However, the FDA gave several examples from adverse event reports of children with high blood levels of tacrolimus or pimecrolimus after the therapies were greatly reduced or halted. “The most significant case was that of an 8-month-old male who developed eczema herpeticum with Pseudomonas sepsis and subsequent cardiac arrest. Protopic ointment was applied over his entire body for 6 months. The serum tacrolimus level was 3.5 ng/mL 2 weeks after Protopic had been discontinued. The patient survived,” Dr. Temeck said.
The manufacturers maintain that no causal relationship has been proved between the ointments and malignancies; a position echoed in FDA documents.
Latency was another concern among the panel members, and they debated the possibility of serious adverse events developing several years after discontinued use. “If we are going to be observing lymphomas in this patient population, it's not going to be a spurt of B-cell lymphomas … there's going to be a longer period of observation that we need in order to conclusively say that we are going to see an increased incidence trait,” said Victor Santana, M.D., of the department of hematology/oncology at St. Jude Children's Research Hospital, Memphis. He also claimed the preclinical data were more convincing of causality.
Dr. Epps expressed further concern that health care providers without dermatologic experience may not provide adequate follow-up care for patients who have used the topical treatments, and that “many don't necessarily know what they're treating.” Specifically, there are skin syndromes for which pimecrolimus and tacrolimus should not be used. They include molluscum, ataxia-telangiectasia, syndromes with eczema, or those that already carry an increased risk of infection or malignancies.
One dissenting panel member said that a black box warning would exert an unnecessary burden on patients and consumers. “The human data presented don't convince me there's a clear risk … The data have not been collected for a sufficient length of time, but I'm weighing that against the argument that it could cause a lot of grief in the parents of the people who have to take these medications. That potential level of grief is unwarranted given the data,” said Dennis Bier, M.D., professor of pediatrics, Baylor College of Medicine, Houston.