Pooled Analysis of the Most Frequent Adverse Events Associated with the Use of Lubiprostone

Purpose: Lubiprostone, a novel ClC-2 activator, has been shown to be efficacious and well tolerated by patients with chronic constipation in short- and long-term clinical trials. To better characterize the most frequent adverse events (AEs) associated with the use of lubiprostone 24 mcg BID, we examined pooled results of patients enrolled in Phase 2 and 3 trials of 3 to 48 weeks' duration. Methods: Data for all safety-evaluable patients were pooled and compared between treatment groups (placebo vs. lubiprostone 24 mcg BID). Nausea, headache, and diarrhea AEs were analyzed for severity, duration, frequency, action taken (eg, drug withdrawn, dose reduced), and outcome. In addition, nausea-related variables were explored in subpopulations of elderly (≥65 years of age) and male patients. Results: The pooled population included 1113 lubiprostone and 316 placebo patients. Approximately 16% were elderly and 13% were male. At least 1 AE occurred in 79.1% of lubiprostone patients, which included 31.1% with nausea, 13.2% with headache, and 13.2% with diarrhea. At least 1 AE occurred in 39.6% of placebo patients, which included 5.2% with nausea, 6.6% with headache, and 0.9% with diarrhea. Of those lubiprostone patients who experienced nausea, 88.7% reported nausea to be mild or moderate in severity. Overall, 74.5% of nausea events reported by lubiprostone patients were intermittent, and the median durations of nausea events were 12 and 7.5 days for lubiprostone and placebo patients, respectively. Notably, mean incidences of nausea per patient were 1.3 and 1.0 for lubiprostone and placebo patients, respectively. With regard to action taken, 64.1% of nausea events required no change in treatment regimen, and 9.6% of events resulted in dose reduction. Nausea was less prevalent in subpopulations, occurring in only 18.8% and 8.2% of lubiprostone elderly and male patients, respectively, compared with 34.5% of female patients. Similarly, the majority of lubiprostone patients experiencing headache and diarrhea had mild to moderate symptom severity (89.8% and 82.3%, respectively). Furthermore, headache and diarrhea events in lubiprostone patients were mostly intermittent (64.2% and 74.0%, respectively), and the median duration of these events were 9 and 4 days, respectively. Discontinuation rates due to nausea, headache, and diarrhea were 8.7%, 3.7%, and 2.2%, respectively. Conclusions: Nausea, headache, and diarrhea associated with lubiprostone use are generally mild to moderate in severity, intermittent, and limited in duration.