Do Not Use! Ziprasidone (GEODON)—A New, More Dangerous, Less Effective Antipsychotic Drug

The Food and Drug Administration’s (FDA) approval last February of ziprasidone (GEODON) for the treatment of schizophrenia is another example of the agency’s weakening by corporate influence and the inadequacy of our 40-year-old legal standard for drug approval that allows new products on the market that are less safe or less effective than drugs already approved for the same uses. Zip-rasidone was previously known as ZELDOX before its brand name was changed to GEODON. Ziprasidone is produced by Pfizer Inc. of New York.

Pfizer submitted a New Drug Application (NDA) to the FDA for ziprasidone on March 18, 1998 . Three months later, on June 17, 1998, the agency sent the company a not-approvable letter based on “… the judgment that ziprasidone prolongs the QTc and that this represents a risk of potentially fatal ventricular arrhythmias [heart rhythm disturbances] that is not outweighed by a demonstrated and sufficient advantage of ziprasidone over already marketed antipsychotic drug products."

The QTc interval is the length of time it takes the ventricles (large chambers of the heart) to discharge and recharge electrically. A prolongation of the QTc interval can lead to heart rhythm disturbances, or cardiac arrhythmias, such as torsade de pointes and other life-threatening arrhythmias. The QTc interval is measured by an electrocardiogram (EKG or ECG) in milliseconds (msec). The subscript “c” indicates that the QT interval has been corrected for the patient’s heart rate. Torsade de pointes is a French phrase that means “twisted point” that describes the appearance of this type of rhythm disturbance on the EKG tracing.

The complete text of the QTc interval warning as it appears in the professional product labeling or “package insert” for ziprasidone appears below.

A major concern expressed by the FDA in its  June 17, 1998 not-approvable letter to Pfizer was that the degree of QTc prolongation observed with ziprasidone may have represented an underestimate in view of the likelihood that most ECGs were obtained when the blood levels of the drug were the lowest. The FDA recommended that Pfizer conduct another study to determine the QTc effect of ziprasidone when the drug’s blood levels were the highest in comparison to other new medications called “atypical antipsychotics” and with several other standard antipsychotic drugs.

Pfizer complied with the FDA’s recommendation for additional study and conducted a direct comparison of ziprasidone at its optimal dose to haloperidol (HALDOL), olanzapine (ZYPREXA), quetiapine (SEROQUEL), risperidone (RISPERDAL), and thioridazine (MELLARIL) with ECGs obtained when the blood levels of these drugs were at their highest.

The study involved 183 patients with psychotic disorders and normal ECGs. Following a screening phase, the study consisted of five different treatment periods:

(1) patients who were eligible for the study had their current drugs stopped over a period of several days as out-patients; (2) the patients were then admitted to a research facility where they were completely withdrawn from their current drugs; (3) the patients were then randomly assigned to one of the six study drugs (ziprasidone, risperidone, olanzapine, quetiapine, thioridazine or haloperidol) with doses increased over 10 to 19 days; (4) after the maximum dose of the study drugs was reached, a potentially interacting drug selected for each study drug was given to the patients; and (5) after the blood levels of the study drugs were stabilized with the combination of the study drug and interacting drug, the patients were withdrawn from treatment. Baseline ECGs were obtained. Additional ECGs were obtained on day 2 of the study, when the blood levels of study drugs were stabilized, and with the potentially interacting drugs. The ECGs were recorded at times estimated to correspond with the maximum blood levels of the study drugs.

The table below summarizes the average change in QTc interval for the six study drugs and the range when the blood levels for the drugs were stabilized and their concentrations were estimated to be at their highest. Thioridazine clearly had the largest effect in lengthening the QTc interval, followed by ziprasidone.

In the September 2000 issue of Worst Pills, Best Pills News we listed thioridazine as a Do Not Use drug after a black boxed warning was required in its professional product labeling alerting physicians and pharmacists to the drug’s ability to prolong QTc interval and the possibility of fatal heart rhythm disturbances.

The experience with thioridazine and another antipsychotic drug, sertindole (SERLECT), places ziprasidone’s effect on QTc interval prolongation in some perspective. Sertindole was recommended for approval by an FDA advisory committee and approved on October 2, 1996, but  the drug was never marketed in this country. Before sertindole’s approval it was known to increase QTc by about 21 milliseconds, a duration similar to that of ziprasidone. However, sertindole was marketed in the United Kingdom but was withdrawn on December 2, 1998 following reports of cardiac arrhythmias and sudden death associated with its use. The European Commission reached a decision on February 25, 2000 on a European wide suspension of the marketing authorization of sertindole.

Ziprasidone’s Effectiveness Compared to Haloperidol’s

Pfizer presented the results of five clinical trials to the FDA in support of ziprasidone’s approval. Four of these tested the effect of the drug in the management of the acute symptoms of schizophrenia. The studies lasted four to six weeks and involved 702 patients who received ziprasidone in doses ranging from 10 milligrams to 200 milligrams, along with 273 patients who received a placebo. One trial included 85 patients who were treated with the old and relatively inexpensive antipsychotic drug haloperidol in a fixed dose of 15 milligrams.

Various rating scales were used to test the efficacy of ziprasidone. A brief description of these scales can be found in the table below. In general, the standard for showing that a drug has a treatment effect (efficacy) is that the average scores on the rating scales improve and that the difference between the averages for those patients receiving ziprasidone, for example, are statistically different from the group of patients receiving the inactive placebo. Overall, Pfizer found that ziprasidone treatment was statistically superior to no treatment at all.

In the single trial in which ziprasidone was compared to 15 milligrams of haloperidol, Pfizer estimated that the treatment effect for haloperidol was greater on the four rating scales used in the study compared to all dosages of ziprasidone tested. Pfizer did not determine whether the difference between the drugs was statistically significant and did not provide sufficient information for us to make this determination.

Inexplicably, the FDA allowed Pfizer to downplay ziprasidone’s unflattering performance compared to haloperidol in the treatment of acute schizophrenia in the drug’s approved product labeling. In the Clinical Trials Section of the labeling, reference is made to the study comparing ziprasidone to haloperidol:

Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three short-term trials, this single study was inadequate to provide a reliable and valid comparison of ziprasidone and haloperidol.

It was grossly unethical of Pfizer not to disclose in much greater detail the results of the ziprasidone-haloperidol comparison in ziprasidone’s labeling and it was irresponsible of the FDA to allow this lapse to go unchallenged by approving this inadequate labeling. We doubt that the results of this study will ever see the light of day in a peer-reviewed medical journal. We also doubt that those unselfish patients who risked themselves by volunteering for clinical trials would have done so if they had known that if the results of the trial they participated in were not favorable to the potential profitability of a new drug being tested the results would withheld from public view.

Pfizer has promoted ziprasidone as being “weight neutral” in a July 19, 2000 press release announcing the FDA advisory committee’s recommendation to approve the drug. QTc interval prolongation was mentioned but no explanation was provided as to its potentially serious consequences. Manufacturers make it a point to minimize potential adverse effects. It remains to be seen if this difference in weight gain claimed by Pfizer will persist between ziprasidone and other antipsychotic drugs when the drug is prescribed to large numbers of patients outside of a controlled experimental setting.

In the FDA's February 2, 2001 letter to Pfizer approving ziprasidone, it was revealed that the company had committed to additional safety and efficacy studies after the drug was marketed. These are: 1) a study to determine if increasing doses of ziprasidone proportionally increase QTc prolongation; 2) a study of sudden unexpected death with ziprasidone and other newer or atypical antipsychotics; and 3) studies to demonstrate possible advantages for ziprasidone.

In our view, given the potential dangers of ziprasidone and its apparent therapeutic inferiority to haloperidol, the postmarketing studies that Pfizer undertook to do should have been required before the drug was approved.

Patients with severe mental illness do not need more new drugs; they need better ones. Until Congress raises the drug approval “bar,” the American public can expect more new drugs like ziprasidone.

What You Can Do

Patients with severe mental illness and family members who are responsible for their care must consider very carefully, along with the attending psychiatrist, whether at this time the risks of ziprasidone outweigh any known therapeutic benefit over older antipsychotic drugs.