PURPOSE: The phosphodiesterase-4 inhibitor roflumilast was approved by the FDA to reduce the risk of exacerbations in COPD patients with severe disease, chronic bronchitis and a history of acute exacerbations. This safety evaluation of 8 studies enrolled patients that were representative of the anticipated approval population receiving 500µg of roflumilast. By focusing on these 8 studies, this analysis may have improved relevance and sensitivity for adverse event (AE) frequencies, compared to previously reported broader multiple-dose safety pool results. Given previously demonstrated associations between phosphodiesterase-4 inhibitors and gastrointestinal (GI) AEs, we examined the frequency of common AEs and GI-AEs using pooled data from the 8 studies, reported in detail for the first time here.
METHODS: Data were pooled from eight 24-52-week, placebo-controlled, phase 2/3 clinical trials of roflumilast 500µg in moderate-to-very severe COPD patients. Frequencies of the most common AEs (≥2% for roflumilast and >placebo) and GI-AEs ≥1% and >placebo are reported.
RESULTS: In this analysis, n=4438 for roflumilast and n=4192 for placebo. The most frequently reported AEs (≥2% higher for roflumilast vs placebo) were diarrhea (9.5% vs 2.7%), weight decreased (7.5%, vs 2.1%), nausea (4.7% vs 1.4%), and headache (4.4% vs 2.1%). Back pain, influenza, insomnia, dizziness, and decreased appetite were reported by ≥2% of patients treated with roflumilast but were <2% greater than placebo. Apart from diarrhea and nausea, other GI-AEs ≥1% with roflumilast and >placebo were abdominal pain (1.9% vs 0.9%), upper abdominal pain (1.3% vs 0.6%), dyspepsia (1.2% vs 1.0%), gastritis (1.1% vs 0.4%) and vomiting (1.3% vs 0.7%). Other than weight decreased and decreased appetite (2.1% vs 0.4%), no other metabolism or investigation AEs were ≥1.0% with roflumilast and >placebo.
CONCLUSIONS: In this pool of 8 COPD trials, roflumilast treatment resulted in no AEs ≥10% and most ≤5% greater than placebo. Roflumilast was associated with more frequent GI-AEs than placebo, although most were ≤2%.
CLINICAL IMPLICATIONS: AE rates observed in this 8-study population, containing patients representative of those approved for roflumilast, were as expected.
DISCLOSURE: Mark Dransfield: Grant monies (from industry related sources): NIH (NHLBI), Other: GSK, Boehringer Ingelheim, Asthmatx, Consultant fee, speaker bureau, advisory committee, etc.: GSK, Boehringer Ingelheim, Vertex, Forest Laboratories, Inc.
Gary Ferguson: Consultant fee, speaker bureau, advisory committee, etc.: Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Pfizer and Pearl, Grant monies (from industry related sources): Boehringer-Ingelheim, Forest, GlaxoSmithKline, Novartis and Pearl
Udo-Michael Goehring: Employee: Nycomed GmbH
Hans Mosberg: Employee: Nycomed GmbH
Manja Brose: Employee: Nycomed GmbH
Dirk Bredenbroeker: Employee: Nycomed GmbH
Hassan Lakkis: Employee: Forest Research Institute
Paul Rowe: Employee: Forest Research Institute
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