Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea

Abstract

Objectives:Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies.Methods:Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events.Results:2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were five events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use.Conclusions:Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association.

Dietary and pharmacological treatment of abdominal pain in IBS

“…The adverse events of pancreatitis and sphincter of Oddi spasm (SOS), each in 0.3% of patients, led to specific exclusions of patients with a history of bile duct obstruction, pancreatitis, severe liver impairment or severe constipation, and in patients who drink more than three alcoholic beverages per day. An updated analysis of safety of eluxadoline in the phase II and III trials shows that clinically apparent SOS events were observed in eluxadoline-treated patients without a gallbladder, and the majority were observed with the higher (100 mg) dose of eluxadoline 100. Nevertheless, the FDA Adverse Event Reporting System received information on 99 cases of pancreatitis, 39 cases of SOS and 220 cases of abdominal pain within 10 months of the availability of the medication to patients with IBS-D 101…”

The place of eluxadoline in the management of irritable bowel syndrome with diarrhea

“…In the phase II and III clinical trials of eluxadoline, 10 events consistent with SOS occurred in patients treated with eluxadoline; 8 in the 100 mg group (0.8%) and 2 in the 75 mg group (0.2%). 18 All SOS events occurred in patients without a gallbladder. A total of 8 of the 10 patients with SOS presented with abdominal pain and elevated aminotransferases; 7 in the 100 mg group (0.7%) and 1 in the 75 mg group (0.1%).…”

Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits

“…60 This was confirmed in a more recent study of nearly 2000 patients with IBS-D with 10 patients developing sphincter of Oddi spasm, most at the higher eluxadoline dose of 100mg. 61 In a recent communication (https://www.fda.gov/Drugs/DrugSafety/ucm546154.htm), the U.S. Food and Drug Administration (FDA) issued a warning that eluxadoline should not be used in patients who do not have a gallbladder. An FDA review found these patients have an increased risk of developing serious pancreatitis that could result in hospitalization or death.…”