Cardiovascular, other safety data raise panel's concerns on sertindole.

SILVER SPRING, MD. -- The majority of a federal advisory panel agreed that sertindole, an oral atypical antipsychotic, has not been shown to be adequately safe as a first-line treatment of schizophrenia, but more than half of the panel agreed that it could be safe enough to use in some patients.

The Psychopharmacologic Drugs Advisory Committee voted 13-0 in early April that sertindole was effective in treating schizophrenia, citing study results that clearly showed the drug's efficacy. But because of continuing uncertainty and concerns surrounding the main safety issue associated with the drug--QT prolongation and the potential for an increased risk of sudden death--the panel voted 12-1 that sertindole had not been shown to be "acceptably safe" as a broad treatment of schizophrenia. The data are not definitive, but the panel agreed that the safety data on cardiovascular risk were strong enough to warrant a vote of no.

However, eight panel members, including the psychiatrists and one of the two cardiologists on the panel, voted that they believed the drug could be used in an "acceptably safe" manner in some groups of patients with schizophrenia. Several panelists said they agreed with Dr. Daniel Pine of the mood and anxiety disorders program at the National Institute of Mental Health, Bethesda, Md., who said the main reason he voted in favor on this question "is the refractory nature of the condition ... and the need for more treatments," and the variability in how patients respond to different drugs.

The manufacturer of sertindole, Lundbeck USA, has also filed for approval of a suicidality claim for the drug. But the panel voted 12-1 that sertindole had not been shown to be effective in treating suicidal behavior associated with schizophrenia. Although there was some evidence suggesting treatment reduced suicidal behavior in a trial that compared sertindole to risperidone, the data were not sufficient to support such a claim, several panelists said. Currently, clozapine (Clozaril) is the only antipsychotic approved with a claim that it can reduce suicidality.

The panel was not asked specifically to vote on whether the drug should be approved.

Sertindole was first considered for approval at the FDA in the late 1990s, but the application was withdrawn in 1998 after concerns that the QTc prolongation associated with the drug was behind the increase in sudden deaths in patients on the drug in Europe, where sertindole was first approved in 1996. But marketing in Europe was suspended in 1999, after postmarketing data raised the concern about an increased risk of fatal arrhythmias associated with the QTc prolonging effects of the drug.

Sertindole was relaunched in Europe in 2006, after the manufacturer had provided enough data to reassure regulators about this risk. This included the Sertindole Cohort Prospective (SCoP) study, which addressed whether the drug's potential to prolong the QTc interval could be associated with a greater risk of sudden death.

At the meeting, Dr. Philip Kronstein, a medical reviewer in the FDA's division of psychiatry products, said that in the SCoP study, there were more cases of sudden cardiac death (which was not a pre-specified secondary end point), among sertindole-treated patients (13), compared with those on risperidone (3), which reflected a five-fold greater risk of sudden cardiac death associated with sertin-dole. There was one case of confirmed and one case of possible Torsades de Pointes (TdP) in sertin-dole-treated patients, and none in risperidone patients; the confirmed case was in a 79-year-old woman, who was not on other medications that could have increased this risk, and who died a few days after TdP was detected, he said.

Sertindole is approved in 46 countries in Europe, Asia, and Latin America. The FDA, which usually follows the advice of its advisory panels, is expected to make a decision by May 15. If approved, Lundbeck will market sertindole in the United States as Serdolect.