Recent safety concerns with ziprasidone, including severe drug interactions with agents which prolong the QTc interval and with those which inhibit or induce cytochrome P450 3A4 (the hepatic enzyme through which ziprasidone is primarily metabolized), has prompted the Pharmacy and Therapeutics Committee to implement limitations on the use of this agent. To ensure patient safety, use is now restricted to psychiatry consults. Sample distribution by Pfizer drug representatives has also been limited to psychiatry departments only. It is imperative that those prescribed ziprasidone be interviewed about all medications they are taking, including over the counter (nonprescription) products, herbals, and prescription medications. This list should then be communicated to other health professionals involved in the care of that patient. In the tables below, you will find a list of drugs that are known to prolong the QTc interval and/or induce torsades as well as a list of drugs which affect hepatic cytochrome P450 enzymes. The URL addresses from which these tables were derived are also referenced. These sites are updated continually, so that the current list can always be accessed.

Ziprasidone is an atypical antipsychotic agent (combined serotonin and dopamine receptor antagonist) indicated in the treatment of schizophrenia. It is a potent 5-HT2A antagonist, with greater affinity for serotonin receptors than other atypicals. Efficacy has been found to be comparable to haloperidol.

Therapy should be initiated at a dose of 20 mg twice daily with food. The dose may be increased, based on response, up to 80 mg twice daily. In mild to moderate hepatic impairment, the AUC of ziprasidone is increased and dosage adjustment may be necessary. Renal impairment and hemodialysis do not alter the pharmacokinetics of ziprasidone. Dose titrations 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 the use of the lowest effective dose.

Ziprasidone is extensively hepatically metabolized, mainly by CYP3A4. Agents which inhibit CYP3A4 are expected to increase the AUC of ziprasidone. Carbamazepine, a CYP3A4 inducer, has been shown to decrease the AUC while ketoconazole, a CYP3A4 inhibitor, has been shown to increase the AUC. At low doses of ziprasidone (40 mg/day), cimetidine (800 mg QD), a nonspecific CYP inhibitor, has shown no effect on ziprasidone pharmacokinetics. Caution should be used when combining ziprasidone with agents which inhibit CYP3A4. Tables 1 and 2 provide a list of common cytochrome P450 inhibitors and inducers.

Ziprasidone’s has the capacity to prolong the QT/QTc interval. QT prolongation has been associated with torsades de pointes-type arrhythmia and sudden death. Ziprasidone is contraindicated and should not be used with any other medications that prolong the QTc interval . This includes medications listed in table 3. Ziprasidone is also contraindicated in patients with a known history of QT prolongation (including long QT syndrome), history of cardiac arrhythmias, recent acute myocardial infarction, or uncompensated heart failure. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

Side effects of ziprasidone include dyspepsia, constipation, nausea, abdominal pain, dry mouth, sedation, headache, postural hypotension, dizziness, insomnia, akathisia, rash, hypokalemia, and hypomagnesemia. Hypokalemia may increase the risk of QT prolongation and arrhythmia. Extrapyramidal effects occurred in 5% of patients in trials. Transient prolactin elevation has been observed, which returned to baseline levels within the dosing interval. Weight gain has not been observed in most trials with ziprasidone. Reductions in total cholesterol, LDL cholesterol, and triglycerides were also observed in ziprasidone-treated patients, independent of weight changes.

Patients on ziprasidone, especially those at risk for hypokalemia or hypomagnesemia (namely those on diuretic therapy), must be monitored for electrolyte disturbances and for any symptoms suggestive of the occurrence of torsades, such as dizziness, palpitations, or syncope. Any deficiency of potassium or magnesium should be corrected before proceeding with treatment to reduce the risk of arrhythmias.