Black box warning recommended for asthma drug

August 2005

Novartis’ long-acting beta₂-agonist Foradil should include a black box warning because life-threatening events seen with GlaxoSmithKline’s Serevent might be seen across the entire class of drugs, according to the FDA’s Pulmonary-Allergy Drugs Advisory Committee.

“In addition to suggesting that more attention be paid to communicating a heightened risk across the class, there may be indications for a heightened risk in children as well,” said Carolyn Kercsmar, MD, of Rainbow Babies and Children’s Hospital in Cleveland and a member of the committee.

Kercsmar and other committee members voted 12 to 0, with one abstention, that Novartis’ product should warn patients that asthma-related deaths have been seen with Serevent.

Committee members made the recommendation after hearing presentations from GSK and Novartis about the safety of their products.

GSK officials discussed several clinical trials in which they noted some safety signals in their products that used salmeterol, an active ingredient in both Serevent (salmeterol) and Advair Diskus (fluticasone and salmeterol).

In 2004, the FDA asked GSK officials to place a black box warning on both products, after data from GSK’s SMART trial showed a small increased risk of life-threatening asthma events when using the medication compared with placebo.

The effect was more pronounced in certain subgroups using the product, including minorities and children, according to an FDA official who spoke during the meeting. GSK officials quickly pointed out, however, that while blacks had almost twice the amount of adverse events with their products than whites included in the trial, the black patients enrolled in the study also had more previous hospitalizations and “more severe asthma as measured by peak expiratory flow” at trial enrollment.

While Novartis’ phase-4 trial did not demonstrate any severe adverse events with their compound, formoterol, committee members concluded the study was underpowered to assess life-threatening asthma events.

Novartis officials said its trial noted more serious adverse events in the 24 µg twice daily (b.i.d.) group compared with the 12 µg b.i.d. group.

Despite black box labeling, committee members agreed that keeping both products available to the public was important.

Committee member Fernando Martinez, MD, with the University of Arizona Respiratory Sciences Center, summed up the panel’s conclusions: “there are individuals in the community whose control is significantly improved using beta agonists; however, … there may be a population of patients with asthma who are not only not controlled by this medication but whose conditions may be rendered worse by this medication.”

Committee members recommended additional studies to prove or disprove the perceived threat from the drugs. They also recommended a case-control surveillance design, which will analyze phenotypic and genotypic information for patients who may be at increased risk for adverse events.

The committee asked the companies to further examine what role combination therapy — compared with inhaled corticosteroid use alone — had on the asthma events.