PURPOSE: Roflumilast, an oral phosphodiesterase-4 (PDE4) inhibitor, has been shown effective in the treatment of COPD. In this analysis, the safety and tolerability of roflumilast were analyzed using a pooled population.
METHODS: Safety data from 14 placebo-controlled, double-blind, Phase II/III studies of roflumilast 500μ g or 250μ g QD versus placebo in subjects with moderate-to-very severe COPD were pooled and analyzed.
RESULTS: In the safety population, 5766 received roflumilast 500μ g, 797 patients received roflumilast 250μ g, and 5491 received placebo. The overall incidence of adverse events (AEs; 67.2%, 60.7%, and 62.8%) and serious AEs (13.5%, 7.2%, and 14.2%) was similar for roflumilast 500μ g, 250μ g and placebo, respectively. Withdrawals due to AEs were low for all treatment groups (14.3% roflumilast 500μ g, 8.9% roflumilast 250μ g, 9.2% placebo). The most frequently reported AEs (≥2% higher for roflumilast vs placebo) were diarrhea (10.1%, 4.9%, 2.6%), decreased weight (6.8%, 0.8%, 1.8%), nausea (5.2%, 2.3%, 1.4%), and headache (4.6%, 3.5%, 2.0%) for roflumilast 500μ g, 250μ g, and placebo, respectively. Pancreatitis (7 roflumilast, 7 placebo) and suicidal behaviors (5 roflumilast, 1 placebo) affected few patients overall. Tumor AEs were reported by 1.6%, 0.5%, and 1.3% for roflumilast 500μ g, 250μ g and placebo, respectively. Psychiatric AEs were reported by 6.0%, 2.8%, and 3.0%, respectively; no psychiatric AE required hospitalization. Exacerbations reported as AEs were more frequently rated as severe with placebo (6.3%) than with roflumilast 500μ g (5.3%). The only AE more frequently rated as severe with roflumilast 500μ g compared with placebo was diarrhea (≥0.5% difference). Apart from decreased weight, the majority (69.3-91.6%) of the most frequently reported AEs lasted < 4 weeks with no difference in duration seen between groups. Weight loss compared to placebo averaged -2.14kg and was most pronounced during the first 4 weeks of roflumilast treatment and was partially reversible after treatment cessation.
CONCLUSION: In this large safety population, roflumilast was well tolerated; the most common AEs were generally mild-to-moderate and short-lived (< 4 weeks).
CLINICAL IMPLICATIONS: Roflumilast was well tolerated in severe-to-very severe COPD patients.
DISCLOSURE: Nicholas Gross, Grant monies (from industry related sources) Nicholas Gross has Research Grants from Boehringer-Ingelheim, Pfizer, Almirall, Forest, Nycomed, AstraZeneca, Dey/Mylan. Peter Calverly’s University has received monies from Nycomed, GSK, AstraZeneca, Boehringer Inghelheim and Novartis to support clinical trials of drugs these companies manufacture. Professor Rabe has been consulting, participated in Advisory Board Meetings and received lecture fees from AstraZeneca, Boehringer, Chiesi Pharmaceuticals, Pfizer, Novartis, Nycomed, MSD, and GSK. Professor Rabe holds no stock or other equities in pharmaceutical companies. The Department of Pulmonology, and thereby professor K.F. Rabe as head of the department has received grants from Novartis, AstraZeneca, Boehringer Ingelheim, Nycomed, Roche and GSK in the years 2005 until 2009.; Employee Hans Mosberg is an employee of Nycomed GmbH.; Consultant fee, speaker bureau, advisory committee, etc. Nicholas Gross received Speaking Honoraria from AstraZeneca, Boehringer, Dey and Consultant/Advisory Board fees from Forest, Nycomed, Almirall, AstraZeneca,, Dey, Elevation Pharma, GlaxoSmithKline. Peter Calverly has received consulting and speaking fees from Nycomed, GSK, AstraZeneca, Boehringer Inghelheim and Novartis. related topics for Nycomed, GSK, Mpex. Leonardo Fabbri reports having served as a consultant to Nycomed, Forrest, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche and Pfizer; having been paid lecture fees by Abbott, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Nycomed, Roche and Pfizer.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Roflumilast is approved in Europe, and under consideration by the FDA in the United States.