Adverse Event Profile of Eluxadoline Over Time in Patients With Irritable Bowel Syndrome With Diarrhea

Abstract

Introduction: Eluxadoline (ELX) has mixed opioid activity: it is a mu-opioid receptor (OR) agonist, and it is also a delta-OR antagonist and a kappa-OR agonist. It is locally active and approved by the FDA for the treatment of irritable bowel syndrome with diarrhea (IBS-D). We evaluated the adverse event (AE) profile of ELX in clinical trials. Methods: One Phase 2 and two Phase 3 trials enrolled patients meeting Rome III criteria for IBS-D to twice-daily (BID) treatment with ELX or placebo (PBO) for 12, 26, and 52 weeks (wks) of doubleblind treatment. Safety data were pooled and AE incidence rates were summarized based on treatment at time of AE. To evaluate AE time course relative to treatment duration, AEs were summarized based on occurrence at 1, 2, 12, and 26 wks of treatment. For patients exposed ≥26 weeks, AEs during the 1st and 2nd 6 months of treatment were compared. Results: 807 and 1032 patients received at least 1 dose of ELX 75 or 100 mg, respectively. Duration of exposure to ELX 75 or 100 mg included 1391, 1001, and 488 patients exposed for 12, 26, and 52 weeks, respectively. Overall rates of AEs and serious AE (SAEs) were similar across the 75 mg, 100 mg, and PBO groups. More AEs led to discontinuation (DC) for ELX than PBO (8.0% vs. 4.3%, respectively) [Table 1]. 44.2% of AEs leading to DC with ELX occurred within the 1st 2 wks; nausea (7.8%), constipation (4.0%), and abdominal pain (0.7%) were the most common AEs during this time. An SAE consistent with sphincter of Oddi spasm (SOS), manifesting as pancreatitis or acute abdominal pain with elevated liver enzymes, occurred in 10 patients with ELX treatment (10/1839, 0.54%) vs. zero PBO patients; in 8 of these, symptoms occurred within the 1st wk. No case of SOS occurred >1 month after starting treatment. All patients with SOS did not have a gallbladder. At 12 wks, AE and SAE rates were comparable across treatment groups and remained similar through 26 wks. Rates of AEs for patients exposed ≥26 wks were comparable across all groups. Importantly, rates of AEs decreased by nearly 50% while rates of SAEs remained unchanged in the 2nd 6 months of treatment compared to the 1st 6 months (Table 2).Table 1: Incidence of AE, SAE, and DC by Interval: Pooled Phase 2 and 3 StudiesTable 2: Incidence of AEs for Patients Exposed ≥26 WeeksConclusion: Overall, AEs tend to occur more frequently early after initiation of ELX treatment, with incidence rates after 2 wks of ELX treatment similar to PBO. Treatment with ELX up to 52 wks showed no additional safety risks. (Support: Furiex Pharmaceuticals, Inc., an affiliate of Actavis, Inc.)