic agonists, can be blocked during concurrent administration of ziprasidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of ziprasidone. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with alpha-1 antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.
    Eplerenone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Epoprostenol: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Eribulin: (Major) Concomitant use of ziprasidone and eribulin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Ertugliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Ertugliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Ertugliflozin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Erythromycin: (Major) Concomitant use of ziprasidone and erythromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Erythromycin is associated with QT prolongation and TdP.
    Erythromycin; Sulfisoxazole: (Major) Concomitant use of ziprasidone and erythromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Erythromycin is associated with QT prolongation and TdP.
    Escitalopram: (Major) Concomitant use of ziprasidone and escitalopram should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Escitalopram has been associated with a risk of QT prolongation and TdP.
    Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with eslicarbazepine.
    Estazolam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone should be considered during co-administration of other CNS depressants, such as antipsychotics, to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Antipsychotics with a higher incidence of sedation, such as olanzapine, clozapine, quetiapine, lurasidone, chlorpromazine, and thioridazine, are more likely to interact with eszopiclone. In one evaluation, concurrent use of eszopiclone and olanzapine reduced psychomotor function as measured by the Digit Symbol Substitution Test (DSST).
    Ethanol: (Moderate) Alcohol may potentiate the CNS effects of the atypical antipsychotics, which have the potential to cause increased sedation, or to impair judgment, thinking, or motor skills. Patients should be appropriately cautioned.
    Ethotoin: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of ziprasidone. Some antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
    Exenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Ezogabine: (Major) Concomitant use of ziprasidone and ezogabine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ezogabine has been associated with QT prolongation. The manufacturer of ezogabine recommends caution during concurrent use of medications known to increase the QT interval.
    Felodipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Fentanyl: (Major) Concomitant use of opiate agonists with ziprasidone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with ziprasidone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking ziprasidone, use a lower initial dose of the opiate and titrate to clinical response. If ziprasidone is prescribed for a patient taking an opiate agonist, use a lower initial dose of ziprasidone and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fingolimod: (Major) Concomitant use of ziprasidone and fingolimod should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Concomitant use of ziprasidone and flecainide should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ziprasidone, is considered contraindicated. Fluconazole is associated with QT prolongation and is a CYP3A4 inhibitor. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
    Fluoxetine: (Major) Concomitant use of ziprasidone and fluoxetine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Concomitant use of ziprasidone and fluoxetine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation and TdP have been reported in patients treated with fluoxetine. (Major) Concomitant use of ziprasidone and olanzapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Fluphenazine: (Major) Concomitant use of ziprasidone and fluphenazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Flurazepam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Fluvoxamine: (Major) Concomitant use of ziprasidone and fluvoxamine should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as ziprasidone. Decreased metabolism of ziprasidone may lead to adverse reactions, such as extrapyramidal symptoms or QT prolongation.
    Food: (Major) It is recommended that patients avoid the use of marijuana, by any route, if they are treated for a psychiatric history, including psychosis and bipolar disorder, as the cannabinoids (the psychoactive ingredients, such as THC) in marijuana can produce psychotoxic effects and may exacerbate psychiatric disorders. A high frequency of use and use of products with high-potency of THC are potential risk factors for psychiatric effects. Additionally, additive CNS effects, such as sedation or CNS depression are possible. Clinical studies suggest that cannabis use may reduce the efficacy of some antipsychotic drugs. In addition, several cannabinoids in marijuana appear to influence the activity of CYP enzymes and P-glycoprotein, which may alter the concentrations of antipsychotics and influence either safety or efficacy, For example, the smoking of marijuana influences the metabolism of some medications in a manner similar to tobacco by inducing CYP1A2.
    Foscarnet: (Major) Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet. Because of these reports, avoid the use of foscarnet with other drugs known to prolong the QT interval. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
    Fosphenytoin: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of ziprasidone. Some antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
    Ganirelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
    Gemifloxacin: (Major) Concomitant use of ziprasidone and gemifloxacin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with ziprasidone due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
    Glasdegib: (Major) Concomitant use of ziprasidone and glasdegib should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Glipizide; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Glyburide; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Goserelin: (Major) Concomitant use of ziprasidone and goserelin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Concomitant use of ziprasidone and granisetron should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Granisetron has been associated with QT prolongation.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Guanabenz: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Guanfacine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Halofantrine: (Severe) Concomitant use of ziprasidone and halofantrine is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Halofantrine has an established risk of QT prolongation and TdP.
    Haloperidol: (Major) Concomitant use of ziprasidone and haloperidol should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation and TdP have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval. In addition, coadministration of ziprasidone and haloperidol may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Halothane: (Major) Concomitant use of ziprasidone and halothane should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Halogenated anesthetics, such as halothane, can prolong the QT interval.
    Histrelin: (Major) Avoid concomitant use of ziprasidone and histrelin due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydantoins: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of ziprasidone. Some antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants, such as ziprasidone, may lead to hypotension, profound sedation, coma, respiratory depression and death. Additionally, coadministration may increase the risk of serotonin syndrome. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation, respiratory depression, and serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and ziprasidone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Hydromorphone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including hydromorphone.
    Hydroxychloroquine: (Major) Concomitant use of ziprasidone and hydroxychloroquine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Hydroxychloroquine prolongs the QT interval and should not be administered with other drugs known to prolong the QT interval.
    Hydroxyzine: (Major) Concomitant use of ziprasidone and hydroxyzine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Hydroxyzine is contraindicated in patients who have a prolonged QT interval. Hydroxyzine is a sedating antihistamine and may also cause additive CNS effects, such as drowsiness, when combined with ziprasidone.
    Ibuprofen; Oxycodone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including oxycodone.
    Ibutilide: (Severe) Concomitant use of ziprasidone and class III antiarrhythmics, such as ibutilide, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class III antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ziprasidone, a partial CYP3A substrate, since ziprasidone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. If concurrent use is required, monitor for ziprasidone-induced adverse effects including QT prolongation, CNS effects, and extrapyramidal symptoms.
    Iloperidone: (Major) Concomitant use of ziprasidone and iloperidone should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Iloperidone has been associated with QT prolongation. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Iloprost: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Imatinib: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme system. The concurrent use of ziprasidone with CYP3A4 inhibitors, such as imatinib, may lead to decreased metabolism of ziprasidone.
    Imipramine: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Incretin Mimetics: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with ziprasidone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ziprasidone has been associated with a possible risk for QT prolongation and/or TdP.
    Insulin Degludec; Liraglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Insulin Glargine; Lixisenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Insulins: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with ziprasidone may result in increased serum concentrations of ziprasidone. Ziprasidone is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, are advised if these drugs are used together.
    Isocarboxazid: (Moderate) Due to the potential for additive CNS and cardiovascular effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Isoflurane: (Major) Concomitant use of ziprasidone and isoflurane should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Halogenated anesthetics, such as isoflurane, can prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4, such as rifampin. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone.
    Isoniazid, INH; Rifampin: (Moderate) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4, such as rifampin. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone.
    Isradipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Itraconazole: (Major) Concomitant use of ziprasidone and itraconazole should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Itraconazole has been associated with prolongation of the QT interval. In addition, ziprasidone is partially metabolized by CYP3A4 and itraconazole is a potent CYP3A4 inhibitor. Concurrent use may increase systemic exposure to ziprasidone. Patients receiving this combination should be monitored for ziprasidone-induced adverse effects such as drowsiness, dizziness, anticholinergic effects, orthostasis, extrapyramidal symptoms, QT prolongation, neuroleptic malignant syndrome, and seizures.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with ziprasidone due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
    Kava Kava, Piper methysticum: (Major) Patients who are taking atypical antipsychotics should only use kava kava with prescriber approval and close monitoring. Additive sedation and CNS effects are possible, and inhibition of antipsychotic metabolism may occur. In addition, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are possible. Atypical antipsychotics are metabolized by various CYP isoenzymes and it is not yet documented if pharmacokinetic interactions occur with kava kava. At least 1 case report of a potential clinically significant interaction with kava kava and an atypical antipsychotic has been reported.
    Ketoconazole: (Severe) Because of the potential for QT prolongation and torsade de pointes (TdP), use of ketoconazole with ziprasidone is contraindicated. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Ziprasidone is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, such as ketoconazole. Also, ziprasidone is partially metabolized via CYP3A4. The concurrent use of ziprasidone with ketoconazole, a potent CYP3A4 inhibitor, causes a 35% to 40% increase in the AUC and Cmax of ziprasidone. While the inhibition of ziprasidone metabolism did not further increase the QTc interval above the administration of ziprasidone alone in this study, some patients might experience such side effects.
    Lapatinib: (Major) Concomitant use of ziprasidone and lapatinib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. If coadministration is necessary, consider ECG and electrolyte monitoring. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with ziprasidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ziprasidone; monitor for potential reduction in efficacy. Ziprasidone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ziprasidone; monitor for potential reduction in efficacy. Ziprasidone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) An increase in the plasma concentration of ziprasidone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ziprasidone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use of ziprasidone with a strong CYP3A4 inhibitor increased the AUC and Cmax of ziprasidone by 35% to 40%.
    Leuprolide: (Major) Concomitant use of ziprasidone and leuprolide should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Major) Concomitant use of ziprasidone and leuprolide should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (Minor) Use these drugs together with caution. Beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Levodopa: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. In general, however, the 'atypical antipsychotics' are less likely to interfere with these therapies than traditional antipsychotic agents (e.g., phenothiazines). Antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. In general, experts consider quetiapine the atypical antipsychotic of choice in Parkinson's patients due to a lower incidence of extrapyramidal symptoms, although the choice of antipsychotic medication must always be made on a case-by-case decision.
    Levofloxacin: (Major) Concomitant use of ziprasidone and levofloxacin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of levofloxacin.
    Levomethadyl: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including levomethadyl.
    Levorphanol: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including levorphanol.
    Linagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Linagliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Liraglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Lithium: (Major) Concomitant use of ziprasidone and lithium should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Lithium has been associated with QT prolongation. Additionally, lithium may be a risk factor for antipsychotic-induced neuroleptic malignant syndrome (NMS); however, this hypothesis has not been confirmed. NMS has been observed occasionally during concurrent use of lithium and either atypical or conventional antipsychotics. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, particularly during concurrent use of haloperidol and lithium. Subsequent rare reports of NMS or NMS-like reactions have been described during coadministration of lithium and atypical antipsychotics. Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor.
    Lixisenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Lofexidine: (Major) Avoid coadministration of lofexidine with ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG if coadministration cannot be avoided. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
    Lomefloxacin: (Moderate) Lomefloxacin has been associated with QT prolongation and infrequent cases of arrhythmia. Other medications which may prolong the QT interval, such as ziprasidone, should be used cautiously when given concurrently with lomefloxacin.
    Long-acting beta-agonists: (Moderate) Ziprasidone should be administered with caution to patients receiving other agents that may prolong the QT interval; ziprasidone has been associated with a risk for QT prolongation. The long-acting beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loop diuretics: (Minor) Monitor of potassium and magnesium levels when loop diuretics are used during ziprasidone therapy. The risk of QT prolongation from ziprasidone is increased in the presence of hypokalemia or hypomagnesemia.
    Loperamide: (Major) Concomitant use of ziprasidone and loperamide should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Loperamide; Simethicone: (Major) Concomitant use of ziprasidone and loperamide should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Concomitant use of ziprasidone and lopinavir; ritonavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Lopinavir; ritonavir is associated with QT prolongation. Coadministration of lopinavir; ritonavir with other drugs that prolong the QT interval may result in additive QT prolongation. (Major) Concomitant use of ziprasidone and ritonavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. The use of ritonavir could result in QT prolongation. In addition, the plasma concentrations of ziprasidone may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor and ziprasidone is a partial CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of ziprasidone by about 35 to 40%.
    Lorazepam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Loxapine: (Major) Caution is advisable during concurrent use of loxapine and other antipsychotics. Loxapine use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of ziprasidone, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of ziprasidone, such as QT prolongation, CNS effects, and extrapyramidal symptoms. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of ziprasidone. If used together, monitor the patient closely for antipsychotic efficacy; dosage increases should be based on clinical evaluation. Ziprasidone is primarily metabolized by CYP3A, and lumacaftor is a strong CYP3A inducer. Coadministration of ziprasidone with carbamazepine (200 mg twice daily for 21 days), another strong CYP3A inducer, resulted in a 35% decrease in AUC of ziprasidone.
    Lurasidone: (Major) Lurasidone administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The risk of these adverse effects may be increased during concurrent use of lurasidone with other antipsychotics. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ziprasidone. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
    Maprotiline: (Major) Concomitant use of ziprasidone and maprotiline should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Meclizine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Mefloquine: (Severe) Concomitant use of ziprasidone and mefloquine is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Mefloquine alone has not been reported to cause QT prolongation; however, there is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval.
    Meglitinides: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Meperidine: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including meperidine.
    Meperidine; Promethazine: (Moderate) Concomitant use of ziprasidone and promethazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of typical adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including meperidine.
    Mephobarbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
    Mesoridazine: (Severe) Concomitant use of ziprasidone and mesoridazine is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Mesoridazine has an established risk of QT prolongation and TdP. In addition, coadministration of ziprasidone with phenothiazines such as mesoridazine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Metaproterenol: (Minor) Use these drugs together with caution. Beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Metaxalone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including metaxalone.
    Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Metformin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Methadone: (Severe) Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including methadone. QT interval prolongation and serious arrhythmia such as torsade de pointes (TdP) have occurred during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Ziprasidone has also been associated with a possible risk for QT prolongation and/or TdP. Both drugs may also cause CNS depression, and this may increase risk for serious respiratory depression from methadone in some patients.
    Methamphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Methocarbamol: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including methocarbamol.
    Methohexital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Methoxsalen: (Moderate) Medications that may cause additive photosensitization when used with ziprasidone include methoxsalen. Patients should limit sunlight and ultra-violet exposure whenever possible, and use proper UV precautions to protect the skin.
    Methyldopa: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Methylphenidate: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Metoclopramide: (Severe) Concomitant use of metoclopramide and antipsychotics is contraindicated by the manufacturer of metoclopramide as the risk of extrapyramidal effects may be increased. Both metoclopramide and antipsychotics antagonize dopamine receptors, which can increase the risk of extrapyramidal effects, including tardive dyskinesia or other dystonic reactions. Additionally, because both antipsychotics and metoclopramide can cause sedation, seizures, or increased prolactin levels, it is possible that the risk of these effects may be increased during concurrent use.
    Metronidazole: (Major) Concomitant use of ziprasidone and metronidazole should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midazolam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Midostaurin: (Major) Concomitant use of ziprasidone and midostaurin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation was reported in patients who received midostaurin in clinical trials. Consider obtaining electrocardiograms to monitor the QT interval if ziprasidone and midostaurin are used together.
    Mifepristone: (Major) Concomitant use of ziprasidone and mifepristone should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Mifepristone has been associated with dose-dependent prolongation of the QT interval. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used.
    Miglitol: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Mirtazapine: (Major) Concomitant use of ziprasidone and mirtazapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Use caution if mitotane and ziprasidone are used concomitantly, and monitor for decreased efficacy of ziprasidone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ziprasidone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ziprasidone. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with ziprasidone.
    Molindone: (Major) Close monitoring is advisable during concurrent use of molindone with other antipsychotics. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), or anticholinergic effects (e.g., constipation, xerostomia) may occur. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Monoamine oxidase inhibitors: (Moderate) Due to the potential for additive CNS and cardiovascular effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Morphine: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including morphine.
    Morphine; Naltrexone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including morphine.
    Moxifloxacin: (Severe) Concomitant use of ziprasidone and moxifloxacin is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nabilone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Nalbuphine: (Moderate) Drugs that can cause CNS depression such as nalbuphine, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Nateglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Nefazodone: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme system. Decreased metabolism of ziprasidone may lead to clinically important side effects. Drugs having the potential to decrease the elimination of ziprasidone via inhibition of CYP3A4 include nefazodone.
    Nelfinavir: (Moderate) Nelfinavir may inhibit the metabolism of other substrates of cytochrome P450 3A4 such as ziprasidone.
    Nicardipine: (Major) Nicardipine is a weak inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of ziprasidone, a CYP3A4 substrate.
    Nifedipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Nilotinib: (Severe) Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including nilotinib. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Nilotinib is is associated with concentration-dependent QT prolongation. Significant prolongation of the QT interval may occur when nilotinib is given with medications with a known potential to prolong the QT interval, including ziprasidone.
    Nimodipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Nisoldipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold, such as ziprasidone, should be carefully evaluated when considering intrathecal radiopaque contrast agents. Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Norfloxacin: (Major) Concomitant use of ziprasidone and norfloxacin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Concomitant use of ziprasidone and octreotide should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Concomitant use of ziprasidone and ofloxacin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin.
    Olanzapine: (Major) Concomitant use of ziprasidone and olanzapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of ziprasidone and ritonavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. The use of ritonavir could result in QT prolongation. In addition, the plasma concentrations of ziprasidone may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor and ziprasidone is a partial CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of ziprasidone by about 35 to 40%.
    Ondansetron: (Major) Concomitant use of ziprasidone and ondansetron should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended.
    Oritavancin: (Moderate) Ziprasidone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of ziprasidone may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including orphenadrine.
    Osimertinib: (Major) Concomitant use of ziprasidone and osimertinib should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.
    Oxaliplatin: (Major) Concomitant use of ziprasidone and oxaliplatin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Monitor ECGs and electrolytes in patients receiving oxaliplatin concomitantly with other drugs known to prolong the QT interval; correct electrolyte abnormalities prior to administration of oxaliplatin.
    Oxazepam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Oxycodone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including oxycodone.
    Oxymorphone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including oxymorphone.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Clinical trial data indicate that ziprasidone causes QT prolongation. There are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. If concurrent use is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Coadministration may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Panobinostat: (Severe) Coadministration of panobinostat and ziprasidone is contraindicated since there is an increased risk for QT prolongation and torsade de pointes (TdP). Ziprasidone is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including panobinostat. Severe arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving panobinostat therapy. Concomitant use of other drugs that are known to prolong the QT interval is not recommended with panobinostat.
    Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with drugs that are dopamine antagonists such as ziprasidone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving ziprasidone and an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Pasireotide: (Major) Concomitant use of ziprasidone and pasireotide should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Concomitant use of ziprasidone and pazopanib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and ziprasidone must be continued, closely monitor the patient for QT interval prolongation.
    Pentamidine: (Severe) Concomitant use of ziprasidone and pentamidine is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Systemic pentamidine has been associated with QT prolongation.
    Pentazocine: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
    Pentazocine; Naloxone: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
    Pentobarbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Pergolide: (Major) Pergolide is a potent dopamine-receptor agonist. Antipsychotic agents may inhibit the clinical antiparkinsonian response to pergolide by blocking dopamine receptors in the brain. In general, the atypical antipsychotics are less likely to interfere with antiparkinsons treatments than traditional antipsychotic agents. However, antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to pergolide.
    Perindopril; Amlodipine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Perphenazine: (Major) Concomitant use of ziprasidone and perphenazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Perphenazine; Amitriptyline: (Major) Concomitant use of ziprasidone and perphenazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Phenelzine: (Moderate) Due to the potential for additive CNS and cardiovascular effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Phenobarbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Phenoxybenzamine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Phentolamine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Phenylephrine; Promethazine: (Moderate) Concomitant use of ziprasidone and promethazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of typical adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Phenytoin: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of ziprasidone. Some antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
    Pimavanserin: (Major) Concomitant use of ziprasidone and pimavanserin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. In addition, both drugs are dopamine antagonists and additive effects are possible; however, an interaction has not been confirmed.
    Pimozide: (Severe) Concomitant use of ziprasidone and pimozide is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Pimozide is associated with a well-established risk of QT prolongation and TdP. In addition, coadministration of ziprasidone with pimozide may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Pirbuterol: (Minor) Use these drugs together with caution. Beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Porfimer: (Moderate) Medications that may cause additive photosensitization when used with ziprasidone include porfimer. Patients should limit sunlight and ultra-violet exposure whenever possible, and use proper UV precautions to protect the skin.
    Posaconazole: (Severe) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ziprasidone, is considered contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes (TdP) and is a strong CYP3A4 inhibitor. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
    Potassium-sparing diuretics: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Pramipexole: (Major) Pramipexole is a potent dopamine-receptor agonist. Dopamine-receptor antagonists, including antipsychotics may antagonize the effects of pramipexole. In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. However, antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Pramlintide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Prazosin: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Prilocaine; Epinephrine: (Major) The alpha-adrenergic effects of epinephrine, and possibly of other adrenergic agonists, can be blocked during concurrent administration of ziprasidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of ziprasidone. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with alpha-1 antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.
    Primaquine: (Major) Concomitant use of ziprasidone and primaquine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Primaquine has the potential for QT prolongation.
    Primidone: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Procainamide: (Severe) Concomitant use of ziprasidone and class 1A antiarrhythmics, such as procainamide, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class 1A antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Prochlorperazine: (Major) Concomitant use of ziprasidone and prochlorperazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Prochlorperazine, a phenothiazine, is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Promethazine: (Moderate) Concomitant use of ziprasidone and promethazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of typical adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Propafenone: (Major) Concomitant use of ziprasidone and propafenone should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Propoxyphene: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including propoxyphene.
    Protriptyline: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quazepam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Quetiapine: (Major) Concomitant use of ziprasidone and quetiapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval. In addition, coadministration of atypical antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
    Quinidine: (Severe) Concomitant use of ziprasidone and class 1A antiarrhythmics, such as quinidine, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class 1A antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Quinine: (Major) Concomitant use of ziprasidone and quinine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Quinine has been associated with QT prolongation and rare cases of TdP.
    Ranolazine: (Major) Concomitant use of ziprasidone and ranolazine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Rasagiline: (Moderate) Atypical antipsychotics may reduce the beneficial effects of rasagiline by blocking dopamine. Additive CNS effects are possible; advise against engaging in tasks requiring mental alertness until the effects of the drug combination are known to the patient. Monoamine oxidase type B inhibitors increase the availability of central dopamine. Antipsychotics may induce pseudoparkinisonism (e.g., shuffling gait, tremor), thereby exacerbating Parkinson's disease symptoms. In addition, dopaminergic medications, including rasagiline, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Atypical antipsychotics may exacerbate sedation or hypotension.
    Remifentanil: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including remifentanil.
    Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Reserpine: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Ribociclib: (Major) Avoid coadministration of ribociclib and ziprasidone due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; the ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib and ziprasidone due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; the ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption.
    Rifabutin: (Moderate) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4, such as rifabutin. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone.
    Rifampin: (Moderate) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4, such as rifampin. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone.
    Rilpivirine: (Major) Concomitant use of ziprasidone and rilpivirine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) The benefits and risks of combining antipsychotics should be considered prior to treatment initiation. Both ziprasidone and risperidone have been associated with a possible risk for QT prolongation and torsade de pointes. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited.
    Ritonavir: (Major) Concomitant use of ziprasidone and ritonavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. The use of ritonavir could result in QT prolongation. In addition, the plasma concentrations of ziprasidone may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor and ziprasidone is a partial CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of ziprasidone by about 35 to 40%.
    Romidepsin: (Major) Concomitant use of ziprasidone and romidepsin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Ropinirole: (Major) Ropinirole is a potent dopamine-receptor agonist. Dopamine-receptor antagonists, including antipsychotics may antagonize the effects of ropinirole. In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. However, antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Rotigotine: (Moderate) Rotigotine is a dopamine-receptor agonist. Dopamine-receptor antagonists, including atypical antipsychotics, should generally be avoided when possible because they may antagonize the effects of rotigotine. In general, atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotics. Use only if the benefit of the drug outweighs the risk of decreased therapeutic response to rotigotine or other treatments. Monitor for an altered clinical response to drug therapy and for additive CNS effects if used together.
    Safinamide: (Moderate) Atypical antipsychotics may reduce the beneficial effects of safinamide by blocking dopamine. Additive CNS effects are possible; advise against engaging in tasks requiring mental alertness until the effects of the combination are known. Monoamine oxidase type B inhibitors increase the availability of central dopamine. Antipsychotics may induce pseudoparkinism (e.g., shuffling gait, tremor), thereby exacerbating Parkinson's disease symptoms. In addition, dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Atypical antipsychotics may exacerbate sedation or hypotension.
    Saquinavir: (Major) Concomitant use of ziprasidone and saquinavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Additionally, because saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4 and may reduce the metabolism of ziprasidone, monitor for ziprasidone-induced adverse effects such as extrapyramidal symptoms, drowsiness, dizziness, nausea, and vomiting, if coadministration is necessary.
    Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Secobarbital: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Selegiline: (Moderate) Due to the potential for additive CNS and cardiovascular effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Semaglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Sertraline: (Major) Concomitant use of ziprasidone and sertraline should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Sevoflurane: (Major) Concomitant use of ziprasidone and sevoflurane should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Halogenated anesthetics, such as sevoflurane, can prolong the QT interval.
    SGLT2 Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Short-acting beta-agonists: (Minor) Use these drugs together with caution. Beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Sibutramine: (Major) Caution and close monitoring should be observed when administering sibutramine with drugs that are dopamine antagonists such as the atypical antipsychotics. Monitor for CNS depression, changes in mood or behavior, and for other drug-related adverse reactions. Sibutramine has not been systematically evaluated in combination with antipsychotic medications. Sibutramine is a serotonin reuptake inhibitor that also inhibits norepinephrine and dopamine reuptake. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Simeprevir: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ziprasidone, which is a CYP3A4 substrate. Monitor patients for adverse effects of ziprasidone, such as QT prolongation, CNS effects, and extrapyramidal symptoms.
    Simvastatin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that are known to induce Antidiuretic Hormone Secretion (SIADH), such as antipsychotics, as these drugs may increase the risk of water retention and/or electrolyte imbalance.
    Solifenacin: (Major) Concomitant use of ziprasidone and solifenacin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
    Sorafenib: (Major) Concomitant use of ziprasidone and sorafenib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Sorafenib has been associated with QT prolongation. If sorafenib and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Sotalol: (Severe) Concomitant use of ziprasidone and class III antiarrhythmics, such as sotalol, is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Class III antiarrhythmics are associated with a well-established risk of QT prolongation and TdP.
    Sparfloxacin: (Severe) Concomitant use of ziprasidone and sparfloxacin is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Sparfloxacin has been associated with QT prolongation and TdP.
    Spironolactone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Sufentanil: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including sufentanil.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Concomitant use of ziprasidone and sulfamethoxazole; trimethoprim should be avoided if possible due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QT prolongation resulting in ventricular tachycardia and TdP has been reported during postmarketing use of sulfamethoxazole; trimethoprim.
    Sulfonylureas: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Sunitinib: (Major) Concomitant use of ziprasidone and sunitinib should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Sunitinib can also cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including TdP.
    Tacrolimus: (Severe) Concomitant use of ziprasidone and tacrolimus is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Tacrolimus causes QT prolongation.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with ziprasidone due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine.
    Telaprevir: (Major) Close clinical monitoring is advised when administering ziprasidone with telaprevir due to an increased potential for ziprasidone-related adverse events. If ziprasidone dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ziprasidone. Ziprasidone is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated ziprasidone plasma concentrations.
    Telavancin: (Major) Concomitant use of ziprasidone and telavancin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Telavancin has been associated with QT prolongation.
    Telithromycin: (Major) Concomitant use of ziprasidone and telithromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Telithromycin is associated with QT prolongation and TdP.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ziprasidone is necessary, as the systemic exposure of ziprasidone may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ziprasidone; consider increasing the dose of ziprasidone if necessary. Ziprasidone is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Terazosin: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Terbutaline: (Minor) Use these drugs together with caution. Beta-agonists may be associated with adverse cardiovascular effects including tachycardia and QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP).
    Terfenadine: (Severe) Use is contraindicated due to the potential risk for QT prolongation and torsade de pointes (TdP). Terfenadine is associated with a well-established risk for QT prolongation and TdP and should not be administered with other drugs with a known association with QT prolongation. Ziprasidone has been associated with a possible risk for QT prolongation and/or TdP and is contraindicated in combination with other drugs that prolong the QT interval, such as terfenadine.
    Tetrabenazine: (Major) Concomitant use of ziprasidone and tetrabenazine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer of tetrabenazine recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc.
    Thiazide diuretics: (Minor) Monitor potassium and magnesium levels when thiazide diuretics are used during ziprasidone therapy. The risk of QT prolongation from ziprasidone is increased in the presence of hypokalemia or hypomagnesemia.
    Thiazolidinediones: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Thiopental: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4 including barbiturates. Additive CNS depressant effects are also possible when ziprasidone is used concurrently with barbiturates.
    Thioridazine: (Severe) Thioridazine has a well-established risk for QT prolongation and torsade de points (TdP) and is contraindicated for use with other drugs that may prolong the QT interval, including ziprasidone. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, seizures, or tardive dyskinesia. The risk of tardive dyskinesia appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Thiothixene: (Major) Caution is advisable during concurrent use of thiothixene and other antipsychotics. Thiothixene use has been associated with adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of loxapine and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Tolcapone: (Major) Atypical antipsychotics are central dopamine antagonists and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of atypical antipsychotics, additive drowsiness may occur with Parkinson's treatments like entacapone or tolcapone. In general, atypical antipsychotics are less likely to interfere with these therapies than traditional antipsychotic agents.
    Tolterodine: (Major) Concomitant use of ziprasidone and tolterodine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Severe) Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including toremifene. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner and medications with a known potential to prolong the QT interval, including ziprasidone, should be avoided with toremifene therapy.
    Tramadol: (Moderate) Concurrent use of tramadol and ziprasidone should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and ziprasidone.
    Trandolapril; Verapamil: (Major) Verapamil may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes.
    Tranylcypromine: (Moderate) Due to the potential for additive CNS and cardiovascular effects, MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.
    Trazodone: (Major) Concomitant use of ziprasidone and trazodone should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP. Therefore, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Treprostinil: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Triamterene: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Triazolam: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Tricyclic antidepressants: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Major) Concomitant use of ziprasidone and trifluoperazine should be avoided if possible. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. In addition, coadministration of ziprasidone with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Trimipramine: (Minor) Concomitant use of ziprasidone and tricyclic antidepressants (TCAs) may increase the risk for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tricyclic antidepressants share pharmacologic properties similar to the Class 1A antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triprolidine: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
    Triptorelin: (Major) Concomitant use of ziprasidone and triptorelin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Vandetanib: (Severe) Concurrent use of vandetanib and ziprasidone is contraindicated because there is an increased risk for QT prolongation and torsade de pointes (TdP). Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, which includes vandetanib. Vandetanib can prolong the QT interval in a concentration-dependent manner, and TdP and sudden death have been reported. Avoid drugs known to prolong the QT interval during vandetanib therapy.
    Vardenafil: (Major) Concomitant use of ziprasidone and vardenafil should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vasodilators: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
    Vemurafenib: (Major) Concomitant use of ziprasidone and vemurafenib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and TdP must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Venlafaxine: (Major) Concomitant use of ziprasidone and venlafaxine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Verapamil: (Major) Verapamil may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes.
    Verteporfin: (Moderate) Medications that may cause additive photosensitization when used with ziprasidone include verteporfin. Patients should limit sunlight and ultra-violet exposure whenever possible, and use proper UV precautions to protect the skin.
    Voriconazole: (Severe) The concurrent use of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ziprasidone, is considered contraindicated. Voriconazole has been associated with QT prolongation as well as rare cases of torsade de pointes (TdP) and is a strong CYP3A4 inhibitor. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
    Vorinostat: (Major) Concomitant use of ziprasidone and vorinostat should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Vorinostat therapy is associated with a risk of QT prolongation.
    Zaleplon: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zaleplon. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of CNS depressants than with zaleplon alone. In premarketing studies, zaleplon potentiated the CNS effects of a phenothiazine antipsychotic for at least 2 to 4 hours. Other antipsychotics may also have additive CNS effects with zaleplon.
    Zolpidem: (Moderate) Additive CNS-depressant effects may occur with the atypical antipsychotics and zolpidem. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Zonisamide: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, it is not known if ziprasidone or its metabolites are excreted in breast milk and it is recommended that women receiving ziprasidone should not breast-feed. However, in one case report, the use of ziprasidone 160 mg/day for one week resulted in a milk to plasma ratio of 0.06 and a relative infant dose of 1.2%. In a separate case, no adverse effects on the growth and development occurred in one nursing infant after maternal use of ziprasidone 40 mg/day for 6 months during breast-feeding. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. There is very limited experience with ziprasidone during breast-feeding; other agents may be preferred especially while nursing a newborn or preterm infant. Alternate medications for consideration include atypical agents such as olanzapine or quetiapine. Data related to the safety of antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The exact mechanism of action of ziprasidone in treating schizophrenia has not been determined. However, it is thought that atypical antipsychotics such as ziprasidone reduce the positive and negative symptoms of schizophrenia through modulation of central dopaminergic and serotonergic activity. Available data suggest that the efficacy of ziprasidone in treating schizophrenia is primarily attributable to high-affinity receptor binding at dopamine D2 and serotonin 5-HT2A receptors where the drug functions as an antagonist. The mechanism of action in bipolar disorder is unknown.[28233]
     
    Dopamine and serotonin mediate various effects in different portions of the brain. According to one hypothesis, a dopamine excess in the mesolimbic tract is thought to be responsible for the positive symptoms of schizophrenia. In the mesocortical tract, a reduction in dopamine activity may be responsible for the negative symptoms of schizophrenia. Reduced dopamine activity in the nigrostriatal tract may be related to decreased metabolic activity in the basal ganglia. Central serotonin hyperactivity may be associated with dopamine hypoactivity in the nigrostriatal and mesocortical tracts. Antipsychotics with a high affinity for serotonin receptors are thought to be more effective for treating the negative symptoms of schizophrenia than those with dopaminergic modulation as a primary mechanism. The tuberoinfundibular tract controls neuroendocrine and hypothalamic function (e.g., prolactin release). Antipsychotic-mediated dopamine receptor blockade in the tuberoinfundibular tract increases prolactin release, which can lead to adverse effects such as amenorrhea, gynecomastia, galactorrhea, decreased libido, and impotence.[43222] [42605]
     
    Ziprasidone inhibits central reuptake of serotonin and norepinephrine. Ziprasidone has a high in vitro binding affinity and functions as an antagonist at alpha-1 receptors, which likely accounts for the orthostatic hypotension observed with this drug. There is also a high in vitro binding affinity for other receptor sites including dopamine D3 and serotonin 5-HT2C, 5-HT1A, and 5-HT1D. Ziprasidone functions as an antagonist at D3 and an agonist at 5-HT1A. As a moderate histamine H1 receptor antagonist, ziprasidone has been associated with somnolence in some patients. Cholinergic and other receptor binding have been negligible.[28233]

    PHARMACOKINETICS

    Ziprasidone is administered orally or intramuscularly (IM). After administration, it is > 99% protein bound to plasma proteins, primarily to albumin and a-1-acid glycoprotein. However, it does not displace other highly-protein bound drugs and is not displaced by other drugs.
     
    Ziprasidone undergoes extensive metabolism (66%) in the liver via reduction primarily by chemical reduction by glutathione as well as enzymatic reduction by aldehyde oxidase with subsequent methylation mediated through thiol methyltransferase. One-third of the drug is cleared via oxidation. Oxidation occurs primarily through hepatic cytochrome P450 isoenzyme CYP3A4; metabolism via CYP1A2 is a lesser contributor. Four major metabolites have been identified including benzisothiazole sulphoxide, benzisothiazole sulphone, ziprasidone sulphoxide, and S-methyldihydroziprasidone. Ziprasidone does not appear to affect metabolism of other drugs cleared via hepatic CYP450 isoenzymes. The drug's mean terminal half-life is roughly 7 hours. Less than 1% and 4% of the parent compound is excreted unchanged in the urine and feces, respectively. The drug is primarily excreted as metabolites in the feces (66%), with 20% of an administered dose excreted in the urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: None
    In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

    Oral Route

    Orally administered ziprasidone has a bioavailability of about 60% when administered with food. Administration with food increases absorption up to two-fold, so the dosage should be administered with food. Peak plasma concentrations occur in 6—8 hours; steady state concentrations are achieved within 1 to 3 days of oral dosing.

    Intramuscular Route

    Intramuscularly administered ziprasidone has a bioavailability of 100%. Peak serum concentrations typically occur at approximately 60 minutes post-dose or earlier and the mean half-life ranges from 2—5 hours. Exposure increases in a dose-related manner and following 3 days of IM dosing, little accumulation is observed.