GAITHERSBURG, MD. - The Food and Drug Administration's Arthritis Advisory Committee's nearly unanimous support for approving celecoxib for juvenile rheumatoid arthritis in a vote last month may alleviate some of the need for child-friendly drug formulations and add another JRA treatment option.
“We need the advantages an additional formulation will give,” and the advantages of having a different medication which is different from naproxen (Naprosyn) and is a selective cyclooxygenase-2 (COX-2) inhibitor “for at least the potential benefits on bleeding, bruising, and hoped for decrease in GI toxicity,” said Dr. Thomas Lehman, chief of pediatric rheumatology at the Hospital for Special Surgery, New York. He pointed out that noncompliance with medication is one of the most difficult issues in pediatric rheumatology.
He added that many children will respond to one NSAID after not responding to another, and that in his own practice, he said it was “very common” to try two or three different NSAIDs, “looking for a good effect and tolerance” before a more potentially toxic drug is considered, unless the child has obvious aggressive disease.
At the Nov. 29 meeting, the federal advisory panel agreed in a 15–1 vote that the risk-benefit ratio of celecoxib was “adequate” to support its approval for treating JRA.
All panelists agreed that the available data showed the COX-2 selective NSAID was effective for this indication, based on a 3-month randomized, double-blind study comparing naproxen (15 mg/kg daily) with celecoxib (6 mg/kg or 12 mg/kg daily). The study included 242 children and adolescents aged 2–16 years with JRA.
The FDA usually follows the recommendations of its advisory panels.
Celecoxib, marketed as Celebrex by Pfizer, was approved for treating osteoarthritis and RA in adults in 1998. Celecoxib remained available after rofecoxib (Vioxx), which was approved for JRA, was taken off the market in 2004 because of an increased cardiovascular risk seen in a large study. An elevated cardiovascular risk was seen in one of three long-term trials comparing celecoxib with placebo, but it remained on the market with the addition of a boxed warning about the possible increase in serious cardiovascular events.
At the committee meeting for pediatric approval, the panelists' vote on safety was split. All panelists were concerned about the absence of long-term safety data of celecoxib in this population. They strongly recommended that the FDA tie approval to a commitment on the part of Pfizer to use a registry study to follow long-term safety issues, including GI, renal, and cardiovascular safety. They agreed that Pfizer's plan to vigorously investigate spontaneous adverse event reports of celecoxib in children and adolescents was inadequate.
Panelist member Dr. Margaret O'Neil, a pediatric rheumatologist at the University of Oklahoma, Oklahoma City, said that “switching from drug A to drug B may be the magic bullet,” so having more options makes it possible to try another drug before proceeding to drugs that are potentially more toxic.
If approved, the oral suspension used in the trial would not be the formulation marketed because of problems producing it on a large scale, so Pfizer has plans to develop a capsule containing a sprinkle formulation that can be added on top of foods such as apple sauce.
The pediatric study of patients with polyarticular and pauciarticular RA was designed to show that celecoxib was not inferior to naproxen. At 12 weeks, both doses of celecoxib studied were considered as effective as naproxen in terms of the ACR Pediatric 30 responses, which ranged from about 70% to 80% in all three treatment groups. Patients on celecoxib had more abdominal pain and headaches, but overall, common adverse events were similar in patients on either drug, and the safety profile was similar to those known for NSAIDs, according to Pfizer.
The efficacy response to celecoxib was sustained throughout the 12-week open-label study of almost 200 of the study participants, including 70 naproxen-treated patients who switched to celecoxib, and no new safety issues were identified.
Speaking for the American College of Rheumatology during the open public hearing, Dr. Balu Athreya, past executive chair of the ACR's pediatric arthritis committee, said that 22 NSAIDs are approved for RA, 5 of which are approved for JRA. Most require dosing 2–4 times a day, he said, noting that pediatric rheumatologists need additional options, with medications that have dosing and safety profiles that are practical for children.
Surveys of pediatric rheumatologists presented at the meeting showed that the available adult formulation of celecoxib is being used off label for JRA.