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Ziprasidone Hydrochloride Approved for Treatment of Schizophrenia, But With Major Warning

Cheryl A. Thompson

Pfizer has received approval to market the oral formulation of ziprasidone (Geodon [PDF]), an antipsychotic agent, for the treatment of schizophrenia. The labeling for the product includes 10 paragraphs of boldface type warning about ziprasidone's tendency to prolong the QTc interval of the electrocardiogram more than most other drugs available for treating schizophrenia.

Ziprasidone's efficacy in treating an acute exacerbation of schizophrenia was assessed in four short-term, randomized, placebo-controlled studies involving two or three dosages of the drug and 1060 inpatients, most of whom met the criteria for the disorder in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition—Revised. Patients in these four- or six-week studies received 20, 40, 60, 80, or 100 mg of ziprasidone twice daily, without dosage increases, or placebo. The lower dosages—20, 40, and 60 mg twice daily—improved patients' symptoms, but not consistently, according to scores on the Brief Psychiatric Rating Scale (total and psychosis cluster), Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions—Severity of Illness scale, and Scale for Assessment of Negative Symptoms (SANS). Higher dosages, tested in one study apiece, improved patients' scores on the four rating scales used; evaluations did not include the SANS.

The ability of ziprasidone to delay the onset or rate of relapse in stable inpatients with chronic schizophrenia was assessed in a 52-week, randomized, placebo-controlled study. Patients who received ziprasidone 20, 40, or 80 mg twice daily fared better than those assigned to placebo, according to scores on the Clinical Global Impressions—Global Improvement scale and the PANSS items for hostility and uncooperativeness.

During a study on the electrocardiographic effects of various drugs used to treat schizophrenia, ziprasidone increased the QTc interval by an average of 9–14 msec more than did risperidone, olanzapine, quetiapine, and haloperidol but about 14 msec less than did thioridazine. At a dosage of 80 mg twice daily, ziprasidone increased the QTc interval by about 10 msec more than placebo.

According to the labeling, no patient who received ziprasidone at a dosage recommended by the company had drug-related torsade de pointes during the premarketing studies. The labeling acknowledges, however, "the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia." Ziprasidone therapy is contraindicated for patients with a history of QT prolongation, recent acute myocardial infarction, or uncompensated heart failure. The drug should not be taken with medications that prolong the QT interval.

Pfizer has told FDA that the company will study the influence of ziprasidone dosage on the QTc interval and the occurrence of sudden unexpected deaths related to the use of atypical antipsychotics. The company will also study whether ziprasidone offers an advantage over other agents for the treatment of schizophrenia.

As during therapy with other antipsychotic agents, the administration of ziprasidone may be associated with the occurrence of neuroleptic malignant syndrome or tardive dyskinesia. The adverse drug reactions most commonly reported during the short-term placebo-controlled studies were somnolence (14%), respiratory disorder (8%), and extrapyramidal syndrome (5%).

After oral administration, ziprasidone is extensively metabolized by aldehyde oxidase and the cytochrome P-450 enzyme system. Food increases the absorption of ziprasidone by up to 100%. More than 99% of the drug circulating in the bloodstream is bound to plasma proteins, primarily albumin and alpha1-acid glycoprotein; studies in vitro, however, indicated that ziprasidone and warfarin do not alter each other's binding to plasma proteins. A steady-state concentration of the drug is reached within three days of starting a dosage regimen.

Ziprasidone therapy should be begun at a dosage of 20 mg twice daily, taken with food. The regimen can be adjusted as often as every two days, but the labeling advises clinicians to observe patients for several weeks before increasing the dosage. Although a dosage of 100 mg twice daily was used in one study, the recommended maximum under most circumstances is 80 mg twice daily.

Geodon is supplied as capsules in four strengths: 20 mg (blue and white), 40 mg (blue), 60 mg (white), and 80 mg (blue and white). Each 60-capsule package includes a patient package insert.

An injectable formulation, ziprasidone mesylate, is under review by FDA.