Ziprasidone is an oral and injectable atypical antipsychotic belonging to the benzisoxazole/benzoisothiazol derivatives class. Atypical antipsychotics are first-line treatment options for the management of schizophrenia and related disorders, with the exception of clozapine. Ziprasidone has also demonstrated efficacy in adults as monotherapy for acute manic or mixed episodes associated with bipolar I disorder and as maintenance treatment for bipolar I disorder in conjunction with lithium or valproate. An intramuscular (IM) injection is approved for the treatment of acute agitation in adults with schizophrenia. Oral ziprasidone has been used 'off-label' for the treatment of Tourette's syndrome, but the data are minimal. The American Academy of Neurology practice guideline for the treatment of tics in people with Tourette's syndrome or chronic tic disorders states that ziprasidone is possibly more likely than placebo to reduce tic severity. However, prescribers should consider the side effect profile of the drug, particularly in comparison with other agents for tics; if ziprasidone is used an ECG is recommended prior to initiation and during treatment. Ziprasidone may produce relatively less weight gain than some atypical antipsychotics. However, due to a greater capacity of ziprasidone to prolong the QTc interval than many other antipsychotics, prescribers should consider the use of other treatment options prior to choosing to prescribe ziprasidone. As with all atypical antipsychotics, the labels include a boxed warning regarding an increased mortality risk in elderly patients with dementia-related psychosis.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-INJECTABLES: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Oral Administration
-Administer the capsules whole. Do not open, crush, or chew the capsule.
-Administer with food to ensure adequate absorption.
-Administer at roughly the same times each day.
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.
Ziprasidone has been associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a rare but potentially fatal condition which consists of a combination of three or more of the following: cutaneous reaction (rash (unspecified) or exfoliative dermatitis), eosinophilia, pyrexia, lymphadenopathy and one or more systemic complications (e.g., hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis). The FDA reviewed information from six non-fatal cases of patients who developed signs and symptoms of DRESS within 11 to 30 days after treatment initiation. Elevated WBC counts and other signs and symptoms indicative of systemic illness were evident in several instances. A complete recovery was documented for all patients after drug discontinuation or administration of antihistamines or steroids. Patients should be instructed to seek immediate medical attention if they develop a rash with elevated temperature and lymphadenopathy. Other severe cutaneous reactions, such as Stevens-Johnson syndrome, have also occurred. If DRESS or severe cutaneous reactions are suspected, ziprasidone should be discontinued. During clinical trials of orally administered ziprasidone in adults for the treatment of schizophrenia or bipolar disorder, the following additional dermatologic and allergic effects occurred more frequently with ziprasidone than placebo: rash (4% vs 3%) and fungal dermatitis (2% vs 1%). In the pre-marketing database, approximately 5% of patients developed a rash and/or urticaria, with discontinuation of treatment in one-sixth of these patients. During clinical trial evaluation, rash (unspecified) was the most common event associated with treatment discontinuation (1%). Rash (maculopapular rash), hives (urticaria), alopecia, atopic dermatitis, exfoliative dermatitis, contact dermatitis, lymphadenopathy, eosinophilia, and vesicular rash / bullous rash were reported infrequently (0.1-1%) during other pre-marketing evaluations of oral ziprasidone for schizophrenia. During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, the following dermatologic effects were reported in one or more treatment groups: furunculosis (0%, 2%, 0%) and hyperhidrosis (0%, 0%, 2%). Allergic reactions including dermatitis, angioedema, hives (urticaria), rash, and orofacial edema have been reported during post-marketing use of the drug; however, a causal relationship has not been established. The manufacturer recommends that ziprasidone be discontinued if rash develops in the absence of an identifiable etiology.
During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, injection site reaction (injection site pain) was reported in all treatment groups (9%, 8%, 7%).
During clinical trials of orally administered ziprasidone in adults, the incidence of extrapyramidal symptoms in ziprasidone-treated patients with schizophrenia was 14% vs 8% in placebo-treated patients; the incidence in patients with bipolar disorder was 31% vs 12% of those receiving placebo. Akathisia occurred more frequently with oral ziprasidone than placebo (8-10% vs 5-7%). Extrapyramidal syndrome, dystonic reaction (i.e., oculogyric crisis), hyperkinesis, pseudoparkinsonism (i.e., hypertonia, tremor, akinesia, hypokinesia, cogwheel rigidity), twitching, and dyskinesia (i.e., choreoathetosis) were reported in at least 1% of patients during other pre-marketing evaluations of oral ziprasidone for schizophrenia. Muscle paralysis was reported infrequently (0.1-1%). Dystonic reactions including torticollis, trismus, and opisthotonos occurred rarely (< 0.1%). Dystonia, hypertonia, and tremor were considered dose-related effects. During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, the following extrapyramidal effects were reported in one or more treatment groups: akathisia (0%, 2%, 0%), unspecified extrapyramidal syndrome (2%, 0%, 0%), hypertonia (1%, 0%, 0%), and cogwheel rigidity (1%, 0%, 0%). EPS reactions are thought to occur from D-2 blockade in the nigrostriatal pathway of the brain and consist of several categories including dystonic reaction, pseudoparkinsonism, and akathisia. Dystonic reaction is a potential effect of all antipsychotics, and may occur in susceptible individuals during the first few days of treatment. This effect is observed more commonly in males, younger age groups, and with high potency antipsychotics. Dystonic reactions may manifest as torticollis with or without throat tightness, difficulty swallowing or breathing, oculogyric crisis, trismus, or protrusion of the tongue. Pseudoparkinsonism may occur 1-2 weeks after initiation of antipsychotic therapy and is more common in elderly patients. Akathisia may develop several days to weeks into therapy and may respond to dosage reduction or concomitant administration of a benzodiazepine (usually lorazepam) or a beta-blocker (e.g., propranolol, metoprolol). Dystonic reaction and akathisia were among the most common events associated with study discontinuation in the ziprasidone-treated group.
During clinical trials of orally administered ziprasidone in adults for the treatment of bipolar disorder, anxiety occurred more frequently with ziprasidone than placebo (5% vs 4%). Anxiety was considered a dose-related effect. Hostility, amnesia, confusion, and delirium were reported in at least 1% of patients during pre-marketing evaluation of oral ziprasidone for schizophrenia. Depression resulted in treatment discontinuation in 1% of patients receiving ziprasidone in short-term clinical trials compared to 0% of patients receiving placebo. During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, the following psychiatric effects were reported in one or more treatment groups: anxiety (2%, 0%, 0%), agitation (2%, 2%, 0%), personality disorder (0%, 2%, 0%), and psychosis (1%, 0%, 0%). Mania/hypomania have been reported during post-marketing use.
Like other antipsychotics, ziprasidone can lower the seizure threshold. Seizure activity was reported in 0.4% of patients receiving ziprasidone during clinical trials. Myoclonia was reported in < 0.1% of patients with schizophrenia during pre-marketing evaluation of oral ziprasidone. Use the drug cautiously in those with a seizure disorder or predisposition to seizures.
During clinical trials of orally administered ziprasidone in adults for the treatment of schizophrenia or bipolar disorder, the following centrally-mediated effects occurred more frequently with ziprasidone than placebo: drowsiness (14-31% vs 7-12%), dizziness (8-16% vs 6-7%), asthenia (5-6% vs 2-3%), hypesthesia (2% vs 1%), and headache (18% vs 17%). Asthenia, dizziness, and drowsiness were considered dose-related. Other CNS effects reported in at least 1% of patients during pre-marketing evaluation of oral ziprasidone for schizophrenia included paresthesias, vertigo, abnormal gait, hypesthesia, ataxia, hypotonia, incoordination, and peripheral neuropathy. Nystagmus, circumoral paresthesia, and hyperreflexia occurred rarely (< 0.1%). During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, the following centrally-mediated effects were reported in one or more treatment groups: headache (3%, 13%, 5%), asthenia (2%, 0%, 0%), dizziness (3%, 3%, 10%), insomnia (3%, 0%, 0%), drowsiness (8%, 8%, 20%), and paresthesias (0%, 2%, 0%). Facial droop and insomnia have been reported during post-marketing use. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study evaluated the effectiveness of selected oral atypical antipsychotics and perphenazine in schizophrenic patients (see Atypical Antipsychotic Overview). In the safety evaluation, drowsiness occurred in 24-31% of patients, with drowsiness being least in the ziprasidone group. However, the authors report that insomnia occurred at the highest incidence in the ziprasidone group (30%); insomnia may have been a more important therapeutic outcome (vs. drowsiness) for the patients with schizophrenia in this study.
During clinical trials of orally administered ziprasidone in adults for the treatment of schizophrenia or bipolar disorder, the following gastrointestinal (GI) effects occurred more frequently with ziprasidone than placebo: nausea (10% vs 7%), constipation (9% vs 8%), dyspepsia (8% vs 7%), diarrhea (5% vs 4%), xerostomia (4-5% vs 2-4%), anorexia (2% vs 1%), hypersalivation (4% vs 0%), and vomiting (5% vs 2%). Anorexia, xerostomia, and hypersalivation were considered dose-related. Anorexia, abdominal pain, and vomiting were reported in at least 1% of patients during other pre-marketing evaluations of oral ziprasidone for schizophrenia. Rectal hemorrhage was reported infrequently (0.1-1%), and fecal impaction, increased gamma glutamyl transpeptidase (GGT), hematemesis, and melena occurred rarely (< 0.1%). During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, the following GI effects were reported in one or more treatment groups: nausea (4%, 8%, 12%), rectal hemorrhage (0%, 0%, 2%), diarrhea (3%, 3%, 0%), vomiting (0%, 3%, 0%), dyspepsia (1%, 3%, 2%), anorexia (0%, 2%, 0%), constipation (0%, 0%, 2%), abdominal pain (0%, 2%, 0%), and xerostomia (1%, 0%, 0%).
A withdrawal or drug discontinuation syndrome (unspecified) has been reported in at least 1% of patients during pre-marketing use of ziprasidone for schizophrenia. Abrupt discontinuation is not recommended, unless required by the patient's medical condition. Otherwise, a tapering schedule is recommended via a gradual 1-2 week reduction in dosage. Patients should be carefully observed for the recurrence of psychotic symptoms during drug discontinuation.
During clinical trials of orally administered ziprasidone in adults for the treatment of schizophrenia or bipolar disorder, the following cardiovascular effects occurred more frequently with ziprasidone than placebo: chest pain (unspecified) (3%), sinus tachycardia (2%), and hypertension (3%). Sinus tachycardia, hypertension, and orthostatic hypotension were reported in at least 1% of patients during other pre-marketing evaluations of oral ziprasidone for schizophrenia. Bradycardia, angina, and atrial fibrillation were reported infrequently (0.1% to 1%). During fixed-dose clinical trials of injectable ziprasidone (2 mg to 20 mg IM per dose) for the acute treatment of agitation in schizophrenia, the following cardiac effects were reported in one or more treatment groups: orthostatic hypotension (0% to 5%), hypertension (0% to 2%), bradycardia (0% to 2%), and peripheral vasodilation (0% to 1%). Orthostatic hypotension was considered dose-related. Ziprasidone is a moderate antagonist of alpha-1 receptors, which may be responsible for the orthostatic hypotension observed with the drug. Rare effects (less than 0.1%) with oral ziprasidone have included first degree AV block, bundle-branch block, phlebitis, pulmonary embolism, cardiomegaly, cerebral infarct, stroke, deep thrombophlebitis, myocarditis, and thrombophlebitis. As with other atypical antispychotics, ziprasidone should not be used in elderly patients with dementia. In placebo-controlled trials in elderly subjects with dementia, patients randomized to selected antipsychotics had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Clinical trial data indicate that ziprasidone also 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. Torsade de Pointes, sinus tachycardia, orthostatic hypotension, and syncope have been reported during postmarketing use of the drug.
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 or higher) on exposed areas of the body. Patients should avoid undue sunlight (UV) exposure and the use of tanning beds.
Hyperprolactinemia has been reported with ziprasidone administration and is likely caused by D-2 blockade in the tuberoinfundibular tract of the brain. Endocrine effects potentially associated with hyperprolactinemia and reported in 0.1% to 1% of patients receiving oral ziprasidone for schizophrenia during premarketing evaluation included amenorrhea, galactorrhea, ejaculation dysfunction, male sexual dysfunction (unspecified), orgasm dysfunction (anorgasmia), and impotence (erectile dysfunction). Gynecomastia and unspecified female sexual dysfunction occurred rarely (less than 0.1%). Galactorrhea has also been reported during postmarketing use. One case of priapism was reported during premarketing evaluation of oral ziprasidone. During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, priapism was reported in 1% of patients receiving the 2 mg dose and no patients receiving the 10 mg or 20 mg dose. Priapism has also been reported during postmarketing use. This rare, but significant side effect is thought to occur from the use of medications with alpha-blocking effects such as ziprasidone.
During clinical trials of orally administered ziprasidone in adults for the treatment of schizophrenia or bipolar disorder, the following respiratory effects, infections, or related symptoms occurred more frequently with ziprasidone than placebo: respiratory tract infection (8% vs 3%), rhinitis (4% vs 2%), pharyngitis (3% vs 1%), dyspnea (2% vs 1%), and increased cough (3% vs 1%). Rhinitis was considered a dose-related effect. Flu syndrome/influenza, fever, and dyspnea were reported in at least 1% of patients during other pre-marketing evaluations of oral ziprasidone for schizophrenia. Pneumonia and epistaxis were reported infrequently (0.1-1%). Hemoptysis and laryngismus (laryngospasm) occurred rarely (< 0.1%). During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, the following respiratory effects were reported in one or more treatment groups: flu syndrome (1%, 0%, 0%) and rhinitis (1%, 0%, 0%).
During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, dysmenorrhea was reported in 2% of the 10 mg group and no patients in the 2 mg or 20 mg groups. During pre-marketing evaluation of oral ziprasidone in the treatment of schizophrenia, genitourinary (GU) effects reported in 0.1-1% of patients included hematuria, polyuria, urinary retention, glycosuria, metrorrhagia, and menorrhagia. Vaginal bleeding/hemorrhage, nocturia, oliguria, and uterine hemorrhage occurred rarely (< 0.1%). GU effects, such as enuresis and urinary incontinence, have been reported during post-marketing use of ziprasidone; however, the incidences are unknown. Causality to the drug has not been established.
During clinical trials of orally administered ziprasidone in adults for the treatment of bipolar disorder, the following effects occurred more frequently with ziprasidone than placebo: tongue edema (3% vs 1%), dysarthria (2% vs 0%), and dysphagia (2% vs 0%). Dysarthria was reported in at least 1% of patients during pre-marketing evaluation of oral ziprasidone for schizophrenia. Effects reported in 0.1-1% of patients included dysphagia and tongue edema. Gum hemorrhage and oral leukoplakia occurred rarely (< 0.1%). During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, unspecified tooth disorder (1%, 0%, 0%) and dysarthria (0%, 2%, 0%) were reported in one or more treatment groups. Swollen tongue has been reported during post-marketing use.
During clinical trials of orally administered ziprasidone in adults for the treatment of schizophrenia or bipolar disorder, abnormal vision/visual impairment occurred more frequently with ziprasidone than placebo (3-6% vs 2-3%). Abnormal vision was considered a dose-related effect. Diplopia was reported in at least 1% of patients during other pre-marketing evaluations of oral ziprasidone for schizophrenia. Conjunctivitis, xerophthalmia, blepharitis, cataracts, and photophobia were reported in 0.1-1% of patients. Ocular hemorrhage, visual field defect, keratitis, and keratoconjunctivitis occurred rarely (< 0.1%).
During clinical trials of orally administered ziprasidone in adults for the treatment of bipolar disorder, myalgia occurred more frequently with ziprasidone than placebo (2% vs 0%). Myalgia and flank pain were reported in at least 1% of patients during pre-marketing evaluation of oral ziprasidone for schizophrenia. Synovitis, reported as tenosynovitis, was noted infrequently (0.1-1%), and myopathy occurred rarely (< 0.1%). During fixed-dose clinical trials of injectable ziprasidone (2 mg, 10 mg, or 20 mg) for the acute treatment of agitation in schizophrenia, back pain was reported in 1% of patients receiving the 2 mg dose and no patients receiving the 10 mg or 20 mg dose.
Tardive dyskinesia (TD) is a syndrome that is typically the result of chronic antipsychotic administration and may be irreversible in some cases. Rare instances of TD have been reported during post-marketing use of ziprasidone. Buccoglossal syndrome (tardive dyskinesia) was reported in at least 1% of patients with schizophrenia receiving oral ziprasidone during pre-marketing evaluation. Several factors appear to increase the likelihood of developing tardive dyskinesia from antipsychotics including the duration of therapy, concomitant affective illness, and if the patient is a female > 40 years old. One or more of the following symptoms may be present including rhythmic involuntary movements of the tongue, mouth, face or jaw, frequent blinking, chewing movements, or involuntary movements of the extremities. The presence of tardive dyskinesia may be masked by increasing the antipsychotic dose; likewise, it may become more obvious by discontinuation of the drug. However, discontinuation of ziprasidone should be considered if symptoms of tardive dyskinesia become apparent. Patients should be routinely monitored for and informed of the symptoms of TD so that early detection and intervention are possible.
A potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS) has been reported in association with administration of the antipsychotics and has been reported during postmarketing use of ziprasidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The cause of NMS is not completely understood; however, dopamine receptor blockade is one of the mechanisms by which NMS is thought to occur. A primary risk factor for developing NMS appears to be the initiation or increase in dose of an antipsychotic. High potency and depot antipsychotics carry the greatest risk. Environmental risk factors include conditions that inhibit heat dissipation such as an elevated ambient room temperature, prolonged heat exposure, the use of patient restraints, or dehydration. NMS occurs more frequently in young adults, which is most likely the result of age of first exposure rather than an age-related risk. NMS occurs more frequently in men, which is thought to be related to the higher likelihood of male versus female exposure to the causative agent. Risk factors for recurrent NMS include a personal history of NMS, increasing age, and certain medical co-morbidities (e.g., electrolyte imbalances, dehydration). Ziprasidone should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered.
Serotonin syndrome has been reported during post-marketing use of ziprasidone; however, a causal relationship has not been established. Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome. Symptoms may include nausea, vomiting, sedation, dizziness, diaphoresis (sweating), mental status changes, myoclonia, restlessness, and elevated blood pressure.
Pooled data from short-term trials of oral ziprasidone in adult patients with schizophrenia indicated that the mean change in weight from baseline in the ziprasidone groups was +0.3-1.1 kg and a decrease of 0.4 kg in the placebo group. A weight gain of at least 7% from baseline occurred in up to 15.5% of patients receiving ziprasidone (<= 200 mg/day) and 4% of patients receiving placebo. Pooled analysis of short-term trials in patients with schizophrenia revealed a statistically significant increase in body weight (i.e., >= 7% increase from baseline) in the ziprasidone group compared to the placebo group (10% vs 4%). In long-term fixed or flexible-dose studies, the mean change from baseline weight in ziprasidone-treated patients ranged from -3.3 kg to +2.5 kg and for placebo ranged from -2.9 kg to -3.8 kg. The proportion of patients with an increase of at least 7% of baseline weight ranged from 2.9-20% of ziprasidone-treated patients and 2.9-5.6% in placebo-treated patients. During long-term therapy, changes in weight from baseline based upon body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (> 7% of body weight) in patients with low BMI (< 23) compared to normal (23-27) or overweight patients (> 27). There was a mean weight gain of 1.4 kg for those patients with a baseline BMI of < 23, no mean change for patients with a BMI in the range of 23-27, and a 1.3 kg mean weight loss for patients with a baseline BMI of > 27. In short-term monotherapy trials of bipolar disorder patients, the mean weight increase in ziprasidone-treated patients was +0.4 kg and for placebo patients was +0.1 kg. In those trials, a weight gain of at least 7% from baseline was reported in 2.4-4.4% of patients receiving ziprasidone and 1.8% of patients receiving placebo. During a 6-month trial of ziprasidone as adjunct treatment to lithium or valproate, clinically significant weight gain (>= 7% of body weight) occurred in 5.6% of patients in both the ziprasidone and placebo groups. Weight gain is a well known side effect of many antipsychotics. In general, blockade of serotonin and/or histamine receptors are thought to be associated with the weight gain typically seen with antipsychotics. Fluid retention and lack of exercise due to the sedative effect of the drugs are other possible causes. Ziprasidone exhibits a lower H1-receptor binding affinity than most other atypical antipsychotics, which likely contributes to its more favorable effect on weight gain than clozapine, olanzapine, or risperidone.
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with atypical antipsychotics. Hyperglycemia was reported in 0.1-1% of patients receiving oral ziprasidone for the treatment of schizophrenia during pre-marketing evaluation; however, no reports of diabetes requiring emergency treatment were reported. During clinical trials in adult patients with schizophrenia, the mean change in random serum glucose ranged from -1.7 to +4.1 in the ziprasidone group and +1.4 in the placebo group. The following specific changes in random serum glucose occurred in the ziprasidone group versus placebo group, respectively: from < 100 mg/dL to >= 126 mg/dL (17.6% vs 15.4%) and from 100-126 mg/dL to >= 126 mg/dL (34% vs 33.3%). In long-term studies, the mean change in random glucose during ziprasidone treatment ranged from -3.4 mg/dL to +1.3 mg/dL and for placebo was +0.3 mg/dL. In monotherapy trials of bipolar disorder patients, the mean increase in fasting glucose from baseline in the ziprasidone group ranged from +0.1-1.6 mg/dL. The following specific changes in fasting serum glucose occurred in the ziprasidone group versus placebo group, respectively: from < 100 mg/dL to >= 126 mg/dL (1.8% vs 1%) and from 100-126 mg/dL to >= 126 mg/dL (15.2% vs 9.9%). Atypical antipsychotics may have effects on glucose metabolism that are independent of their effect on weight gain; one study noted that patients taking atypical agents (e.g., clozapine, olanzapine, quetiapine) were 9% more likely to have a new diagnosis of diabetes mellitus than patients taking older therapies. Elevations in triglyceride levels may also occur. While a causal relationship has not been determined, temporal associations suggest that atypical antipsychotic therapy may precipitate or unmask diabetes mellitus in some patients; glucose levels normalize in most patients after discontinuation of the drug. A positive rechallenge has been demonstrated in some of these cases. The possibility of impaired glucose tolerance should be considered in patients that develop symptoms of hyperglycemia or diabetes, such as increased thirst, polyuria, polyphagia, and weakness. Patients developing signs or symptoms suggestive of diabetes while receiving an atypical antipsychotic should be tested for diabetes. Dosage reduction, if clinically possible, may improve glycemic control. 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.
Clinical trial data and post-marketing reports indicate that leukopenia, neutropenia, and agranulocytosis have occurred during the use of antipsychotic agents. Hematologic effects that were reported in 0.1-1% of patients during the pre-marketing evaluation of oral ziprasidone in schizophrenia included anemia, ecchymosis, leukocytosis, leukopenia, and eosinophilia. Rare events (< 0.1%) included thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, and thrombocythemia. Patients with a history of drug-induced leukopenia or neutropenia or history of clinically significant low white blood cell (WBC) count should be carefully monitored while receiving an antipsychotic, including regular laboratory monitoring of the complete blood count (CBC) during the first few months of therapy. Consideration should be given to discontinuing treatment if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Ziprasidone should be discontinued in patients who develop severe neutropenia (ANC < 1000/mm3).
During pre-marketing evaluation of oral ziprasidone in patients with schizophrenia, endocrine effects including hypothyroidism, hyperthyroidism, and thyroiditis were reported rarely (< 0.1%).
During pre-marketing evaluation of oral ziprasidone in the treatment of schizophrenia, tinnitus was reported in 0.1-1% of patients.
Metabolic and nutritional disorders reported in 0.1% to 1% of patients receiving oral ziprasidone for the treatment of schizophrenia during premarketing evaluation included increased creatine phosphokinase, increased alkaline phosphatase, dehydration, increased lactic dehydrogenase, albuminuria, and hypokalemia. Rare effects (less than 0.1%) included increased BUN, increased creatinine, hyperlipidemia, hyperkalemia, hypochloremia, hypoglycemia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemic reaction, hypomagnesemia, ketosis, and respiratory alkalosis.
Elevated hepatic enzymes were reported in 0.1-1% of patients during pre-marketing evaluation of oral ziprasidone for schizophrenia. Hepatobiliary effects that have been reported in less than 0.1% of patients receiving ziprasidone include jaundice, cholestatic jaundice, hepatitis, hepatomegaly, and fatty liver deposit (steatosis).
During clinical trials of orally administered ziprasidone in adults for the treatment of schizophrenia or bipolar disorder, accidental injury occurred more frequently with ziprasidone than placebo (4% vs. 1 to 2%). General effects that were reported in at least 1% of patients during other premarketing evaluations of oral ziprasidone for schizophrenia included accidental fall, face edema, and chills. Peripheral edema was reported infrequently (0.1 to 1%).
Hyperlipidemia, including hypercholesterolemia and hypertriglyceridemia, have been observed in patients receiving atypical antipsychotics. Ziprasidone appears to have less adverse effects on lipid parameters than many other antipsychotics. In adults with bipolar disorder, the following mean changes from baseline in fasting lipids occurred in the low-dose ziprasidone group (20-40 mg PO bid), high-dose ziprasidone group (60-80 mg PO bid), and placebo group, respectively: total cholesterol (-2.8, -3.4, -1.6), LDL (-3, -3.1, -1.97), HDL (-0.09, +0.3, -0.9), and triglycerides (+0.95, -3.5, +8.6). In adult patients with bipolar disorder, the percentage of patients with changes in fasting lipids in the ziprasidone group versus the placebo group were as follows: total cholesterol increase by >= 40 mg/dL (8.1% vs 4.5%), total cholesterol change from < 200 mg/dL to >= 200 mg/dL (2.5% vs 1.3%), total cholesterol change from 200-240 mg/dL to >= 240 mg/dL (9.4% vs 17.2%), LDL increase by >= 30 mg/dL (10.9% vs 6.3%), LDL increase from < 100 mg/dL to >= 160 mg/dL (0% vs 1.1%), LDL increase from 100-160 mg/dL to >= 160 mg/dL (9.3% vs 9.9%), HDL decrease from >= 40 mg/dL to < 40 mg/dL (7.8% vs 10.9%), triglyceride increases >= 50 mg/dL (17.8% vs 21.7%), triglyceride increase from < 150 mg/dL to >= 200 mg/dL (6.7% vs 7.3%), and triglyceride increase from 150-200 mg/dL to >= 200 mg/dL (27.6% vs 29.8%). In adult schizophrenic patients, the percentage of patients with changes in fasting lipids in the ziprasidone group versus the placebo group were as follows: total cholesterol increase by >= 40 mg/dL (11.1% vs 10%), total cholesterol increase from < 200 mg/dL to >= 200 mg/dL (3.9% vs 0%), total cholesterol increase from 200-240 mg/dL to >= 240 mg/dL (27.1% vs 26.8%), triglyceride increases by >= 50 mg/dL (34.1% vs 20.4%), triglyceride increase from < 150 mg/dL to >= 200 mg/dL (14.7% vs 7.9%), and triglyceride increase from 150-200 mg/dL to >= 200 mg/dL (46.7% vs 29.3%). In long-term studies in schizophrenia, the mean change in non-fasting cholesterol in ziprasidone-treated patients ranged from -19.7 mg/dL to +2.5 mg/dL and for placebo was -28 mg/dL; the mean change from baseline in non-fasting triglycerides for ziprasidone treated patients ranged from -39.3 mg/dL to +26.3 mg/dL and for placebo was +12.9 mg/dL.
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. Hypothermia was reported in approximately 1% of patients in premarketing evaluation of ziprasidone.
Thirst and polydipsia have occurred during treatment with antipsychotics. Polydipsia may be psychogenic in nature or a result of antipsychotic-induced metabolic complications such as diabetes; therefore, careful evaluation is recommended. Hyponatremia can develop from polydipsia which can progress to water intoxication, with symptoms such as confusion, lethargy, psychosis, and in severe cases, seizures or death. Some data suggest that antipsychotic-induced hyponatremia is most likely the result of syndrome of inappropriate antidiuretic hormone (SIADH). During clinical trial evaluation of ziprasidone, polydipsia was reported infrequently (0.1% to 1%) and hyponatremia was reported rarely (less than 0.1%).
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.
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.
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. Complete a fall risk assessment upon antipsychotic initiation in patients with conditions, diseases, or taking concurrent medications that could exacerbate orthostasis and recurrently during long-term therapy in at-risk patients. Clinical trial data also 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 postmarketing use of the drug. Given the potential for QT prolongation, ziprasidone is contraindicated for use in patients receiving medications known to prolong the QT interval. Use ziprasidone with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, cerebrovascular disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Assess baseline magnesium and potassium concentrations in high-risk patients, with periodic monitoring as clinically indicated. Discontinue ziprasidone in any patient with persistent QT interval measurements greater than 500 milliseconds.
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 is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Regular evaluation for movement disorders is recommended (e.g., AIMS, DISCUS). Factors associated with a greater susceptibility to tardive dyskinesia include an age above 55 years, female gender, white or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, prior or current akathisia, significant parkinsonism, or acute dystonic reaction. The rate of tardive dyskinesia in adults treated with a first generation antipsychotic appears to be at least 3 times that observed with second generation antipsychotics. 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 arise after drug discontinuation. Antipsychotics may suppress the signs and symptoms of tardive dyskinesia and thereby mask the underlying process; however, the syndrome may also remit partially or completely if the antipsychotic is withdrawn. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. 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.
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).
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.
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.
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.
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.
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 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.
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.
The presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some geriatric patients. The use of ziprasidone injection has not been systematically evaluated in adults 65 years of age and older. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric adults; avoid use of ziprasidone if possible due to an increase in morbidity and mortality in geriatric patients with dementia receiving antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections (primarily pneumonia). An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in geriatric adults and use should be avoided except for treating schizophrenia, bipolar disorder, or as part of antiemetic regimens during chemotherapy. In general, avoid use in those with delirium, dementia, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in those with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk reduction strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored at initiation and after dose changes. The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates antipsychotic use in residents of long-term care facilities (LTCFs) and use must be supported by an appropriate clinical indication that is thoroughly documented within the medical record. When used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the antipsychotic as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. Indications, dosages, and the duration of antipsychotic treatment in the geriatric adult should be in accordance with prescribing labels, published literature recommendations, and expert guidelines. "As needed" (PRN) use for acute behavioral/medical situations in the LTCF must be limited to 14 days, and any use beyond this duration requires that the attending physician/prescribing practitioner evaluate the patient prior to continued use.
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.
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.
Available data from published epidemiologic studies of pregnant women exposed to ziprasidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother from untreated schizophrenia or bipolar disorder during pregnancy, including relapse, hospitalization, and suicide. Schizophrenia and bipolar disorder are associated with increased adverse perinatal outcomes, including preterm birth. Animal studies using doses similar to the recommended human dose indicate that ziprasidone may cause fetal structural abnormalities, decreased fetal weight, delayed skeletal ossification, and decreased postnatal survival. Teratogenicity has been observed in some animal studies at doses above the maximum recommended human dose (MRHD). Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Complications have ranged from self-limited to requiring intensive care 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. It is not known if antipsychotics, through their effect on prolactin, would affect labor or obstetric delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to ziprasidone; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-961-2388.
The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for ziprasidone and any potential adverse effects on the breastfed child from ziprasidone or from the mother's underlying condition. Limited data indicate that ziprasidone is present in human milk. 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. However, because there is very limited experience with ziprasidone during breast-feeding, alternate medications for consideration include atypical agents such as olanzapine or quetiapine. 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, extrapyramidal symptoms, poor feeding, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events.
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 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.
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.
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 acute treatment of mania or mixed episodes and as an adjunct to lithium or valproate for maintenance therapy:
Oral dosage:
Adults: 40 mg PO twice daily for 1 day, then 60 or 80 mg PO twice daily. Adjust dose based on clinical response and tolerability.
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* or chronic tic disorders*:
Oral dosage:
Children and Adolescents 7 years and older: Safety and efficacy not established; limited data in pediatric patients. Initially 5 to 10 mg/day PO, then gradually titrate weekly to a final range of 10 to 40 mg/day, usually given in 2 divided doses. In one 56-day study (n = 28, age: 7 to 17 years), the mean daily dose of ziprasidone was 28.2 mg. Max: 40 mg/day PO. The American Academy of Neurology practice guideline states that ziprasidone is possibly more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; however, the evidence is insufficient to determine the efficacy of ziprasidone relative to other antipsychotics used to treat tics. Monitoring for side effects such as QT prolongation is imperative if ziprasidone is used.
For the treatment of severe behavioral or psychological symptoms of dementia* (BPSD)*:
Oral dosage:
Adults: Ziprasidone has not been well studied for BPSD. In one open-label study, ziprasidone was initiated at 40 mg PO twice daily, and titrated to clinical effect/tolerance. The mean dosage after titration was 78.4 mg/day. Dosage range allowed: 40 to 160 mg/day, in divided doses.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
Acebutolol: (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.
Acetaminophen; Aspirin; 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; Caffeine; Dihydrocodeine: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering dihydrocodeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; 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.
Acetaminophen; 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.
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 : (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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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; 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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering hydrocodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Oxycodone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering oxycodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Adagrasib: (Major) Avoid concomitant use of adagrasib and ziprasidone due to the potential for increased ziprasidone exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for ziprasidone-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ziprasidone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the AUC of ziprasidone by approximately 35% to 40%.
Alfentanil: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering alfentanil with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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; Hydrochlorothiazide, HCTZ: (Moderate) 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.
Alogliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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. 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. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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.
Amifampridine: (Major) Carefully consider the need for concomitant treatment with atypical antipsychotics and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Atypical antipsychotics may increase the risk of seizures.
Amiloride: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. (Moderate) 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.
Aminolevulinic Acid: (Moderate) Medications that may cause additive photosensitization when used with ziprasidone include aminolevulinic acid. Patients should limit sunlight and ultra-violet exposure whenever possible, and use proper UV precautions to protect the skin.
Amiodarone: (Contraindicated) Avoid concomitant use of ziprasidone and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Avoid coadministration of amisulpride with ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Amisulpride causes dose- and concentration- dependent QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
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. (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; Celecoxib: (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. (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. (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; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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. (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; 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: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
Amphetamine; Dextroamphetamine Salts: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
Amphetamine; Dextroamphetamine: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
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) Avoid use of apomorphine and ziprasidone together if possible due to a risk for additive QT prolongation and sedation. Also, apomorphine and ziprasidone can reduce the effectiveness of each other through opposing effects on dopamine. Addtive CNS effects are also possible. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. 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 general, atypical antipsychotics are less likely to interfere with Parkinson's disease treatments than traditional antipsychotics. Monitor for movement disorders, unusual changes in moods or behavior, sedation, fast, irregular heartbeat, and diminished effectiveness of either agent if coadministration cannot be avoided.
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: (Contraindicated) 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; Caffeine; 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.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (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) Because of the potential for additive sedation and CNS depression, caution should be observed when administering oxycodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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.
Atenolol: (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.
Atenolol; Chlorthalidone: (Moderate) 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. (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.
Atomoxetine: (Major) Concomitant use of ziprasidone and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Azilsartan: (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.
Azilsartan; Chlorthalidone: (Moderate) 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. (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.
Azithromycin: (Major) Concomitant use of ziprasidone and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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: (Contraindicated) 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; 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.
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.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with ziprasidone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid 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 benzhydrocodone is initiated in a patient taking a ziprasidone, reduce initial dosage and titrate to clinical response. If ziprasidone is prescribed in a patient taking an opioid 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. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and ziprasidone because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. 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.
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: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
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.
Betaxolol: (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.
Bexagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bisoprolol: (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.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
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.
Brimonidine; Timolol: (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.
Bromocriptine: (Moderate) The effectiveness of bromocriptine may be reduced by most of the atypical antipsychotics, via their action as dopamine antagonists. Monitor the patient for reduced response to bromocriptine. The atypical antipsychotics elevate prolactin to various degrees. Atypical antipsychotics may also aggravate diabetes mellitus and cause metabolic changes including hyperglycemia; use caution if bromocriptine is taken for diabetes. 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; 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.
Brompheniramine; 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.
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.
Brompheniramine; Pseudoephedrine; 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.
Bumetanide: (Moderate) Monitor 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.
Bupivacaine; 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.
Buprenorphine: (Major) Avoid the use of buprenorphine and ziprasidone together due to a risk for QT prolongation; additive sedation and CNS depression may also occur. 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) Avoid the use of buprenorphine and ziprasidone together due to a risk for QT prolongation; additive sedation and CNS depression may also occur. 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) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant atypical antipsychotic and buspirone use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Butalbital; Acetaminophen: (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.
Butalbital; Acetaminophen; 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.
Butalbital; Acetaminophen; Caffeine; Codeine: (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. (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Butalbital; Aspirin; Caffeine; Codeine: (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. (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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: (Moderate) Cabergoline should not be coadministered with ziprasidone due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of ziprasidone may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as ziprasidone.
Cabotegravir; 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.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Candesartan: (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.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and ziprasidone. Concurrent use may result in additive CNS depression.
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.
Captopril: (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.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
Carbamazepine: (Moderate) Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted when carbamazepine is used with ziprasidone. 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.
Carbidopa; Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
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.
Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as ziprasidone. Similar to other antipsychotics, cariprazine administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. The incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, but the risk appears to be increased.
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.
Carteolol: (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.
Carvedilol: (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.
Celecoxib; Tramadol: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering tramadol with ziprasidone. Tramadol is associated with reports of serotonin syndrome when given with other serotonergic drugs; there are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and ziprasidone. Concurrent use may result in additive CNS depression.
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.
Cetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
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; Amitriptyline: (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) Avoid coadministration of chloroquine with ziprasidone due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
Chlorothiazide: (Moderate) 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.
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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (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; 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.
Chlorpheniramine; Hydrocodone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering hydrocodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (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; Ibuprofen; 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.
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: (Contraindicated) 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: (Moderate) 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.
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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) 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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Clofazimine: (Major) Concomitant use of clofazimine and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Codeine; Guaifenesin: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Codeine; Phenylephrine; Promethazine: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering codeine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (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: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
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.
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) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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.
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. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
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. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. 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.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextroamphetamine: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
Dextromethorphan; 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.
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; Quinidine: (Contraindicated) 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.
Diazoxide: (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.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
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) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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; 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.
Diphenoxylate; Atropine: (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.
Disopyramide: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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.
Dorzolamide; Timolol: (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.
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.
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: (Contraindicated) 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: (Contraindicated) 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) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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 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.
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.
Elvitegravir; Cobicistat; 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.
Elvitegravir; Cobicistat; 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.
Empagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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, Enalaprilat: (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.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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) Concomitant use of encorafenib and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease ziprasidone exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to ziprasidone and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ziprasidone is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased the exposure of ziprasidone by approximately 35%.
Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Entrectinib: (Major) Avoid coadministration of entrectinib with ziprasidone due to the risk of QT prolongation. Entrectinib has been associated with 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.
Enzalutamide: (Moderate) Monitor for decreased efficacy of ziprasidone when coadministered with enzalutamide. Coadministration may decrease ziprasidone exposure. Ziprasidone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of ziprasidone by approximately 35%.
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.
Eprosartan: (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.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Erythromycin: (Major) Concomitant use of ziprasidone and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Concomitant use of ziprasidone and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Esketamine: (Moderate) Closely monitor patients receiving esketamine and ziprasidone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
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.
Esmolol: (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.
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).
Ethacrynic Acid: (Moderate) Monitor 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.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethiodized Oil: (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.
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.
Etrasimod: (Major) Concomitant use of etrasimod and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Exenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
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.
Fenfluramine: (Moderate) Use fenfluramine and ziprasidone with caution due to an increased risk of serotonin syndrome and additive CNS depression. Monitor for excessive sedation, somnolence, and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fenoldopam: (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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering fentanyl with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fexinidazole: (Major) Concomitant use of fexinidazole and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluconazole: (Contraindicated) 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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
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.
Fosinopril: (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.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
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.
Fostemsavir: (Major) Concomitant use of ziprasidone and fostemsavir 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. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Furosemide: (Moderate) Monitor 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.
Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of ziprasidone and gabapentin. Concurrent use may result in additive CNS depression.
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.
Gilteritinib: (Major) Avoid concomitant use of ziprasidone with gilteritinib 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.
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.
Glimepiride: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glipizide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glyburide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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 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 (i.e., goserelin) may prolong the QT/QTc 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.
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.
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.
Histrelin: (Major) Concomitant use of ziprasidone and histrelin 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. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering hydrocodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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.
Hydralazine: (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.
Hydralazine; Isosorbide Dinitrate, ISDN: (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: (Moderate) 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.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) 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. (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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering hydrocodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hydrocodone; Ibuprofen: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering hydrocodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hydromorphone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering hydromorphone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Hydroxychloroquine: (Major) Concomitant use of ziprasidone and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of ziprasidone and hydroxyzine should be avoided due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including ziprasidone. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
Ibuprofen; Oxycodone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering oxycodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Ibutilide: (Contraindicated) 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.
Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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 Aspart: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Degludec: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Detemir: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Glargine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Glulisine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Lispro: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin, Inhaled: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulins: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Iodixanol: (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.
Iohexol: (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.
Iomeprol: (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.
Iopamidol: (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.
Iopromide: (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.
Ioversol: (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.
Irbesartan: (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.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
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: (Major) Avoid concomitant use, or use in rapid succession, of monoamine oxidase inhibitors (MAOIs) and ziprasidone. If concomitant use is necessary, monitor for signs and symptoms of serotonin syndrome, blood pressure, and for unusual drowsiness and sedation. Concomitant use increases the risk for serotonin syndrome and additive hypotension and CNS depression. If serotonin syndrome occurs, discontinue therapy.
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.
Isophane Insulin (NPH): (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Isosulfan Blue: (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.
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.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ziprasidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of ziprasidone, further increasing the risk for adverse effects. Ziprasidone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of ziprasidone by approximately 35% to 40%.
Labetalol: (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.
Lansoprazole; Amoxicillin; 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.
Lapatinib: (Major) Concomitant use of ziprasidone and lapatinib 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. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and ziprasidone. Inform patients taking this combination of the risks and symptoms of excessive CNS depression and serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Lefamulin: (Major) Avoid coadministration of lefamulin with ziprasidone as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and atypical antipsyhotics. Dosage adjustments of lemborexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
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.
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 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 (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Concomitant use of ziprasidone and leuprolide 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. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levamlodipine: (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.
Levobunolol: (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.
Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Levofloxacin: (Major) Concomitant use of ziprasidone and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ziprasidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of ziprasidone, further increasing the risk for adverse effects. Ziprasidone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of ziprasidone by approximately 35% to 40%.
Levorphanol: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering levorphanol with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Lidocaine; 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.
Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Lisdexamfetamine: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
Lisinopril: (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.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
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) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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.
Lonafarnib: (Moderate) Monitor for an increase in ziprasidone-related adverse effects, including QT prolongation, CNS effects, and extrapyramidal symptoms, if coadministered with lonafarnib. Coadministration use may increase ziprasidone exposure. Ziprasidone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of ziprasidone by approximately 35% to 40%.
Loop diuretics: (Moderate) Monitor 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 loperamide and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with ziprasidone due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with 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. (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.
Losartan: (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.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
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.
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.
Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and ziprasidone, 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 antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
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.
Mecamylamine: (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.
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: (Contraindicated) 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) Because of the potential for additive sedation and CNS depression, caution should be observed when administering meperidine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
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) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Methadone: (Contraindicated) 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: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
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.
Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving atypical antipsychotics. There is a potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. There also may be additive sedation. Discontinue these medications at the first signs of dyskinesia.
Metolazone: (Moderate) 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.
Metoprolol: (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.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
Metronidazole: (Major) Concomitant use of metronidazole and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Minoxidil: (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.
Mirtazapine: (Major) Concomitant use of ziprasidone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Mobocertinib: (Major) Concomitant use of mobocertinib and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moexipril: (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.
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: (Major) Avoid concomitant use, or use in rapid succession, of monoamine oxidase inhibitors (MAOIs) and ziprasidone. If concomitant use is necessary, monitor for signs and symptoms of serotonin syndrome, blood pressure, and for unusual drowsiness and sedation. Concomitant use increases the risk for serotonin syndrome and additive hypotension and CNS depression. If serotonin syndrome occurs, discontinue therapy.
Morphine: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering morphine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Morphine; Naltrexone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering morphine with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Moxifloxacin: (Contraindicated) 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.
Nadolol: (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.
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) Monitor for excessive sedation and somnolence during coadministration of lumateperone and nalbuphine. Concurrent use may result in additive CNS depression.
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.
Nebivolol: (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.
Nebivolol; 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.
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: (Contraindicated) 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.
Nirmatrelvir; 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%.
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.
Nitroprusside: (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.
Ofloxacin: (Major) Concomitant use of ziprasidone and ofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Olanzapine; Fluoxetine: (Major) Concomitant use of ziprasidone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (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.
Olanzapine; Samidorphan: (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.
Oliceridine: (Moderate) Concomitant use of oliceridine with ziprasidone may cause excessive sedation and somnolence. Limit the use of oliceridine 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. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
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.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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. (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.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
Omeprazole; Amoxicillin; 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.
Ondansetron: (Major) Concomitant use of ziprasidone and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Opicapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
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.
Osilodrostat: (Major) Avoid coadministration of osilodrostat with 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 in patients with multiple confounding factors. Osilodrostat is associated with dose-dependent QT prolongation.
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.
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) Because of the potential for additive sedation and CNS depression, caution should be observed when administering oxycodone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Oxymorphone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering oxymorphone with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking ziprasidone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis or serotonin syndrome. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension and serotonergice effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis or serotonin syndrome. Ozanimod may also result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Ziprasidone causes QT prolongation; there are postmarketing reports of TdP and serotonin syndrome in patients with multiple confounding factors.
Pacritinib: (Major) Concomitant use of pacritinib and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. 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 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, tardive dyskinesia, or seizures.
Panobinostat: (Contraindicated) 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: (Contraindicated) 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; 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.
Perindopril: (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.
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. (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.
Phenelzine: (Major) Avoid concomitant use, or use in rapid succession, of monoamine oxidase inhibitors (MAOIs) and ziprasidone. If concomitant use is necessary, monitor for signs and symptoms of serotonin syndrome, blood pressure, and for unusual drowsiness and sedation. Concomitant use increases the risk for serotonin syndrome and additive hypotension and CNS depression. If serotonin syndrome occurs, discontinue therapy.
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.
Phenobarbital; Hyoscyamine; Atropine; 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.
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.
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.
Photosensitizing agents (topical): (Moderate) Medications that may cause additive photosensitization when used with ziprasidone include aminolevulinic acid. Patients should limit sunlight and ultra-violet exposure whenever possible, and use proper UV precautions to protect the skin.
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: (Contraindicated) 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.
Pindolol: (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.
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. 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.
Pioglitazone; Glimepiride: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. 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. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pioglitazone; 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. 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. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pitolisant: (Major) Avoid coadministration of pitolisant with ziprasidone as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs 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.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking ziprasidone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Clinical trial data indicate that ziprasidone causes QT prolongation; there are post marketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
Porfimer: (Major) Avoid coadministration of porfimer with ziprasidone due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like ziprasidone may increase the risk of a photosensitivity reaction.
Posaconazole: (Contraindicated) 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: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope.
Pramipexole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or pramipexole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and pramipexole may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with pramipexole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
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.
Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of ziprasidone and pregabalin. Concurrent use may result in additive CNS depression.
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: (Contraindicated) 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.
Promethazine; Dextromethorphan: (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.
Promethazine; Phenylephrine: (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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propranolol: (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.
Pseudoephedrine; 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.
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.
Quinapril: (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.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
Quinidine: (Contraindicated) 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.
Quizartinib: (Major) Concomitant use of quizartinib and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ramipril: (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.
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) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or rasagiline during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rasagiline may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with rasagiline than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Regular Insulin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Regular Insulin; Isophane Insulin (NPH): (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Relugolix: (Major) Concomitant use of ziprasidone and relugolix 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. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of ziprasidone and relugolix 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. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Remifentanil: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering remifentanil with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Remimazolam: (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.
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.
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.
Rifapentine: (Moderate) Monitor for decreased efficacy of ziprasidone when coadministered with rifapentine. Coadministration may decrease ziprasidone exposure. Ziprasidone is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of ziprasidone by approximately 35%.
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: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or ropinirole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and ropinirole may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with ropinirole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
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. 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.
Rotigotine: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, excess sedation, and diminished effectiveness of the atypical antipsychotic or rotigotine during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rotigotine may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with rotigotine than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Sacubitril; 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.
Safinamide: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or safinamide during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and safinamide may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with safinamide than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
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) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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) Monitor for loss of selegiline efficacy, signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, and unusual drowsiness and sedation during concomitant atypical antipsychotic and selegiline use. Dopamine antagonists, such as atypical antipsychotics, may diminish the effectiveness of selegiline. Concomitant use may increase the risk for serotonin syndrome or additive CNS depression. If serotonin syndrome occurs, discontinue therapy.
Selpercatinib: (Major) Avoid coadministration of ziprasidone with selpercatinib due to the potential for additive QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. 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 observed with selpercatinib therapy.
Semaglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sertraline: (Major) Concomitant use of ziprasidone and sertraline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
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) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Siponimod: (Major) Avoid coadministration of siponimod and ziprasidone due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes in patients with multiple confounding factors.
Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 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. Sorafenib has also been associated with QT prolongation.
Sotagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sotalol: (Contraindicated) Avoid concomitant use of ziprasidone and sotalol due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Spironolactone: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. (Moderate) 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.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and ziprasidone. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering sufentanil with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. 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.
Suvorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of suvorexant and atypical antipsyhotics. Dosage adjustments of suvorexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with other CNS depressants.
Tacrolimus: (Contraindicated) 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) Concomitant use of ziprasidone and tamoxifen increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tapentadol: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering tapentadol with ziprasidone. Tapentadol is associated with reports of serotonin syndrome when given with other serotonergic drugs; there are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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.
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.
Telmisartan; 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. (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.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
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.
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: (Moderate) 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.
Thioridazine: (Contraindicated) 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.
Timolol: (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.
Tirzepatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Tolcapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
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: (Contraindicated) 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.
Torsemide: (Moderate) Monitor 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.
Tramadol: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering tramadol with ziprasidone. Tramadol is associated with reports of serotonin syndrome when given with other serotonergic drugs; there are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering tramadol with ziprasidone. Tramadol is associated with reports of serotonin syndrome when given with other serotonergic drugs; there are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trandolapril: (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.
Trandolapril; Verapamil: (Major) Verapamil may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes. (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.
Tranylcypromine: (Major) Avoid concomitant use, or use in rapid succession, of monoamine oxidase inhibitors (MAOIs) and ziprasidone. If concomitant use is necessary, monitor for signs and symptoms of serotonin syndrome, blood pressure, and for unusual drowsiness and sedation. Concomitant use increases the risk for serotonin syndrome and additive hypotension and CNS depression. If serotonin syndrome occurs, discontinue therapy.
Trazodone: (Major) Concomitant use of ziprasidone and trazodone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. (Moderate) 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.
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.
Triclabendazole: (Major) Concomitant use of triclabendazole and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
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 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 (i.e., triptorelin) may prolong the QT/QTc interval.
Tucatinib: (Moderate) Monitor for ziprasidone-related adverse effects, including QT prolongation, CNS effects, and extrapyramidal symptoms, if coadministered with tucatinib. Concurrent use may increase the exposure of ziprasidone. Ziprasidone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of ziprasidone by approximately 35% to 40%.
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.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (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.
Vandetanib: (Contraindicated) 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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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 increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Major) Verapamil may reduce ziprasidone metabolism via inhibition of CYP3A4 isoenzymes.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with ziprasidone is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like ziprasidone may increase the risk of a photosensitivity reaction.
Voclosporin: (Major) Avoid concomitant use of ziprasidone and voclosporin due to the risk of 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. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; 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.
Voriconazole: (Contraindicated) 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) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Zolpidem: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zolpidem due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Limit the dose of Intermezzo sublingual tablets to 1.75 mg/day.
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.
Zuranolone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
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.
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.
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.
Ziprasidone is administered orally or intramuscularly. Ziprasidone is more than 99% protein bound to plasma proteins, primarily to albumin and alpha1-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 CYP3A4 and CYP1A2. Four major metabolites have been identified including benzisothiazole sulphoxide, benzisothiazole sulphone, ziprasidone sulphoxide, and S-methyldihydroziprasidone. The mean terminal half-life of oral ziprasidone in adults is 7 hours and the half-life of the intramuscular formulation in adults is 2 to 5 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 (CYP450) isoenzymes and drug transporters: None
Ziprasidone is a minor substrate of CYP1A2 and CYP3A4. In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs metabolized primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
-Route-Specific Pharmacokinetics
Oral Route
Orally administered ziprasidone has a bioavailability of about 60% when administered with food. Administration with food increases absorption up to 2-fold; oral ziprasidone should be administered with food. Peak plasma concentrations occur in 6 to 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 to 5 hours. Exposure increases in a dose-related manner and little accumulation is observed following 3 days of IM dosing.
-Special Populations
Hepatic Impairment
The AUC of ziprasidone may be increased in those with hepatic impairment, such as that caused by hepatic cirrhosis (AUC increased 13% and 34% in patients with Childs-Pugh Class A and B cirrhosis, respectively, versus controls); the half-life increased from 4.8 hours in normal controls to 7.1 hours in patients with cirrhosis. The manufacturer has not recommended oral dosage adjustments for hepatic impairment. Ziprasidone IM has not been evaluated in patients with hepatic dysfunction.
Renal Impairment
Renal impairment alone is unlikely to affect the pharmacokinetic parameters of oral ziprasidone; the cyclodextrin excipient of the IM injection is cleared by renal filtration and thus the IM injections should be administered with caution to those with impaired renal function. Ziprasidone is not removed by hemodialysis.
Geriatric
Population pharmacokinetic studies revealed that geriatric patients exhibit pharmacokinetic parameters similar to younger adults; therefore, dosage modifications of ziprasidone based on age are not recommended.
Gender Differences
Population pharmacokinetic evaluation of patients in controlled trials has revealed no evidence of clinically significant gender-related differences in the pharmacokinetics of ziprasidone; therefore, dosage modifications based upon gender are not recommended.
Other
Smoking
Ziprasidone is not a major substrate of CYP1A2. Population pharmacokinetic evaluation has not revealed any significant pharmacokinetic differences between tobacco smokers and nonsmokers.