New molecular entity: Roflumilast oral treatment was approved by FDA as treatment to reduce risk of COPD exacerbations.
According to the National Heart, Lung and Blood Institute, mortality due to chronic obstructive pulmonary disease (COPD) is on the rise and currently the fourth leading cause of death. It is estimated that 12 million Americans have been diagnosed with COPD, and an additional 12 million have the disease but are unaware. On March 1, 2011, roflumilast was approved by FDA as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations (not the relief of acute bronchospasm). While the exact mechanism of action of roflumilast and its active metabolite (roflumilast N-oxide) is not completely understood, it is hypothesized that its pharmacologic effect is a result of selective inhibition of phosphodiesterase 4, which leads to accumulation of intracellular cyclic adenosine monophosphate in lung cells.
Efficacy. The efficacy of roflumilast 500 μg once daily in patients with COPD was evaluated in four 1-year long randomized trials. Initial placebo-controlled trials enrolled patients with severe COPD (inclusive of those with chronic bronchitis and/or emphysema) and a history of smoking of at least 10 pack-years. These trials failed to demonstrate significant reductions in the rate of COPD exacerbations with roflumilast. However, 2 subsequent randomized trials enrolling patients with severe COPD associated with chronic bronchitis, at least a 20 pack-year smoking history, and at least 1 COPD exacerbation in the previous year (eg, overall sicker patients) were able to demonstrate statistically significant (15% to 18%) relative reductions in the risk of COPD exacerbations. Improvements in forced expiratory volume in 1 second (FEV1) of approximately 50 mL also were seen.
Safety. In randomized clinical trials lasting between 6 months and 1 year, 14.8% of patients receiving roflumilast discontinued therapy due to adverse reactions (compared to 9.9% of placebo-treated patients). The most common adverse reactions seen with roflumilast (occurring in ≥2% of patients) were diarrhea (9.5%), weight decrease (7.5%), nausea (4.7%), headache (4.4%), back pain (3.2%), influenza (2.8%), insomnia (2.4%), dizziness (2.1%), and decreased appetite (2.1%). During clinical trials, roflumilast use was found to be associated with an increased incidence of psychiatric adverse reactions. Three cases of suicidal ideation and behavior (1 resulting in death) were seen in patients taking roflumilast. Other serious adverse reactions of note (occurring more frequently in roflumilast-treated patients) included atrial fibrillation, lung and prostate cancer, acute pancreatitis, and acute renal failure.