Atypical Antipsychotics To Add Warning About Metabolic Effects In Kids

FDA likely will move metabolic information to the warning section in labeling for all atypical antipsychotics, according to Division of Psychiatry Products Director Thomas Laughren.

The agency is conducting a comprehensive assessment of metabolic data for all the atypical antipsychotics and will update labeling for individual drugs as the reviews are completed, he told the Pediatric Advisory Committee Dec. 8. Sponsors were asked to submit all pediatric metabolic data in a certain format, broken down in certain ways, to facilitate agency analyses.

"As we get our metabolic reviews ... probably all of this information is eventually, for all of these drugs, going to end up in the warning section," Laughren said.

Metabolic side effects - ranging from lipid abnormalities to diabetes to weight gain - are a recognized complication of atypicals in the adult population. For the past year, FDA has been evaluating the impact when the drugs are used in pediatric populations and the advisory committee reviewed the findings during its Dec. 8 review of pediatric adverse events for 13 medications (¹ (Also see "Safety Review Of Antipsychotics Finds Reasons For More Evaluation In Pediatric Patients" - Pink Sheet, 4 Dec, 2009.)).

FDA expects to wrap up the project in the next year or so, Laughren said following the meeting. Data evaluation for the atypicals is being conducted in parallel, but the data were submitted at different times so they will not be completed at the same time.

Additional labeling changes should be forthcoming for atypical antipsychotics including Merck's Saphris (asenapine), Vanda's Fanapt (iloperidone), Pfizer's Geodon (ziprasidone), Johnson & Johnson's collection - Invega (paliperidone), long-acting Invega Sustenna , Risperdal (risperidone, also available as a generic) and long-acting Risperdal Consta - and generic clozapine.

Additions to the warning section already are incorporated in labeling that accompanied FDA's approval of pediatric indications for Lilly's Zyprexa (olanzapine) on Dec. 4 and AstraZeneca's Seroquel (quetiapine) on Dec. 2, Laughren pointed out. Pfizer received a "complete response" letter Oct. 30 seeking additional study information for the Geodon sNDA for pediatric indications.

The scope of the safety update that went along with the pediatric approvals was not limited to the metabolic warning. A wealth of new risk information on pediatric patients has been added to the Seroquel label, Laughren said. The Zyprexa label required fewer revisions since it already contained a good bit of this information.

Abilify Label Inadequate On Kids' Weight Gain

Bristol-Myers Squibb and Otsuka may have to revise the warning recently added for Abilify (aripiprazole). A warning about hyperglycemia and diabetes mellitus is part of labeling that accompanies an indication approved in November to treat irritability in pediatric patients (6-17 years) with autism (² (Also see "BMS' Abilify Gains Third Pediatric Indication: Autism-Related Irritability" - Pink Sheet, 23 Nov, 2009.)).

But the warning section does not mention weight gain. This prompted the advisory panel to conclude unanimously that the label does not "adequately reflect the pediatric risk of excessive weight gain."

The labeling changes need to be "more than just moving information," Geoffrey Rosenthal, University of Maryland, contended, calling for the addition of information from more recent studies.

Supporting the placement of weight gain in the precautions section, Benedetto Vitiello, National Institute of Mental Health, noted that weight gain is one of the first signals clinicians should look at as they monitor their patients. General practitioners and pediatricians need guidance on monitoring for weight gain, Aziza Shad, Georgetown University, added.

Avital Cnaan, Children's National Medical Center, suggested including specifics on the long-term potential for weight gain in children. Give prescribers a "sense of how bad it could get," she urged.

While it is likely that the metabolic information for Abilify will be moved to the warning section, Laughren told the committee, the warning probably will point out that "the metabolic signal for aripiprazole is quite modest in terms of weight gain."

Another addition to the labeling, he said, will be a finding from the data review that higher doses of Abilify result in higher weight gain.

- Cathy Dombrowski ( ³ [email protected])