Roflumilast is a PDE4 inhibitor designed to target both the systemic and pulmonary inflammation associated with COPD. It acts by inhibiting PDE4, a major cyclic adenosine monophosphate (cAMP)-metabolising enzyme found in structural and inflammatory cells important to the pathogenesis of COPD. This inhibition results in reduced sputum neutrophils in patients with COPD. The major active metabolite, roflumilast N-oxide, acts in the same way.1
Efficacy of roflumilast was assessed in two trials with identical design involving 3,091 adults with a history of severe to very severe COPD associated with chronic bronchitis and at least one exacerbation in the previous year.2 Patients were randomised to receive roflumilast 500 microgram once a day or placebo, taken in the morning for 52 weeks. Patients were permitted to use long-acting β2-agonists (LABAs) or short-acting anticholinergics during the studies plus short-acting β2-agonists as required; use of inhaled corticosteroids or theophylline was not allowed.1
In a pooled analysis of the two studies, roflumilast was associated with an increase of 48ml in pre-bronchodilator FEV1 compared with placebo (p<0.0001).2 The rate (per patient per year) of moderate or severe exacerbations was 1.14 with roflumilast and 1.37 with placebo, corresponding to a relative risk reduction of 17 per cent.2
The difference in exacerbation rates between treatments was independent of concomitant LABA use. The total number of exacerbations (excluding severe events) requiring treatment with systemic corticosteroids or antibiotics, or both, was also lower in the roflumilast group than in the placebo group.2
Adverse events occurred in more patients in the roflumilast group than in the placebo group (67 per cent versus 62 per cent) and were associated with a greater rate of treatment discontinuation in the roflumilast group than in the placebo group (14 per cent versus 11 per cent).2
Safety and efficacy of roflumilast were assessed in two double-blind, multicentre studies involving patients aged over 40 years with moderate to severe COPD who were randomly assigned to receive roflumilast 500 microgram or placebo once daily for 24 weeks in addition to either salmeterol (n=933) or tiotropium (n=743).3 Adherence to treatment was similar in all groups with mean compliance between 94 and 97 per cent.3
Roflumilast was associated with a significant increase in mean pre-bronchodilator FEV1 in both studies compared with placebo (49ml in the salmeterol study and 80ml in the tiotropium study). Similar improvements were noted in post-bronchodilator FEV1 and in pre- and post-bronchodilator FVC. Roflumilast had a variable effect on symptomatic outcomes such as respiratory symptoms, use of rescue medications, and exacerbations in both trials.3
The most frequently reported adverse events in both studies were COPD-related; the most common treatment-related adverse events were diarrhoea, nausea and weight loss, with no major differences between the two trials. The probability of treatment discontinuation in both studies was greater in patients receiving roflumilast.3
- Daxas Summary of product characteristics, July 2010
- Calverly P et al. Lancet 2009; 374: 685-94.
- Fabbri L et al. Lancet 2009; 374: 695-703.
Further information: Merck Sharp & Dohme Ltd