Drugs with pediatric exclusivity: panel urges additional adverse drug reporting.

GAITHERSBURG, MD. -- The Food and Drug Administration should require an additional year of pediatric adverse event reporting on three drugs that received pediatric exclusivity in 2002, the FDA's pediatric subcommittee of the Anti-Infective Drugs Advisory Committee agreed.

The additional time is necessary because of the small number of pediatric adverse events reported in conjunction with the use of oxybutynin (Ditropan) for treatment of overactive bladder, atorvastatin (Lipitor) for lowering cholesterol, and simvastatin (Zocor) for lowering cholesterol.

The five adverse pediatric events associated with oxybutynin included psychiatric reactions (depression, hallucination, aggression, panic, and anger), acidosis, osmolality decrease, and bladder disorder.

Those events occurred in patients aged 2-11 years old, said Dr. Solomon lyasu of the FDA's Center for Drug Evaluation and Research in Rockville, Md.

Depression, panic, abnormal behavior, acidosis, anxiety, bladder disorder, and osmolality decrease are not noted on the label as possible adverse events, Dr. Iyasu said.

The psychiatric events were primarily reported from patients with possible underlying psychiatric disorders.

The other adverse events occurred in children who were on multiple drugs, including Paxil (paroxetine), or were related to overdose, he noted.

None of the four pediatric adverse events reported with simvastatin occurred in the United States, and none could be solely attributed to the drug. Two were in utero exposures and two occurred in patients taking multiple medications.

In addition, Dr. Iyasu presented 1-year postpediatric exclusivity safety data for sertraline (Zoloft) approved for pediatric obsessive-compulsive disorder; in adults it is approved for depression, posttraumatic stress disorder, social anxiety disorder, and panic disorder.

There were 53 pediatric adverse events--including four deaths--in 49 children. Most of the events involved the use of more than one drug and could have been confounded by underlying medical disorders, Dr. Iyasu said.

It is also important to point out that none of the pediatric deaths could be directly tied to the use of sertraline alone.

One of the deaths occurred in a school-aged child who also had been taking amitriptyline and clonidine.

Autopsy results indicated death attributable to chronic multiple drug toxicity.

Another death occurred in a premature infant delivered of an HIV-positive mother who had taken sertraline for depression during the last trimester.

Two suicides occurred among adolescent patients. One child committed suicide after a 1-week trial of sertraline. But that child had remained significantly depressed during therapy and had been previously considered a suicide risk.

The second suicide occurred in an adolescent with no history of depression who had taken the drug intermittently over a 10-day period without a prescription.

Investigators concluded the suicide was related to drug abuse. But they were not able to determine whether the use of sertraline was causally related.

The adverse events also included 13 psychiatric events, 10 neurologic events, and 13 perinatal events. The perinatal events included four congential malformations, four infants with possible neonatal with drawal syndrome, two with developmental abnormalities, and two premature births.

More adverse events probably occur each year than are reported, Dr. Iyasu noted. "Adverse event reporting is a spontaneous, voluntary system, so underreporting is possible. They are soft data, but [they are] the best data we have."

Mid-Atlantic Bureau