Ziprasidone

Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count 3.

Cases of dermatologic reactions (including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported; may be fatal. Symptoms of DRESS include a combination of 3 or more of the following: severe skin eruption (rash or exfoliative dermatitis), fever, lymphadenopathy, eosinophilia and one or more systemic complications (eg, hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis). Discontinue use if DRESS or other severe cutaneous reactions are suspected.

Has been reported with atypical antipsychotics; risk profile may differ between agents.

Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease).

May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk.

Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. There is limited documentation with ziprasidone and specific risk associated with this agent is not known.

May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.

Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.

May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

Rare cases of priapism have been reported.

May result in QTc prolongation (dose related), which has been associated with the development of malignant ventricular arrhythmias (torsades de pointes) and sudden death. Observed prolongation was greater than with other atypical antipsychotic agents (risperidone, olanzapine, quetiapine), but less than with thioridazine. Avoid hypokalemia, hypomagnesemia. Use caution in patients with bradycardia. Discontinue in patients found to have persistent QTc intervals >500 msec. Patients with symptoms of dizziness, palpitations, or syncope should receive further cardiac evaluation. Also see Contraindications.

Use has been associated with a fairly high incidence of rash (5%); discontinue if alternative etiology is not identified.

Moderate to highly sedating, use with caution in disorders where CNS depression is a feature; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI. Disease-related concerns:

Use is contraindicated in patients with recent acute myocardial infarction (MI), QT prolongation, or uncompensated heart failure. Avoid use in patients with a history of cardiac arrhythmias; use with caution in patients with history of MI or unstable heart disease.

Elderly patients with dementia-related behavioral disorders treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death (APA [Reus 2016]). Ziprasidone is not approved for the treatment of dementia-related psychosis.

Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

Use with caution in patients with hepatic disease or impairment.

Use with caution in patients with Parkinson disease; antipsychotics may aggravate the motor disturbances of Parkinson disease (APA [Lehman 2004]; APA [Reus 2016]).

Use the intramuscular formulation with caution in patients with renal impairment.

Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors. Concurrent drug therapy issues:

CNS effects may be potentiated when used with other sedative drugs or ethanol. Dosage form specific issues:

Use the intramuscular formulation with caution in patients with renal impairment; formulation contains cyclodextrin, an excipient which may accumulate in renal insufficiency, although the clinical significance of this finding is uncertain (Luke, 2010). Other warnings/precautions:

When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or two episodes within 5 years (APA [Lehman 2004]).