Do Not Use Eluxadoline (VIBERZI) for Irritable Bowel Syndrome

Eluxadoline (VIBERZI) was approved by the Food and Drug Administration (FDA) in May 2015 as a twice-daily oral treatment for irritable bowel syndrome with diarrhea as the predominant symptom (IBSD) in adults.[1]

As an opioid, eluxadoline is a controlled substance and works primarily by targeting mu-opioid receptors in the gut to:

• slow down movement of the muscles in the intestines and colon;
• decrease the amount of water and electrolytes in the stool; and
• increase the contraction of the anal sphincter muscle.[2]

Together, these actions can reduce the frequency and volume of bowel movements. The drug also may reduce abdominal pain by inhibiting the delta-opioid receptor in the gut.[3]

We have designated eluxadoline as Do Not Use because it is associated with serious adverse effects — including severe, sometimes fatal, pancreatitis — that outweigh its limited benefits.

Overview of irritable bowel syndrome[5]

Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition characterized by intermittent abdominal pain and altered bowel habits. The pain is typically crampy in nature. The location and severity of the pain can vary widely.

Altered bowel habits seen with IBS range from diarrhea to constipation. Patients may have diarrhea alternating with constipation, predominantly diarrhea or predominantly constipation, each alternating with normal bowel habits. IBS patients with diarrhea usually have frequent stools of small to moderate volume. These generally occur during the day, most often in the morning or following a meal. Stools in patients with constipation are often hard and may be pellet shaped. Psychological stress and eating may worsen symptoms, and having a bowel movement may relieve symptoms.

For a patient to be diagnosed with IBS, all known physical diseases that can cause such symptoms — such as infections, tumors and inflammatory bowel disease — must first be excluded.

Clinical trials

FDA approval for eluxadoline was based on two large randomized clinical trials.[6] For both trials combined, more than 2,400 adult patients with IBS-D were randomly assigned to eluxadoline at a dose of either 100 milligrams (mg) or 75 mg or to a placebo twice daily.

The trials demonstrated that through 26 weeks of treatment, more IBS-D subjects treated with eluxadoline (31 percent for the 100-mg dose and 27 percent for the 75-mg dose) met the trials’ primary endpoint for symptom improvement than those receiving a placebo (17 percent).[7]

During these clinical trials, however, patients were allowed to take loperamide, an older antidiarrheal medication, to treat uncontrolled diarrhea. Therefore, the symptomatic relief observed during clinical testing for some subjects may reflect the antidiarrheal benefits of loperamide, not eluxadoline.

Serious adverse effects

Product labeling for eluxadoline warns about several gastrointestinal adverse effects, including abdominal pain, nausea, constipation and gastrointestinal obstruction (blockage).[8] Although eluxadoline is intended to relieve the abdominal pain associated with IBS-D, abdominal pain adverse events occurred in more subjects in the eluxadoline group (4.6 percent for the 100-mg dose and 4.1 percent for the 75-mg dose) than in the placebo group (2.6 percent).[9]

One way eluxadoline can cause sudden abdominal pain is by triggering spasms in the sphincter of Oddi.[10] The sphincter of Oddi is a circular muscle that controls the flow of digestive juices (bile from the liver and gallbladder and digestive enzymes from the pancreas) into the intestines. Such spasms are a known adverse effect of opioids such as eluxadoline and can lead to inflammation of the pancreas (pancreatitis) and liver damage.[11],[12] The risk of these adverse events is greatest in patients who have had their gallbladders removed or previously had a blockage in the ducts (tubes) that drain digestive juices from the liver, gallbladder or pancreas.

During the randomized clinical trials, the most common serious adverse event was pancreatitis, which occurred in 11 subjects, all of whom were in the eluxadoline groups.[13] Three of these cases were determined to have been caused by sphincter of Oddi spasms in patients without a gallbladder.[14]

In March 2017, the FDA issued a drug safety warning about the increased risk of serious pancreatitis that could lead to hospitalization or death in patients taking eluxadoline.[15] From May 2015, when the drug was first approved, through February 2017, the FDA received reports of 120 cases of serious pancreatitis or death linked to use of the drug. Most of the cases occurred in patients without a gallbladder, but cases of pancreatitis requiring hospitalization have also occurred in patients with a gallbladder. Symptoms of pancreatitis developed in many patients after they took just one or two doses of the drug.

Although not mentioned on the drug’s label, eluxadoline may increase the risk of serious adverse cardiac events. During clinical testing, adverse cardiac events occurred in more subjects in the eluxadoline group (approximately 2 percent) than those in the placebo group (1 percent).[16] In fact, there were three heart attacks and one sudden death in subjects treated with eluxadoline and no such events in subjects receiving a placebo.[17]

Additional adverse events linked to eluxadoline are described in the text box above.

What You Can Do

Due to serious safety concerns and no evidence demonstrating that it is more effective than other, safer treatment options, you should not use eluxadoline.

Psychological counseling focused on stress minimization and relaxation techniques may help control IBS symptoms.

You also should consult your doctor about dietary modifications, including a diet known as the low- FODMAP diet, which avoids foods containing certain sugars and certain fibers that are capable of causing diarrhea, constipation, gas, bloating and abdominal pain. A gluten-free diet also may help some IBS patients.

References

[1] Actavis Pharma. Label: Eluxadoline (VIBERZI). January 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206940s001lblmg.pdf. Accessed April 10, 2017.

[2] Eluxadoline (Viberzi) for irritable bowel syndrome with diarrhea. Med Lett Drugs Ther. 2016;58(1485):4-5.

[3] Ibid.

[4] Actavis Pharma. Label: Eluxadoline (VIBERZI). January 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206940s001lblmg.pdf. Accessed April 10, 2017.

[5] Wald A. Clinical manifestations and diagnosis of irritable bowel syndrome in adults. UpToDate. January 26, 2017. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-irritable-bowel-syndrome-in-adults. Accessed April 10, 2016.

[6] Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med. 2016 Jan 21;374(3):242-253.

[7] Ibid.

[8] Actavis Pharma. Label: Eluxadoline (VIBERZI). January 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206940s001lblmg.pdf. Accessed April 10, 2017.

[9] Food and Drug Administration. Summary review for VIBERZI (eluxadoline) NDA206940. May 27, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206940Orig1s000SumR.pdf. Accessed April 11, 2017.

[10] Ibid.

[11] Behar J, Corazziari E, Guelrud M, et al. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology. 2006;130(5):1498–1509.

[12] Druart-Blazy A, Pariente A, Berthelemy P, Arotçarena R. The underestimated role of opiates in patients with suspected sphincter of Oddi dysfunction after cholecystectomy. Gastroenterol Clin Biol. 2005;29(12):1220-1223.

[13] Food and Drug Administration. Summary review for VIBERZI (eluxadoline) NDA206940. May 27, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206940Orig1s000SumR.pdf. Accessed April 11, 2017.

[14] Food and Drug Administration. Cross Discipline Team Leader Review for VIBERZI (eluxadoline) NDA 206940. March 30, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206940Orig1s000CrossR.pdf. Accessed April 11, 2017.

[15] Food and Drug Administration. Drug safety communication: FDA warns about an increased risk of serious pancreatitis with irritable bowel drug Viberzi (eluxadoline) in patients without a gallbladder. March 15, 2017. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM546542.pdf. Accessed April 11, 2017.

[16] Food and Drug Administration. Cross Discipline Team Leader Review for VIBERZI (eluxadoline) NDA 206940. March 30, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206940Orig1s000CrossR.pdf. Accessed April 11, 2017.

[17] Ibid.