PURPOSE:To assess the long-term tolerability of budesonide/formoterol pressurized metered-dose inhaler (pMDI) in chronic obstructive pulmonary disease (COPD) patients.
METHODS:This was a 12-month randomized, double-blind, multicenter trial (NCT00206167) of 1964 patients ≥40 years with moderate to very severe COPD. After 2 weeks of treatment based on previous therapy (inhaled corticosteroids [ICSs], short-acting bronchodilators allowed), patients received budesonide/formoterol pMDI 160/4.5μg ×2 inhalations (320/9μg), budesonide/formoterol pMDI 80/4.5μg ×2 inhalations (160/9μg), formoterol DPI 4.5μg ×2 inhalations (9μg), or placebo, all twice daily.
RESULTS:Overall discontinuation was higher in placebo (36.4%) versus both budesonide/formoterol groups (27.1–28.9%). The percentage of patients reporting ≥1 adverse event (AE) was slightly higher for active treatments (60.4–65.4%) versus placebo (55.7%). Oral candidiasis and voice effects (local ICS effects) occurred more frequently for budesonide/formoterol 320/9 (10.3%) and 160/9 (5.7%) versus formoterol (0.6%) and placebo (2.5%). Pneumonia-related AEs were slightly less frequent for active treatments (3.4–4.0%) versus placebo (5.0%). The incidence of AEs potentially associated with β2-adrenergic agonists was low (7.4%) but higher for active treatments (6.5–9.5%) versus placebo (4.8%), with a somewhat higher incidence of cardiac-related AEs (7.1–8.5%) versus placebo (5.0%). Atrial fibrillation AEs were more common for active treatments (0.8–2.2%) versus placebo (0%). Discontinuations due to AEs were low (12.1%) and similar across treatments. The incidence of serious AEs was higher for formoterol (18.0%) versus budesonide/formoterol treatments (14.0–16.0%) and placebo (12.9%). Bone mineral density (patient subset) was stable during study across treatments. Increases in lenticular opacity scores and intraocular pressure (patient subset) were small and similar across treatments. No clinically important treatment group differences were observed for 24-h Holter monitoring or electrocardiograms, including atrial fibrillation data (a discrepancy from AE data warranting further investigation).
CONCLUSION:Both budesonide/formoterol pMDI doses were well tolerated versus formoterol and placebo over 12 months with no indication of an increased risk for pneumonia with budesonide/formoterol.
CLINICAL IMPLICATIONS:These results support long-term use of budesonide/formoterol pMDI in moderate to very severe COPD patients.
DISCLOSURE:Stephen Rennard, University grant monies Dr. Tashkin: AstraZeneca grants to Regents of the University of California; 6-month RCT of Symbicort pMDI in COPD ($7,136) and 1-year RCT of Symbicort pMDI in Hispanic-American patients with asthma ($4,841.27); Grant monies (from industry related sources) Dr. Rennard: Almirall, Centocor, GlaxoSmithKline, IFSH, Lorillard, Novartis, Philip Morris, Roche; Shareholder Dr. Goldman: AstraZeneca; Employee Ms. McElhattan and Drs. Goldman and Silkoff: AstraZeneca; Consultant fee, speaker bureau, advisory committee, etc. Dr. Rennard: Adams, Abbott, Almirall, Altana, Anthera, AstraZeneca, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Roche, Quintiles, TareGen.Dr. Tashkin: AstraZeneca; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Budesonide/formoterol pMDI is not approved for use in patients with COPD.