Rifaximin (XIFAXAN): Another Poor Choice for Treating Irritable Bowel Syndrome

The Food and Drug Administration (FDA) approved rifaximin (XIFAXAN) in May 2015 for the treatment of irritable bowel syndrome (IBS) with diarrhea as the predominant symptom (IBS-D) in adults.[1]

Rifaximin is a broad-spectrum oral antibiotic that the FDA originally approved in 2004 for the treatment of traveler’s diarrhea caused by Escherichia coli bacteria.[2] In 2010, the FDA expanded the drug’s approval to include prevention of recurrent hepatic encephalopathy (a brain disorder that can occur in patients with severe liver disease).[3] The exact way that rifaximin works in the treatment of IBS-D is unclear, but it is thought to achieve benefit by altering the bacteria in the intestines.[4]

We have designated rifaximin as Do Not Use for the treatment of IBS-D because it offers minimal short-term benefits, and its long-term effectiveness and safety, including the potential risk of promoting antibiotic resistance, is not known.

Overview of irritable bowel syndrome[5]

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

The FDA’s approval of rifaximin for the treatment of IBS-D was based on evidence from three randomized clinical trials.

The first two trials, called TARGET 1 and TARGET 2, were identical. Subjects in each trial received either rifaximin or a placebo three times daily for 14 days and then were followed for 10 weeks. Slightly more subjects in the rifaximin groups than in the placebo groups reported adequate relief of symptoms during at least two of the first four weeks after treatment (41 percent versus 32 percent, respectively).[6] However, symptoms recurred in many patients over the 10-week follow-up period. The FDA initially rejected approval of rifaximin, in part due to concerns that evidence from these short-term trials was “inadequate for a chronic condition.”[7] The agency requested that the manufacturer provide additional data to support the drug’s effectiveness in IBS-D patients with recurrent symptoms.

As a result of this request, the drug’s manufacturer conducted a third clinical trial called TARGET 3. This trial evaluated up to two additional 14-day treatments with rifaximin, separated by 10 weeks, in adults with IBS-D who had experienced symptomatic relief after an initial 14-day treatment with the drug but developed recurrent symptoms.[8] Of the 2,579 subjects initially enrolled in the TARGET 3 trial, less than half (1,074) experienced symptomatic relief from an initial 14-day course of rifaximin, and of these, nearly two-thirds experienced recurrent symptoms.[9] In these subjects with recurrent symptoms, those receiving additional treatment with rifaximin were slightly more likely to have decreased abdominal pain compared with those receiving a placebo (51 percent versus 42 percent, respectively). However, additional treatment with rifaximin did not provide improvement in diarrhea symptoms compared with placebo. In fact, the incidence of diarrhea was two times greater in subjects receiving rifaximin than in those receiving a placebo (2 percent versus 1 percent, respectively).

Serious adverse effects

Most antibiotics are used for the short-term treatment of bacterial infections, not for the prevention of recurrent symptoms due to a chronic condition such as IBS-D that has no proven underlying bacterial cause.

Similar to many antibiotics, rifaximin can alter the balance of bacteria in the intestines and may increase the risk of certain infections.[10],[11],[12] For example, during the TARGET 3 trial, the incidence of influenza and bronchitis was greater in subjects taking rifaximin (2 percent and 3 percent, respectively) than in those receiving a placebo (1 percent and 2 percent, respectively).[13]

The FDA-approved product labeling for rifaximin also warns about the development of antibiotic-resistant bacteria.[14]

In a 2011 meeting of the FDA’s Gastrointestinal Drug Advisory Committee, the majority of committee members voiced concerns about long-term, repetitive use of rifaximin for the prevention of symptoms in IBS-D patients given the risks of infections and the development of antibiotic-resistant bacteria.[15]

Rifaximin, like most antibiotics, can cause Clostridium difficile (C. difficile) colitis — a potentially fatal infection of the colon. Symptoms of C. difficile colitis range from mild diarrhea to severe, bloody diarrhea and may include fever, nausea, loss of appetite and weight loss. As noted in the FDA-approved product labeling for rifaximin, C. difficile infection can occur as late as two or more months after stopping treatment with the drug.[16]

Against the recommendation of the FDA’s Gastrointestinal Drug Advisory Committee,[17] the FDA did not require the manufacturer to conduct long-term surveillance studies for C. difficile in patients taking rifaximin for IBS-D.

Rifaximin may increase the risk of liver damage. During the TARGET 3 trial, use of rifaximin was associated with more than a two-fold greater incidence of elevated liver enzymes on blood tests — an early sign of liver toxicity — compared with use of a placebo (2 percent versus 1 percent, respectively).[18]

Rifaximin may be associated with muscle pains and spasms.[19] Of note, during the TARGET 3 trial, subjects taking rifaximin were three times more likely to have elevated creatine phosphokinase (CPK) blood levels compared with those receiving a placebo (3 percent versus 1 percent, respectively).[20] Such CPK elevations often occur in patients who have muscle injury.

Rifaximin also is associated with serious hypersensitivity (allergic) reactions, including angioedema (the sudden swelling of the face, hands, feet and/or throat) and anaphylaxis.[21] Adverse skin reactions, including exfoliative dermatitis (inflammation and shedding of the skin over large areas of the body) have been reported in some patients.

Finally, although it is not known whether rifaximin is harmful to an unborn human fetus, animal studies suggest rifaximin causes abnormal fetal development.[22] This concern is compounded by the fact that rifaximin can decrease the effectiveness of some oral contraceptives.[23]

What You Can Do

Due to evidence of limited clinical benefit, with no evidence demonstrating that it is more effective than other, safer treatment options, and the risk of serious adverse effects, you should not use rifaximin to treat IBS-D.

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] Food and Drug Administration. Supplement approval letter for XIFAXAN (rifaximin) sNDA 021361. May 27, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/021361Orig1s012ltr.pdf. Accessed August 25, 2017. August 25, 2017.

[2] Food and Drug Administration. Approval letter for XIFAXAN (rifaximin) NDA 021361. May 25, 2004. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/21361ltr.pdf. Accessed August 25, 2017.

[3] Food and Drug Administration. Approval letter for XIFAXAN (rifaximin) NDA 022554. March 24, 2010. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/022554s000ltr.pdf. Accessed August 25, 2017.

[4] Rifaximin (Xifaxan) for irritable bowel syndrome with diarrhea. Med Lett Drugs Ther. 2015 Aug 3;57(1474):109-111.

[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 August 22, 2017.

[6] Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan 6;364(1):22-32.

[7] Food and Drug Administration. Gastrointestinal Drugs Advisory Committee Meeting background package. November 16, 2011. https://wayback.archive-it.org/7993/20170405221559/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM279643.pdf. Accessed August 25, 2017.

[8] Salix Pharmaceuticals. Label: rifaximin (XIFAXAN). March 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=e2991a17-fa65-49bd-a5e3-c41f2179dd9e&type=pdf&name=e2991a17-fa65-49bd-a5e3-c41f2179dd9e. Accessed August 25, 2017.

[9] Lembo A, Pimentel M, Rao SS, et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2016;151(6):1113-1121.

[10] Pfeiffer JK, Virgin HW. Viral immunity. Transkingdom control of viral infection and immunity in the mammalian intestine. Science. 2016;351(6270). pii:aad5872. doi: 10.1126/science.aad5872.

[11] Ferrer M, Martins dos Santos VA, Ott SJ, Moya A. Gut microbiota disturbance during antibiotic therapy: A multi-omic approach. Gut Microbes. 2014;5(1):64-70.

[12] Brown RL, Clarke TB. The regulation of host defences to infection by the microbiota. Immunology. 2017;150(1):1-6.

[13] ClinicalTrials.gov. NCT 01543178: Irritable Bowel Syndrome With Diarrhea (IBS-D) Rifaximin Re-Treatment Study (TARGET3). https://clinicaltrials.gov/ct2/show/results/NCT01543178?term=NCT+01543178&rank=1§=X40156#othr. Accessed August 25, 2017.

[14] Salix Pharmaceuticals. Label: rifaximin (XIFAXAN). March 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=e2991a17-fa65-49bd-a5e3-c41f2179dd9e&type=pdf&name=e2991a17-fa65-49bd-a5e3-c41f2179dd9e. Accessed August 25, 2017.

[15] Food and Drug Administration. Summary minutes of the Gastrointestinal Drugs Advisory Committee Meeting. November 16, 2011. https://wayback.archive-it.org/7993/20170404152452/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM283448.pdf. Accessed August 25, 2017.

[16] Salix Pharmaceuticals. Label: rifaximin (XIFAXAN). March 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=e2991a17-fa65-49bd-a5e3-c41f2179dd9e&type=pdf&name=e2991a17-fa65-49bd-a5e3-c41f2179dd9e. Accessed August 25, 2017.

[17] Food and Drug Administration. Summary minutes of the Gastrointestinal Drugs Advisory Committee Meeting. November 16, 2011. https://wayback.archive-it.org/7993/20170404152452/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM283448.pdf. Accessed August 25, 2017.

[18] ClinicalTrials.gov. NCT 01543178: Irritable Bowel Syndrome With Diarrhea (IBS-D) Rifaximin Re-Treatment Study (TARGET3). https://clinicaltrials.gov/ct2/show/results/NCT01543178?term=NCT+01543178&rank=1§=X40156#othr. Accessed August 25, 2017.

[19] Salix Pharmaceuticals. Label: rifaximin (XIFAXAN). March 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=e2991a17-fa65-49bd-a5e3-c41f2179dd9e&type=pdf&name=e2991a17-fa65-49bd-a5e3-c41f2179dd9e. Accessed August 25, 2017.

[20] ClinicalTrials.gov. NCT 01543178: Irritable Bowel Syndrome With Diarrhea (IBS-D) Rifaximin Re-Treatment Study (TARGET3). https://clinicaltrials.gov/ct2/show/results/NCT01543178?term=NCT+01543178&rank=1§=X40156#othr. Accessed August 25, 2017.

[21] Salix Pharmaceuticals. Label: rifaximin (XIFAXAN). March 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=e2991a17-fa65-49bd-a5e3-c41f2179dd9e&type=pdf&name=e2991a17-fa65-49bd-a5e3-c41f2179dd9e. Accessed August 25, 2017.

[22] Ibid.

[23] Ibid.