Lipitor, Zocor Pediatric Safety Surveillance Needs More Time, FDA Cmte. Says

Pediatric safety surveillance for Pfizer's Zoloft and Lipitor should continue for another year, the Anti-Infective Drugs Pediatric Advisory Subcommittee advised FDA during a June 12 meeting.

The committee recommended a similar extension for Johnson & Johnson's Ditropan and Merck's Zocor .

The committee agreed that surveillance of reports to FDA's Adverse Events Reporting System for the four drugs should continue due to a small number of event reports and relatively low use by pediatric patients.

The meeting was the first pediatric drug update as mandated by the Best Pharmaceuticals for Children Act. The Office of Drug Safety has 90 days to complete an adverse event review for the first year following pediatric approval. FDA has granted six-month exclusivity to 74 products.

"These reports do not provide any safety signals that indicate that the agency needs to do anything except continue to actively assess the evolving benefit-risk profile of these products," FDA said in a "Talk Paper" issued June 12. "Continued reporting of suspected safety concerns is critical so that new safety information can be evaluated."

The agency outlined the protocol for the reviews at the Anti-Infective Drugs Pediatric Advisory Subcommittee's March meeting and presented a review of Zoloft based on 10 months of data (¹ (Also see "Pediatric Adverse Event Analysis By FDA Will Project Incidence Rates" - Pink Sheet, 31 Mar, 2003.), p. 9). [For a ² video replay of either meeting, go to FDAAdvisoryCommittee.com.]

Pediatric Drug Development Division Medical Team Leader Solomon Iyasu, MD, presented full reports to the advisory committee on Zoloft (sertraline) and Ditropan (oxybutynin) and preliminary reports on Lipitor (atorvastatin) and Zocor (simvastatin).

The AERS database contained 54 reports for Zoloft in the year following pediatric approval, Iyasu told the committee. Forty of the events were serious, with five deaths. Two of the deaths were suicides; FDA is reviewing emotional lability data for another SSRI, GlaxoSmithKline's Paxil .

Most event reports involved multiple drug exposures in patients with confounding medical disorders, and generally were similar to those seen in adult Zoloft patients, Iyasu told the committee. There was "little to suggest" that the events were caused by Zoloft, he said.

FDA also reported a breakdown of events by Zoloft indication, the majority of which occurred when sertraline was used for off-label indications. Zoloft was approved for use in pediatric patients with obsessive/compulsive disorder Feb. 2, 2002.

The AERS database had 16 reports in Zoloft patients treated for depression; four in patients with attention deficit/hyperactivity disorder; and one each for vocal cord disorder, stress emotional problems, anxiety and adjustment disorder. Three patients with OCD reported an adverse event while on Zoloft.

The AERS pediatric database for J&J's Ditropan is much smaller, with five reports in the drug's first year following pediatric approval. All of the events were serious, with no deaths reported. Ditropan was approved for children for detrusor muscle overactivity in association with a neurological condition Feb. 8, 2002.

While a number of the reported events are not listed in the precautions or warnings sections of Ditropan labeling - such as depression and panic reaction - "the number of events are just too few and uninterpretable" to draw any conclusions, Iyasu said.

FDA also presented preliminary reports for the two statins. During the year following the start of Zocor's pediatric exclusivity Feb. 22, 2002, eight adverse events were reported to the AERS database. All the events were serious, with one death. The leading indication was treatment of hyperlipidemia.

No Lipitor adverse events were reported in the year following pediatric approval, according to FDA's preliminary report on the cholesterol-lowering agent. The leading pediatric indication during the 12-month period was hypercholestrolemia; the indication was approved for pediatric patients Feb. 22, 2002.

At FDA's request, the committee suggested ways to improve the reporting process. Committee Chair Joan Chesney, MD, University of Tennessee, recommended that the committee receive the FDA pediatric reports ahead of the meeting, as advisory committees do when considering products or indications for approval.