DISCUSSION: Roflumilast has an overall low incidence of adverse events. Compared to placebo, the incidence of severe adverse events was less in both the 500 mcg and 250 mcg treatment groups. With the most common adverse effect being diarrhea, Roflumilast is tolerated well in patients with moderate to severe COPD. However acute pancreatitis has been described in a small subset of patients. In one benefit-harm assessment, acute pancreatitis had an incidence rate of 0.077 per 1000 person-years. In a separate double blind placebo-controlled study, the incidence was equal to that of the placebo. While rare, the FDA does recognize pancreatitis as a possible severe gastrointestinal adverse effect. Of the patients who developed pancreatitis, increased mortality was noted in those receiving treatment doses of 500 mcg, suggesting a possible dose-dependent relationship on mortality from Roflumilast induced pancreatitis. While there is no proven mechanism for the cause, Roflumilast may cause pathology via duct constriction, accumulation of toxic metabolites or hypersensitivity. The associated elevation of cAMP, an intended effect within the lung parenchyma, may play a role in the side-effects experienced elsewhere in the body.