Newly Approved Nebulizer Formulation of Formoterol an Effective Bronchodilator

Rabiya S Tuma, PhD

May 22, 2007

May 22, 2007 (San Francisco) -- Earlier this month, the US Food and Drug Administration (FDA) approved formoterol fumarate inhalation solution (FFIS, Perforomist), a nebulized formulation of formoterol fumarate, for treatment of chronic obstructive pulmonary disease (COPD). Data from a phase 3 randomized controlled double-blind study, which were presented here at the 103rd International Conference of the American Thoracic Society, show that FFIS works as well as the standard dry powder formulation (FA, Foradil). Patients using either formulation have significantly better lung function, with up to 12 weeks of regular use, than those receiving placebo.

To assess the efficacy of FFIS, Nicholas J. Gross, MD, PhD, emeritus professor of medicine at Stritch-Loyola School of Medicine and staff physician at Hines VA Hospital in Chicago, Illinois, and colleagues randomized 351 patients to twice-daily treatment with FFIS, FA, or placebo for 12 weeks, following a 4- to 14-day placebo run-in period. The researchers measured lung function by serial spirometry over a 12-hour period on day 1, and again during week 12. Quality of life was measured at the same time points using the St. George Respiratory Questionnaire (SGRQ). Eligible patients were 40 years or older, had a history of 10 or more pack-years of smoking, and had moderate to severe COPD.

The baseline forced expiratory volume in 1 second (FEV 1) was 1.32 (standard deviation [SD], 0.43) for the 123 patients assigned to FFIS, 1.28 (SD, 0.39) for the 114 patients assigned to FA, and 1.32 (SD, 0.48) for the 114 patients taking placebo. An intent-to-treat analysis showed that lung function was significantly improved in both treatment groups, with an endpoint FEV 1 area under the curve from 0 to 12 h (AUC 0-12) of 1.51 (SD, 0.52) in the FFIS group and 1.49 (SD, 0.46) in the FA. Patients in the placebo group remained largely unchanged, with a FEV 1 AUC 0-12 of 1.33 (SD, 0.57; P < .0001 for both). After the first study day, patients on the active drug were also significantly less likely to use albuterol as rescue medication than were those receiving placebo ( P < .0003).

As expected, the drug is more effective at controlling symptoms than placebo, which is what was required for regulatory approval, Dr. Gross told Medscape. "The trial also does show that [the new formulation] is exactly equivalent [to] Foradil, which was by design. The FDA was worried about safety and didn't want one that was more potent than Foradil, and obviously the company didn't want one that was less."

Quality-of-life measures also improved, relative to placebo, for patients on FFIS, with a reduction in the overall SGRQ score of 4.9 points ( P ≤ .03). There was a nonsignificant drop in the overall score for patients on FA treatment (approximately 4 points). Both active-drug arms showed significant improvement in the symptom subscore, but neither showed statistically significant improvement in the activity subscore, relative to placebo. Finally, only patients in the FFIS arm showed statistically significant improvement, relative to placebo, in terms of the impact subscore.

In a separate poster presentation, Harold S. Nelson, MD, professor of medicine at the National Jewish Medical and Research Center in Denver, Colorado, described the safety analysis from the phase 3 study. Of the patients in the FFIS arm, 63 (51.2%) experienced 1 or more adverse events, as did 69 (60.5%) patients in the FA arm and 65 (57.0%) patients in the placebo arm . The most common adverse events were headache (5.7%, 4.4%, 7.0% in the FFIS, FA, and placebo arms, respectively), nausea (4.9%, 3.5%, and 2.6%), diarrhea (4.9%, 1.8%, and 3.5%), COPD exacerbation (4.1%, 6.1%, and 7.9%), nasopharyngitis (3.3%, 1.8%, and 1.8%), and dry mouth (3.3%, 1.8%, and 1.8%). Insomnia occurred in 3 patients (2.4%) in the FFIS arm and in none of the patients in the other 2 arms. Cough occurred in only 2 patients (1.6%) in the FFIS arm, but occurred in 5 (4.4%) in each of the other 2 arms.

Three adverse events were judged to be drug-related: dry mouth, nausea, and insomnia. One patient (0.8%) in the FFIS group experienced a serious adverse event, as did 3 patients (2.6%) in the FA group and 5 patients (4.4%) in the placebo group. The only serious adverse event to occur in more than 1 patient was COPD exacerbation, which occurred in 2 patients in the placebo arm.

The number of discontinuations due to adverse events were equal in the 2 active-drug arms, with 4 patients each (3.3% in the FFIS arm and 3.5% in the FA arm). Ten patients (8.8%) in the placebo arm discontinued the trial early.

Finally, the researchers saw no "clinically relevant changes or differences" between the treatment groups in terms of either electrocardiogram or Halter monitoring during the trial. There were 2 patients (1.8%) in each of the FA and placebo arms who had an increase in Bazett's corrected QT interval (QTcB) of 60 or longer. None of the patients in the FFIS arm had such long prolongations. Two (1.6%) patients in the FFIS arm had increases in their Fridericia's corrected QT interval (QTcF) of 60 seconds or longer, as did 1 (0.9%) patient in each of the other 2 arms.

The newly approved formulation "gives us an additional option for those patients who prefer nebulizers," said James F. Donohue, MD, professor of medicine and chief of the Pulmonary Division at the University of North Carolina School of Medicine in Chapel Hill, including patients who have trouble with metered dose inhalers.

Until recently, the only drugs available in a nebulizer formulation were short-acting agents. Because FFIS requires only twice-daily dosing, it is preferable to those older other agents. "I am a believer in the open airway approach," Dr. Donohue told Medscape. "The longer you're bronchodilated, the better. It keeps the lungs inflated, keeps them open. That is a good thing to do, rather than having them close and having to rescue periodically."

The phase 3 study was supported by Dey, LP.

ATS 103rd International Conference: Thematic Poster Session, A47. Presented May 20, 2007.


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