FDA Removes Boxed Warning for ICS/LABA Asthma Therapies

The US Food and Drug Administration (FDA) has removed its Boxed Warning indication for drug labels of medicines containing both inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs).

The FDA called for the warning removal after reviewing 4 large clinical safety trials that indicated the combined therapies do not result in significantly more serious asthma-related side effects versus ICS monotherapy, when treating asthma.

A call for safety clinical trials for review was originally issued in 2011, to companies manufacturing fixed-dose combination therapies containing both ICS and LABA (GlaxoSmithKline [GSK], Merck, and AstraZeneca). The studies were 26-week, randomized, double-blind, active-controlled trials involved 41,297 patients, according to the FDA.

ICS/LABA in fixed-dose combination regimens for asthma showed no significant increase in adverse effects versus ICS, and subgroup analyses (by gender, adolescents 12-18 years old, and African Americans) were consistent with the primary endpoint results.

The 4 trials also assessed the efficacy of ICS/LABA products by asthma exacerbation in patients. Exacerbation was defined as the deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days, or an in-patient hospitalization or emergency department visit that required systemic corticosteroids. ICS/LABA combinations reduced asthma exacerbations versus ICS, with the majority of exacerbations requiring 3 days or more of systemic corticosteroids.

In a separate statement regarding the warning removal, GSK noted the action will affect the labeling from its marketed therapies fluticasone furoate/vilanterol (BREO ELLIPTA), and 2 forms of fluticasone propionate/salmeterol (FCS) (ADVAIR DISKUS, ADVAIR HFA).

With FCS being the sole ICS/LABA fixed-dose combination treatment approved for children 4 to 11 years old in the US at the time of the FDA’s earlier request, GSK conducted a separate but similarly-designed study with this age group.

In 2 clinical safety studies comparing FCS to fluticasone propionate monotherapy, researchers found no excess risk of the GSK treatment when used to treat adolescent and adult patients with asthma, and children aged 4 to 11 years old with asthma, as measured by asthma-related events (death, intubations, or hospitalizations).

The label change comes at a time of emerging therapy options for asthma and chronic obstructive pulmonary disease (COPD). Anne M. Ditto, MD, professor of allergy and immunology at Northwestern University's Feinberg School of Medicine, recently told MD Magazine that, though ICS are the common maintenance therapy for asthma, biologics are available for different patient populations.

“We can streamline the therapy a little more, individualize the therapy a little more, for patients [when we know the type of asthma], but I think it's also important from an allergic standpoint,” Ditto said.

Referring to deaths and safety issues surrounding patients with asthma, Ditto pointed to diagnosis, not the therapies.

“We have a lot of good treatments for asthma, but unfortunately, I think asthma is still underdiagnosed and in many circumstances for a lot of different reasons undertreated,” Ditto said.