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Weekly UpdatesADELPHI, M D. -- The approval of quetiapine and olanzapine for schizophrenia and bipolar mania, and ziprasidone for bipolar mania in pediatric patients is likely--now that most members of a Food and Drug Administration advisory panel have agreed that they were safe and effective for the proposed indications.
At the end of a 2-day meeting last month, the FDA's Psychopharmacologic Drugs Advisory Committee voted separately on the three drugs and their proposed indications. based on the short-term data presented by the three manufacturers: Astra Zeneca Pharmaceuticals LP, which markets quetiapine as Seroquel; Pfizer, which markets ziprasidone as Geodon; and Eli Lilly, which markets olanzapine as Zyprexa.
All three are approved for treating schizophrenia and bipolar disorder in adults, for acute and maintenance treatment. The only atypicals approved previously for treating schizophrenia and bipolar disorder for pediatric populations are aripiprazole (Abilify) and risperidone (Risperdal). However, all the atypicals are used off-label for psychiatric indications in children and adolescents, and information about pediatric use is included on their labels.
The advisory panel was not asked specifically to rule on whether to recommend approval of the drugs, but voted instead on safety and efficacy. The number of abstentions was unusually high, particularly for ziprasidone. After the meeting, Dr. Thomas Laughren, director of the FDA's division of psychiatry products, said this might have been a reflection in part of the diversity of the committee, which included experts in cardiology and endocrinology, and members of the pediatric advisory committee.
Among the panelists, "there was appropriate concern about the incidence of significant side effects with each of these medications, and a general acknowledgment that we don't have sufficient data regarding the safety or efficacy associated with long-term or ongoing use," Dr. David Fassler, a child and adolescent psychiatrist in Burlington, Vt., said in an interview after the meeting.
But the results of the clinical trials met the established criteria for efficacy for short-term use, and there was also "widespread agreement that schizophrenia and bipolar disorder are very real illnesses which do affect children and adolescents, and the committee felt that despite the known risks, these medications should be available as treatment options for children and adolescents with schizophrenia or bipolar disorder," added Dr. Fassler, also a clinical professor of psychiatry at the University of Vermont, Burlington.
He testified on behalf of the American Psychiatric Association during the open public hearing portion of the meeting.
In his testimony, Dr. Fassler recommended that the FDA require manufacturers to conduct postmarketing studies to address the long-term safety and efficacy of these drugs, referred to the need for more studies that directly compare the different medications, and called for a moratorium on direct-to-consumer advertising of the products for the pediatric indications if approved.
The votes were as follows:
* The panel voted 17-1 that data on quetiapine showed it was effective for treating schizophrenia in adolescents aged 13-17 years, and 16-0, with 2 abstentions, that the drug was "acceptably safe" for treating schizophrenia in this population. The panel also voted 17- 0, with 1 abstention, that quetiapine was effective in treating bipolar mania in children and adolescents aged 10-17 years, and voted 13-0, with 5 abstentions, that it was safe in this group. A concern among those abstaining was safety in children aged 10-12.
* The panel voted 12-2, with 4 abstentions, that ziprasidone was shown to be effective for the treatment of manic or mixed episodes associated with bipolar disorder in patients aged 10-17 years. However, the panel voted 8-1, with 9 abstentions, that the data had shown the drug was acceptably safe in treating this population. Among the reasons the nine panelists cited for abstaining was that a large number of patients had been lost to follow-up in the study.
* The panel voted 11-5, with 2 abstentions, that olanzapine had been shown to be effective as a treatment for schizophrenia in patients aged 13-17, with the majority--10 panelists--voting that it had been shown to be "acceptably safe" for this indication.
However, four panelists voted no on the safety question and four abstained, citing concerns that included the well-known metabolic effects of olanzapine. The panel also voted 17-0, with 1 abstention, that the drug had been shown to be effective for treating bipolar mania for the same age group, and voted 11-4, with 3 abstentions, that it had been shown to be acceptably safe in this age group for this indication.
Those voting in the affirmative on safety and efficacy for both indications said they considered the drug as a second-line treatment, because of its metabolic effects. If approved, the olanzapine label would advise clinicians to consider drugs before this one, because of concerns about its metabolic effects, Dr. Laughren told the panel.
The FDA usually follows the recommendations of its advisory panels.
During the deliberations, the endocrinologist on the panel, Dr. Frank Greenway, of the Pennington Biomedical Research Center, Baton Rouge, La., said the beneficial effects of the drugs balanced against the metabolic effects were "a reasonable trade-off."
One of the panelists, Dr. Kenneth Towbin, chief of clinical child and adolescent psychiatry in the mood and anxiety disorders program at the National Institute of Mental Health, Bethesda Md., said he was concerned about a "slippery slope," where the approval of these drugs for 10- to 17-year-old children and adolescents would increase the use of these drugs for children as young as ages 2 through 6.
The labels of these drugs should include information pointing out the absence of data showing they are effective in very young children, he advised. Noting that bipolar mania is an episodic condition, he also recommended that labeling include some information about distinguishing bipolar disorder from other mood dysregulation disorders in pediatric patients.
One panelist expressed concern about a 'slippery slope,' where the approval of these drugs for 10- to 17-year-olds would increase their use for children as young as 2 through 6.
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