Ziprasidone Mesylate Injection
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.
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.
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.
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.
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.
Dosing and Administration:
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:
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.
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.