Roflumilast: doubtful efficacy but clear harms in COPD.

Avoidance of irritants such as tobacco smoke slows the progression of severe chronic obstructive pulmonary disease (COPD). Drugs have only a modest, purely symptomatic effect; a bronchodilator is combined with an inhaled corticosteroid when exacerbations are frequent. Oxygen therapy prolongs survival in very severe disease. Roflumilast, a nonsteroidal antiinflammatory drug that inhibits type 4 phosphodiesterase, has been authorised in the European Union for the treatment of severe COPD. Roflumilast has not been compared with an inhaled corticosteroid. Its evaluation is primarily based on 8 double-blind, randomised, placebo-controlled trials lasting from 24 to 52 weeks, in a total of approximately 9000 patients. In four trials, the average frequency of exacerbations fell by about 0.2 episodes per patient per year, but the statistical significance of the difference was variable. Even in the most favourable trials, roflumilast did not reduce the frequency of hospitalisation for exacerbations. In six trials (including the four previous trials), roflumilast led to a statistically significant increase in forced expiratory volume in one second, by about 50 ml on average, but the clinical relevance of this improvement is questionable. An inherently unreliable indirect comparison suggests that roflumilast is less effective than an inhaled corticosteroid. Treatment was stopped because of adverse reactions in 14% of patients taking roflumilast, versus 8.5% in the placebo groups. The most common adverse effects were gastrointestinal disorders (diarrhoea, nausea), weight loss, and neuropsychiatric disorders (insomnia, anxiety, depression). Concerns have been raised about the carcinogenic potential of roflumilast. Roflumilast is metabolised by cytochrome P450 isoenzymes CYP 3A4 and CYP 1A2, creating a high potential for pharmacokinetic interactions. In practice, it is better not to use roflumilast. For patients with severe COPD and repeated exacerbations, the standard treatment remains an inhaled bronchodilator combined with an inhaled corticosteroid, or oxygen therapy in some cases.