Vol. VI, No. I
  January/February 2003

  Marcia Wyman,
  Pharm.D.

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 Pharmacotherapy
 Update Index

Ziprasidone Mesylate Injection
(Geodon™ for Injection)
by Marcia Wyman, Pharm.D.

Indications:
Intramuscular ziprasidone is FDA-approved for the treatment of acute agitation in schizophrenic patients for whom treatment with ziprasidone is appropriate and who need intramuscular antipsychotic medication for rapid control of agitation. Since there is no experience on the use of intramuscular ziprasidone in patients already receiving oral ziprasidone therapy, concomitant administration is not recommended.

Pharmacology:
Ziprasidone is an atypical antipsychotic agent of the benzisothiazole class, which structurally resembles risperidone (Risperdal®). Ziprasidone is a combined serotonin and dopamine receptor antagonist. It also has activity at the serotonin and dopamine transport or reuptake sites; however, the importance of this activity is unknown.

Ziprasidone is a less potent dopamine D₂ receptor blocker than serotonin blocker. Its in vitro affinity for D₂ receptors is equal to risperidone and 5-fold lower than haloperidol. It has similar affinity for D₃ receptors, an 8-fold lower affinity for D₄ receptors, and a 100-fold lower affinity for the D₁ receptors.

Ziprasidone also has moderate affinity for the alpha₁ adrenergic receptor, histamine₁ receptors, and 5-HT₆ and 5-HT₇ receptors. It has a very low affinity for alpha₂ and beta adrenergic receptors, 5-HT₃, 5-HT₄, muscarinic or nicotinic acetyl-choline, mu or sigma opiate, benzodiazepine, adenosine A₁, neurokinin-1, corticotropin releasing hormone, cholecystokinin A and B, and histamine H₂ and H₃ receptors.

Pharmacokinetics:
Peak ziprasidone levels are reached within 0.5 to 1 hour following intramuscular administration. Intramuscular bioavailability is 100%. In contrast, peak ziprasidone levels are reached approximately 6 to 8 hours after oral administration. Oral bioavailability is 59%. Ziprasidone is extensively plasma protein bound (greater than 99%). Following intramuscular administration, the mean half-life is 2 to 5 hours.

The cytochrome P450 (CYP) 3A4 isoenzyme is responsible for the primary oxidative metabolites, including the major metabolites ziprasidone sulfoxide and ziprasidone sulfone. CYP1A2 may also contribute, although overall lessthan one-third of ziprasidone's metabolic clearance is mediated by CYP 450 catalyzed oxidation. Aldehyde oxidase is the primary mediator of the oxidative reduction. Twelve metabolites have been identified, with the major metabolites being inactive.

Clinical Studies:
Most of the studies conducted with injectable ziprasidone used similar inclusion and exclusion criteria. The most common inclusion criteria were: patients with acute psychosis related to schizophrenia, schizoaffective disorder, bipolar disorder, schizophreniform disorder, delusional disorder, or brief psychotic disorder. Common exclusion criteria were acute psychosis related to substance abuse or organic origin, abnormal electrocardiogram, imminent risk of suicide or homicide, or a history of substance abuse or dependence in the previous two months.

Contraindications/Warnings/Precautions:
Ziprasidone is contraindicated in patients with a known hypersensitivity reaction to the drug or components of its formulation.

QTc prolongation may occur with ziprasidone therapy. Ziprasidone is contraindicated in patients with a known history of QT prolongation (including long QT syndrome) or a history of cardiac arrhythmias, with recent acute myocardial infarction, or with uncompensated heart failure. Because of the risk of QTc prolongation, ziprasidone should not be used with other medications that prolong the QTc interval (e.g., quinidine, dofetilide, sotalol, other Class Ia and III antiarrhythmics, mesoridazine, chlorpromazine, droperidol, pimozide, thioridazine, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, probucol, or tacrolimus). Ziprasidone is also contraindicated with other drugs that have demonstrated QT prolongation and have the effect described in their prescribing information as a contraindication or a boxed or bolded warning. Evaluation is recommended for patients experiencing symptoms suggestive of the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Ziprasidone therapy should be discontinued in patients with persistent QTc measurements greater than 500 msec.

The risk of the occurrence of torsade de pointes or sudden death in association with medications that prolong the QT interval may also be increased in the presence of hypokalemia or hypomagnesemia. Patients who are at risk for electrolyte disturbances should have baseline potassium and magnesium levels determined prior to therapy. Low serum potassium or magnesium levels should be replenished prior to initiating therapy. Serum electrolytes should be periodically monitored if diuretic therapy is introduced during ziprasidone therapy.

QTc prolongation was observed in some studies evaluating ziprasidone. At the 160 mg/day oral dose, a QTc increase of 10 msec was observed. In addition, the effects of a number of oral antipsychotics on the QT interval at peak serum concentrations have been determined. Ziprasidone produced a QTc prolongation 9 to 14 msec greater than that observed with haloperidol, olanzapine, risperidone, and quetiapine and QTc prolongation approximately 14 msec less than that observed with thioridazine. The QTc prolongation observed with ziprasidone averaged 10 to 20 msec. Co-administration of a metabolic inhibitor (ketoconazole 200 mg twice daily) with ziprasidone increased blood levels and QTc only slightly compared to the use of ziprasidone alone.

The QTc prolonging effects of intramuscular ziprasidone and haloperidol have also been compared in a single-blind study enrolling 58 subjects. At peak concentration following administration of intramuscular ziprasidone and haloperidol, QTc prolongation was observed with both agents. The mean increase in QTc from baseline for ziprasidone was 4.6 msec after the first dose and 12.8 msec following the second dose. The mean increase in QTc from baseline for haloperidol was 6 msec after the first dose and 14.7 msec after the second dose. None of the patients in either group had a QTc greater than or equal to 500 msec. As a part of Pfizer' s approval commitments for oral ziprasidone, the company agreed to perform a dose-response study for the QTc effect, a study of sudden unexpected death with ziprasidone and other atypical antipsychotics, and studies to demonstrate the possible advantages for ziprasidone.

Class labeling regarding the risk of Neuroleptic Malignant Syndrome (NMS) has been included in the ziprasidone labeling. The clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability, elevated creatinine phosphokinase, myoglobinuria, and acute renal failure. Tardive dyskinesia class labeling can also be found in the product labeling. Chronic administration of antipsychotic medications can increase the risk of developing tardive dyskinesia. Therefore, if chronic administration is necessary, the product should be used in the lowest dose possible and for the shortest duration possible. If signs and symptoms of tardive dyskinesia occur, the drug should be discontinued, if possible. However, some patients may require treatment with ziprasidone despite the presence of tardive dyskinesia.

Adverse Reactions:
The most common adverse effects associated with the use of intramuscular ziprasidone include somnolence, nausea, injection site pain, dizziness, and postural hypotension.

In studies comparing intramuscular ziprasidone and haloperidol, haloperidol therapy was associated with a much greater incidence of akathisia, extrapyramidal symptoms (EPS), dystonia, and hypertonia. Following intramuscular administration of ziprasidone in a clinical trial enrolling 79 patients, very few episodes of dystonia, akathisia, respiratory depression, or excessive sedation were observed. In another study, akathisia occurred in 1 of 63 patients treated with intramuscular ziprasidone.

An analysis of four short-term, placebo-controlled trials reported that the incidence of treatment associated EPS and akathisia for oral ziprasidone versus placebo was 4.7% and 8.4% versus 1.1% and 7%, respectively. The comparative incidence rates for EPS and akathisia for oral haloperidol were 14.1% and 28.2%, respectively.

Drug-Drug Interactions:
Ziprasidone should not be administered with any medication that prolongs the QT interval. Caution is recommended when ziprasidone is administered in combination with other centrally acting agents due to the central nervous system effects of ziprasidone. Ziprasidone may enhance the effects of some antihypertensive agents due to its potential for inducing orthostatic hypotension. Ziprasidone may also antagonize the effects of levodopa and dopamine agonists.

Ziprasidone inhibits CYP2D6, but only at concentrations much higher than are achieved therapeutically. It does not inhibit CYP3A4, CYP1A2, CYP2C9, or CYP2C19.

The protein binding of ziprasidone was not altered by warfarin or propranolol, and ziprasidone did not alter the protein binding of either agent.

Clinically important pharmacokinetic or pharmaco-dynamic interactions have not been observed when ziprasidone has been administered concomitantly with antacids, cimetidine, dextromethorphan, ethinyl estradiol and levonorgestrel containing oral contraceptives, or lithium. Pharmacokinetic interactions were not observed when ziprasidone was administered concomitantly with benztropine, lorazepam, or propranolol.

Recommended Monitoring:
Patients at risk for electrolyte disturbances should have baseline potassium and magnesium measurements. Serum potassium and magnesium monitoring is also recommended for patients starting diuretics while on ziprasidone therapy.

Dosing and Administration:
The recommended dose of ziprasidone injection is 10 to 20 mg as needed (maximum dose: 40 mg/day). The injection is only FDA-approved for intramuscular (IM) administration. Doses of 10- and 20-mg may be administered IM every 2 hours or 4 hours, respectively. Use of injectable ziprasidone for more than 3 days has not been studied. If long-term therapy is necessary, a switch to oral ziprasidone should be made as soon as possible.

An insufficient number of elderly patients and patients with either hepatic or renal dysfunction were treated in the clinical trials to provide recommendations on dosage adjustments. In patients with renal dysfunction, the cyclodextrin excipient may accumulate since it is cleared from the body by renal filtration.

Specific Product Information:
Ziprasidone for injection is reconstituted by adding 1.2 mL of Sterile Water for Injection to the vial and shaking vigorously until the entire drug is dissolved. Upon reconstitution, each mL of solution in the preservative-free, single-dose vial contains 20 mg of ziprasidone and 4.7 mg of methanesulfonic acid solubilized by 294 mg of sulfo-butylether beta-cyclodextrin sodium. It should be noted that the total quantity of ziprasidone in each reconstituted vial is 30 mg per 1.5 mL.

Prior to reconstitution, the lyophilized ziprasidone injectable should be stored at room temperature. Following reconstitution, the solution may be stored, protected from light, for up to 24 hours at room temperature or up to 7 days refrigerated.

Cost Comparison and Formulary Status: See Table 1.
Both ziprasidone oral capsules and injection are on the CCF Formulary. However, both formulations of ziprasidone are restricted to the Department of Psychiatry due to safety concerns.

Summary:
Ziprasidone is the first injectable atypical, antipsychotic medication. Injectable ziprasidone has comparable efficacy to injectable haloperidol with a lower incidence of EPS.

Ziprasidone has, however, been associated with a greater degree of QTc interval prolongation than haloperidol. Consequently, ziprasidone therapy should be avoided in patients who are predisposed to QTc interval abnormalities. Even though ziprasidone is more expensive than haloperidol, it may be a significant therapeutic alternative in patients who are sensitive to neuroleptic-induced movement disorders.