Ziprasidone Finally Completes FDA’s Obstacle Course

The U.S. Food and Drug Administration (FDA) gave final marketing approval last month to Pfizer Inc. for its long-awaited, novel antipsychotic medication, ziprasidone. The FDA approval came, however, with two caveats attached.

First, Pfizer will not be able to use its chosen brand name, and second, this new option for treating schizophrenia will carry significant warnings about its safety.

Ziprasidone, an atypical antipsychotic agent that is chemically unrelated to either the older phenothiazines or the other newer atypical antipsychotic agents, remained bogged down in the FDA approval process far longer than most new drugs.

The drug was submitted for approval in March 1997. Pfizer’s nearly four-year battle to win approval centered on convincing the FDA that the new drug offered sufficient enough new benefits for patients with schizophrenia to outweigh its potential for serious side effects.

At press time, Pfizer expected to have the new drug on pharmacy shelves by late March or early April. The FDA declined to approve Pfizer’s original trade name, Zeldox, because of, it said, “similarities in spelling or pronunciation which may cause confusion with the proprietary name or the established name of a different drug or ingredient.”

The FDA was concerned about similarities between Zeldox and two other medications, Zyvox, Pharmacia & Upjohn’s latest high-powered antibiotic, and Zoladex, a chemotherapeutic drug for prostate cancer made by AstraZeneca.

The FDA approved Pfizer’s request to use the trade name Geodon (pronounced gee-oh-don) instead of Zeldox.

Ziprasidone’s Efficacy

As with other atypical antipsychotics, the precise mechanism of action of the new drug is not known. Ziprasidone is, however, known to be a potent serotonin and dopamine antagonist that appears to be effective across its dose range of 20 mg to 100 mg, twice daily. The agent is also known to be a histamine H-1 antagonist as well as an adrenergic alpha-1 receptor antagonist, which may account for some of its observed side effects.

According to the FDA’s approval documents for ziprasidone, the agency never questioned the drug’s efficacy in treating both the positive and negative symptoms of schizophrenia. A series of clinical trials involving more than 4,500 inpatients with schizophrenia established the efficacy of ziprasidone in improving visual and auditory hallucinations, delusions, lack of motivation, and social withdrawal.

Ziprasidone’s clinical trials are the largest ever conducted to win approval of an antipsychotic medication. However, the FDA noted in 1998 that there was no evidence “of any superior antipsychotic efficacy for ziprasidone compared with any other antipsychotic drugs, either in typical schizophrenic patients or in those shown refractory to standard antipsychotic therapy.”

Pfizer conducted both short-term (four weeks and six weeks) and long-term (one year) studies of the new drug’s efficacy. Four out of Pfizer’s five studies documented significant improvements as measured by the Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale, as well as the Clinical Global Impression and the Scale for Assessing Negative Symptoms, both in the short-term and year-long studies.

One four-week study failed to distinguish ziprasidone from placebo.

In the clinical trials, no age, gender, or race effects were noted for the new drug.

No studies have been completed in children despite 1999 FDA regulations requiring all applications for new active ingredients, new dosage forms, new indications, or new dosage regimens to contain an assessment of the safety and effectiveness of the product in pediatric patients. The FDA, in its approval letter for ziprasidone, granted a waiver of the pediatric requirement pending the collection and review of additional safety data.

Both the number of premarket studies and the number of patients followed on ziprasidone are unusually large, according to the Pharmaceutical Research and Manufacturers of America. The FDA has frequently approved new drug applications in the last several years with only two or three studies documenting a significant effect distinguishable from placebo, and with far fewer total number of patients studied.

Concerns for Safety

As with any of the antipsychotic medications, the side-effect profile for ziprasidone is significant and was the reason for the four-year review by the FDA. The initial 1997 application for approval was denied by the FDA the following summer, based on the agency’s “judgment that ziprasidone prolongs the QTc [interval] and that this represents a risk of potentially fatal ventricular arrhythmias that is not outweighed by a demonstrated and sufficient advantage of ziprasidone over already marketed antipsychotic drug products.”

According to the FDA’s “not approvable” letter, dated June 17, 1998, the agency was concerned that ziprasidone lengthened a particular period of the cardiac cycle during which the heart is resetting its electrolytes, sodium, potassium, and calcium, making it more vulnerable to rhythm disturbances.

The effect is common to antipsychotic medications; however, the delay seen in clinical trials was longer for ziprasidone than other currently marketed antipsychotic agents. The FDA acknowledged that although the theory is certainly sound, to date there are no data to link the prolonged QTc interval caused by antipsychotic medications, including ziprasidone, to an increase in morbidity or mortality.

Pfizer responded by conducting further clinical trials, pitting ziprasidone against haloperidol, olanzapine, risperidone, and quetiapine. The cardiac effects of each of the drugs were measured and monitored at optimum doses. Each drug was then compared with thioridazine, the older antipsychotic known to exhibit the strongest effect on the QTc interval and now designated by FDA as a second-line drug due to its strong potential for cardiac arrhythmias (Psychiatric News, August 18, 2000).

The study revealed that the prolonging effect on the QTc interval for ziprasidone was indeed longer than the four comparison atypical antipsychotics, but was much shorter than that seen with thioridazine. As a result, the approved labeling of ziprasidone includes extensive language warning of the theoretical potential for the drug to cause cardiac arrhythmias. In fact, the “Indications” section includes the wording, “When deciding among the alternative treatments available for this condition [schizophrenia], the prescriber should consider the finding of ziprasidone’s greater capacity to prolong the QT/QTc interval compared with several other antipsychotic drugs.”

Side-Effect Profile

In addition to prolonging the QTc interval, ziprasidone exhibits other potential side effects common to antipsychotic agents. In clinical trials, the most commonly reported treatment-emergent adverse events were somnolence (14 percent), extrapyramidal syndrome (5 percent), and “respiratory disorder”—described as “cold symptoms and upper respiratory infection”—(5 percent). Other reported side effects include nausea, dry mouth, constipation, and dyspepsia.

Absent from the side-effect profile for ziprasidone is a tendency for the drug to cause weight gain. In fact, the drug appears to be “weight neutral,” according to Pfizer’s FDA application. This is significantly different from its fellow antipsychotics’ tendency to induce often significant gains in a patient’s weight. Weight gain has long been considered a barrier to patient compliance with antipsychotic medications.

In approving ziprasidone, the FDA has required Pfizer to complete postmarketing clinical studies including a dose response study for the drug’s effect on the QTc interval, a study of sudden unexpected death with ziprasidone and other atypical antipsychotics, and further studies to demonstrate possible advantages for ziprasidone over other currently marketed antipsychotic medications.

The FDA’s approval documents for ziprasidone, including approved labeling, are available at www.fda.gov/cder/approvals/index.htm by clicking on the letter “Z” and scrolling down to ziprasidone. ▪