Use of a 4-week up-titration regimen of roflumilast in patients with severe COPD

Background: The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy. Methods: In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1: 1: 1 to 4 weeks' treatment with ROF 250 mu g once daily (OD), 500 mu g every other day (EOD), or 500 mu g OD, each followed by ROF 500 mu g OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment. Results: Patients in the 250 mu g OD/500 mu g OD group had significantly fewer treatment discontinuations (odds ratio [OR] 0.66 [95% CI 0.47-0.93], p=0.017) and lower rates of AEs of interest such as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (OR 0.63 [95% CI 0.47-0.83], p=0.001) compared with those in the 500 mu g OD group. Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 mu g EOD/500 mu g OD, the difference was not significant (OR 0.76, p=0.114, and OR 0.78, p=0.091, respectively) compared with ROF 500 mu g OD. Conclusion: A dose of ROF 250 mu g OD for 4 weeks before escalation to the approved maintenance dose of 500 mu g OD resulted in reduced treatment discontinuation and improved tolerability.