Ziprasidone: Did You Know?

Volume IV, Number 3 | May/June 2001
Mandy Leonard, Pharm.D., BCPS

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Ziprasidone (Geodon™; Pfizer) is a new atypical antipsychotic agent indicated for the treatment of schizophrenia (See Table 1). Ziprasidone is a combined serotonin and dopamine receptor antagonist and also has activity at the serotonin and dopamine transport or re-uptake sites. It is in the benzisothiazole class and has a similar structure and receptor affinities to risperidone. See Table 2 for the pharmacokinetics of ziprasidone.

Table 1:  FDA-Approved Indications of Atypical Antipsychotics

Table 2:  Pharmacokinetics of Ziprasidone

Ziprasidone should be used with caution in patients who have had adverse events with prior use of an atypical antipsychotic, central nervous system disorders, gastrointestinal disease, hepatic or renal insufficiency, or are pregnant. Some warnings associated with ziprasidone use include QTc prolongation, neuroleptic malignant syndrome, and tardive dyskinesia. Since QTc prolongation may occur with ziprasidone therapy, this agent should not be used 1) with other medications that prolong the QTc interval (e.g., quinidine, moxifloxacin, dofetilide, pimozide, sotalol, thioridazine); 2) in patients with a known history of QTc prolongation (including long QT syndrome); and 3) in patients with a history of cardiac arrhythmias, recent acute myocardial infarction, or with uncompensated heart failure. Ziprasidone therapy should be discontinued in patients with persistent QTc measurements >500_msec.

Neuroleptic malignant syndrome (NMS) is also a risk with ziprasidone therapy. The clinical manifestations of NMS include hyperpyrexia muscle rigidity, altered mental status and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia), elevated creatinine phosphokinase, myoglobinurea (rhabdomyolysis), and acute renal failure.

A third complication with the use of ziprasidone may be tardive dyskinesia (TD). TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements. Chronic administration of antipsychotic medications can increase the risk of developing tardive dyskinesia.

Ziprasidone therapy is contraindicated 1) in patients with hypersensitivity to any component of the agent, 2) in patients with medications that prolong the QT interval, 3) in patients with a known history of QT prolongation, 4) in patients with a recent acute myocardial infarction, and 5) in patients with uncompensated heart failure.

Ziprasidone is classified as a pregnancy-risk category C; hence, studies in animals have revealed adverse effects on the fetus and there are no studies in women or studies in animals and women have yet to be performed. Also, there are no additional data available regarding ziprasidone use during pregnancy.

Some of the adverse effects of ziprasidone include dyspepsia, constipation, nausea, abdominal pain, dry mouth, sedation, headache, postural hypotension, dizziness, insomnia, and rash. It is one of the atypical antipsychotic agents not to be associated with weight gain, making it unique in its class.

Some possible drug interactions that may occur with ziprasidone include ketoconazole and cimetidine. Ziprasidone should not be administered in combination with other centrally acting agents due to its central nervous system effects. Ziprasidone may also enhance the effects of some antihypertensive agents due to its potential for inducing orthostatic hypotension, as well as antagonize the effects of levodopa and dopamine agonists. And finally, because of the risk of ziprasidone causing QTc prolongation, it should not be administered with any medication that prolongs the QT interval.

Ziprasidone is available as 20-, 40-, 60-, and 80-mg capsules. Therapy should be initiated at a dose of 20 mg administered orally twice daily with food. The dose may be increased based on response up to 80 mg twice daily. Dosage adjustments should occur at intervals of not less than 2 days. Patients should be observed for improvement for several weeks before upward dosage adjustment to ensure use of the lowest effective dose. There is no dosage adjustment required for mild to moderate renal or hepatic impairment or for the elderly. The cost of ziprasidone is the same for all strengths: $234 for a one month supply ($7.80 per day).

Even though there are warnings associated with ziprasidone due to its potential to prolong the QT interval, it still has a place in therapy. Ziprasidone may be most effective in patients who are resistant to standard antipsychotic agents and patients with therapy limiting extrapyramidal symptoms or other adverse effects, such as weight gain and increased cholesterol. Ziprasidone was recently added to the Cleveland Clinic Foundation Formulary of Accepted Drugs, however, its use is restricted to the Department of Psychiatry. Additionally, before ziprasidone therapy is initiated at CCF, patients must have a baseline EKG.

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