By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved two new treatments for irritable bowel syndrome with diarrhea (IBS-D). Eluxadoline is a new chemical entity that is a mu-opioid receptor agonist and a delta-opioid receptor antagonist, which causes reductions in gastrointestinal contraction. The second treatment is a new indication for rifaximin, an antibiotic previously approved for the treatment of traveler’s diarrhea and recurring hepatic encephalopathy. Eluxadoline is marketed by Patheon Pharmaceuticals and marketed as Viberzi. The brand name for rifaximin is Xifaxan.
INDICATIONS
Both drugs are approved for treatment of IBS-D.
DOSAGE
Eluxadoline: 100 mg twice daily taken with food.1 The dose should be reduced to 75 mg twice daily with food in patients without a gallbladder, unable to tolerate the 100 mg dose, with mild or moderate hepatic impairment, or taking concomitantly OATP1B1 inhibitors (e.g., antiretroviral protease inhibitors, cyclosporine, rifampin, or gemfibrozil).
Rifaximin: 550 mg three times a day for 14 days.2 Treatment may be repeated twice if recurrence occurs.
POTENTIAL ADVANTAGES
Eluxadoline and rifaximin provide new treatments with different mechanisms of action. Rifaximin offers a 14-day treatment course, compared to chronic administration for eluxadoline.
POTENTIAL DISADVANTAGES
Eluxadoline is contraindicated in patients with known or suspected biliary duct obstruction, dysfunction of the sphincter of Oddi, alcoholism, history of pancreatitis, severe hepatic impairment, or severe constipation. The drug has the potential to increase the spasm of the sphincter of Oddi.1 The effect of antibiotic resistance of GI flora with long-term and wide-spread use of rifaximin is not known.5
COMMENTS
Irritable bowel syndrome (IBS) is a common, difficult-to-treat, functional GI disorder characterized by recurrent symptoms.5 There are no well-linked measurable physiological abnormalities or measurable biologic markers. Patient-reported outcomes are the only way to assess treatment efficacy.3 The FDA guidance for IBS recommends studies enroll subjects who meet the specified Rome III IBS diagnostic criteria.3 These include a weekly average of worst daily (in the past 24 hours) abdominal pain score of ≥ 3.0 on a 0 to 10 point scale, as well as stool consistency, which is defined as at least one stool with a consistency of type 6 (mushy or fluffy) or type 7 (watery) Bristol stool score (BSS) on at least 2 days per week or an average daily BSS score of ≥ 5.5 and at least 5 days with a BSS score ≥ 5 over the week before randomization.
Response is defined as ≥ 30% improvement from baseline in the weekly average abdominal pain in the past 24 hours score and at least a 50% reduction in the number of days in a week with a daily stool consistency of BSS type 6 or 7 compared to baseline, or a reduction in the BSS to < 5 on at least 50% of the days within a 12-week time interval.
Eluxadoline was evaluated in two 26-week randomized, double-blind, placebo-controlled trials (n = 2426). Subjects were randomized to 100 mg or 75 mg twice daily, or they were given a placebo. The response rates over 26 weeks for the two studies were 23% and 30% for 75 mg, 29% and 33% for 100 mg, and 19% and 20% for placebo.1 Treatment differences were 4% and 10% for the lower dose and 10% and 13% for the 100 mg dose. The results were statistically different than placebo for the 100 mg dose in both studies and for the 75 mg dose in one study. Eluxadoline appears to have greater benefit in improving stool consistency than abdominal pain.
Rifaximin was evaluated in three randomized, double-blind, placebo-controlled trials, with two studies meeting Rome II criteria and one that included subjects who met Rome III criteria (n = 2579).2,4 Subjects were randomized to 550 mg three times daily or placebo for 14 days, and treatment success was evaluated at the end of a 4-week follow-up period. Responders were followed for recurrence. The response rate during weeks 3 to 6 was 38% for rifaximin and 31% for placebo, with a treatment difference of 7% (95% confidence interval, 0.9-16.9). Fifty-nine percent of responders had a recurrence with a median time of 10 weeks (range 6 to 24 weeks).
Common side effects for eluxadoline include nausea, constipation, and abdominal pain in the range of 6-8%. Common side effects for rifaximin were similar to placebo.4
CLINICAL IMPLICATIONS
Both drugs appear to provide modest benefit in IBD-D. The absolute percent differences were 10-13% for eluxadoline and 7% for rifaximin, with a 59% recurrence. Response rates were modest compared to placebo. There are no direct comparisons between the two drugs. Alosetron is the only other currently FDA-approved treatment for IBS. However, the drug carries a boxed warning for serious complications of constipation and acute ischemic colitis and is only approved for females. As of 2014, the American College of Gastroenterology does not have a highly effective treatment for IBS-D when considering a wide variety of treatments from diet, probiotics, antispasmodics, antidepressants, rifaximin, alosetron, etc.5 Rifaximin is currently available at a wholesale cost of $1177 per treatment course. Eluxadoline is a opioid and is expected to be a schedule drug. Its expected availability is early 2016.
REFERENCES
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Viberzi Prescribing Information. Patheon and Forest Pharmaceuticals. May 2015.
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Xifaxan Prescribing Information. Patheon and Salix Pharmaceuticals. May 2015.
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Guidance for Industry. Irritable Bowel Syndrome — Clinical Evaluation of Drugs for Treatment. Available at: www.fda.gov/downloads/drugs/guidances/ucm205269.pdf. Accessed June 22, 2015.
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Pimentel M, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011;364:22-32.
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Ford AC, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109(Suppl 1):S2-S25.
