Rifaximin is an antibiotic for the treatment of irritable bowel syndrome with diarrhea (IBS-D) and IBS-related bloating. Rifaximin works by reducing or altering bacteria in the gut. In studies it has been found to improve IBS symptoms of belly pain, and diarrhea (watery or loose stools) after a 10–14 day course of treatment. It is only slightly absorbed in the gut and is generally tolerated well.
May 27, 2015 – The U.S. Food and Drug Administration (FDA) today approved rifaximin (Xifaxan®) for treating irritable bowel syndrome with diarrhea (IBS-D) in adult men and women.
The safety and effectiveness of Xifaxan for treatment of IBS-D were established in three double-blind, placebo-controlled trials. In the first two trials, 1,258 patients were randomly assigned to receive Xifaxan or placebo for 14 days, and then followed for a 10-week treatment-free period. More Xifaxan-treated patients reported improvements in abdominal pain and stool consistency than those on placebo.
A third trial evaluated repeat courses of Xifaxan, because patients with IBS-D can develop recurrent signs and symptoms after a single treatment course of Xifaxan. A total of 636 patients with recurrence were randomized to receive either Xifaxan or placebo for two additional 14-day courses separated by 10 weeks. More patients treated with Xifaxan than placebo were responders in abdominal pain and stool consistency in this phase of the study.
The most common side effects in patients treated with Xifaxan for IBS-D include nausea and an increase in alanine aminotransferase (ALT), a liver enzyme measured in blood.
If diarrhea does not improve or worsens after treatment with Xifaxan, then evaluation for development of a severe infectious diarrhea, C. difficile enterocolitis, should be performed. Caution should be used when using Xifaxan in patients with severe liver impairment or when combined with certain other drugs.
September 19, 2014 – The supplemental new drug application (sNDA) for the antibiotic, rifaximin 550 mg, has been accepted for review by the U.S. Food & Drug Administration (FDA). A decision from the FDA regarding the approval status of the drug for the treatment of IBS-D is expected in early 2015.
Salix Pharmaceuticals announces Initiation of Clinical Trial to Assess Repeat Treatment with Rifaximin
July 1, 2014 – Salix Pharmaceuticals reported positive results from the TARGET 3 – Phase 3 study to evaluate the efficacy and safety of repeat 14 day treatment with rifaximin for the treatment of IBS with diarrhea (IBS-D) in people who responded to an initial 14 day treatment course with rifaximin. Compared to placebo, subjects treated with rifaximin showed statistically significant improvement in IBS-related abdominal pain and stool consistency during the 4 week treatment-free follow-up period in the double blind repeat treatment phase.
Salix is seeking marketing approval from the FDA for rifaximin as a treatment option for irritable bowel syndrome with diarrhea.
February 21, 2012 – Salix Pharmaceuticals announced the initiation of TARGET 3 – a Phase 3 study to evaluate the efficacy and safety of repeat treatment with Xifaxan (rifaximin) for irritable bowel syndrome with diarrhea (IBS-D). The study will involve approximately 800 adults with IBS-D who have previously responded to an initial treatment course of rifaximin 550mg, three times a day, for 14 days. In this study, these patients will take a repeat treatment of 550 mg rifaximin three times daily for another 14 day course. TARGET 3 is randomized, double-blind, placebo-controlled and will be conducted in approximately 250 sites throughout the United States.
FDA Approves new Clinical Trial Looking at Repeat Treatment with Rifaximin
November 16, 2011 – Salix Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) Gastrointestinal Drugs Advisory Committee supported the Salix/FDA developed proposed design of a clinical trial to evaluate the safety, efficacy and durability of response with repeat treatment cycles of Xifaxan (rifaximin) for irritable bowel syndrome with diarrhea (IBS). A multi-center, randomized, double-blind, placebo-controlled trial with IBS patients will look at the efficacy and safety of rifaximin on repeat treatment.
Patient enrollment is planned during the first quarter of 2012. About 24 months could be required for the company to complete the trial and secure an FDA decision regarding approval.
FDA Delays Approval Consideration of Rifaximin
March 8, 2011 - Salix Pharmaceuticals confirmed that the U.S. Food and Drug Administration (FDA) wants more information about rifaximin. The FDA is not ready to grant a new marketing approval for rifaximin for the treatment of non-constipation irritable bowel syndrome (Non-C IBS) and IBS-related bloating. The FDA may require that another clinical trial be performed, which could take years to complete. Salix said it will request a meeting to discuss this with the FDA.
Rifaximin is currently approved by the FDA for treatment of travelers’ diarrhea (under the trade name of Xifaxan®), but at lower doses and shorter duration of therapy than being studied in IBS. The FDA had originally set a target date of March 7, 2011 to complete the Priority Review for expanding the uses of rifaximin to include treatment of IBS.
Rifaximin Shows Promise for Treatment on Non-Constipated IBS
January 6, 2011 – Results from two Phase 3 clinical trials involving 1,260 non-constipated male and female patients with irritable bowel syndrome (Non-C IBS) were reported in the January 6, 2011 issue of the New England Journal of Medicine (NEJM) showing adequate relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools.
Results from the multiple center studies indicated that 550mg rifaximin, taken orally 3 times a day for 14 days, achieved adequate relief of global IBS symptoms (primary endpoint) and adequate relief of IBS-related bloating (key secondary endpoint) in a significantly greater proportion of patients, compared with placebo, during the primary evaluation period (first 4 weeks following treatment) as well as during the entire study period (10 weeks following treatment). The statistically significant weekly findings in the primary endpoint and key secondary endpoint noted above were supported by daily findings in the secondary endpoints of global IBS symptoms, bloating, stool consistency and abdominal pain and discomfort. Additionally, the NEJM publication includes results of an analysis of a composite endpoint of abdominal pain or discomfort and loose or watery stools as outlined in the March 2010 draft FDA Guidance for Industry relating to the clinical evaluation of products for treatment of IBS. The safety profile of rifaximin was similar to that of placebo.
Rifaximin is a gut-selective antibiotic with negligible systemic absorption and broad-spectrum activity in vitro against both gram-positive and gram-negative pathogens. It is currently approved by the U.S. Food and Drug Administration (FDA) for treatment of travelers’ diarrhea (under the trade name of Xifaxan®), but at lower doses and shorter duration of therapy than being studied in IBS. It is not yet approved by the FDA for the treatment of IBS. The FDA has set a target date of March 7, 2011 to complete the Priority Review for expanding the uses of Xifaxan (rifaximin) to include treatment of non-constipation irritable bowel syndrome (Non-C IBS) and IBS-related bloating.
Salix Pharmaceuticals Announces FDA Acceptance For NDA Priority Review For Xifaxan550 For Treatment Of Non-Constipation Irritable Bowel Syndrome
August 9, 2010 – Salix announced the U.S. Food and Drug Administration (FDA) accepted for Priority Review the Company’s efficacy supplement to the New Drug Application (NDA) for XIFAXAN® (rifaximin) 550 mg tablets for the proposed indication of treatment of non-constipation irritable bowel syndrome (Non-C IBS) and IBS-related bloating.
The filing included data which showed XIFAXAN550 demonstrated that a 14-day course, taken three times daily, achieved adequate relief of IBS symptoms in a significantly greater proportion of patients during the first four weeks following two weeks of treatment, as well as over three months (2-week treatment plus 10-week follow-up), compared with placebo. The safety profiles were similar between XIFAXAN 550 mg and placebo.
Salix Pharmaceuticals Announces NDA Submission to the FDA For Xifaxan550 For Treatment Of Non-Constipation Irritable Bowel Syndrome
June 08, 2010 – Salix Pharmaceuticals, Ltd. today announced that the Company has submitted an efficacy supplement to NDA 21–361 for XIFAXAN® (rifaximin) 550 mg tablets for the proposed indication of treatment of non–constipation irritable bowel syndrome (Non–C IBS) and IBS–related bloating.
By regulation, the Food and Drug Administration (FDA) has 60 days to conduct a filing review to determine if the application is sufficiently complete to permit a substantive review. Salix has requested Priority Review for this application. By regulation, the FDA should determine the review classification for this application within the 60–day period referenced above.
Phase 3 Studies Report Rifaximin Shows Promise for Treatment on Non-Constipated IBS
NEW ORLEANS, LA, May 3, 2010 – Results from two Phase 3 clinical trials involving 1,260 non-constipated male and female patients with irritable bowel syndrome (IBS) were presented at the annual Digestive Disease Week (DDW) meeting in May 2010. Results from the multiple center studies indicated that 550mg Rifaximin, taken orally 3 times a day for 14 days, achieved adequate relief of IBS symptoms over a period of 12 weeks (2 weeks of treatment plus 10 weeks of follow-up). Adequate relief was demonstrated in a statistically greater proportion of patients on the drug compared to placebo. Improvement was reported in overall IBS symptoms and IBS specific symptoms of bloating, stool consistency and abdominal pain and discomfort.
Rifaximin is a broad-spectrum antibiotic that targets bacterial overgrowth in the small intestine. It is only slightly absorbed in the gut. While rifaximin is generally well tolerated, as with all antibiotics side-effects may occur. It is currently approved by the U.S. Food and Drug Administration (FDA) for treatment of travelers’ diarrhea (under the trade name of Xifaxan®), but at lower doses and shorter duration of therapy than being studied in IBS. It is not yet approved by the FDA for the treatment of IBS. Rifaximin is marked by Salix Pharmaceuticals.
Salix Presents New Phase II Data Evidence Demonstrating the Clinical Utility of Rifaximin in Irritable Bowel Syndrome (IBS)
Results Presented at American College of Gastroenterology Annual Meeting Demonstrate Quality of Life Benefits and IBS Symptom Severity as Predictor of Clinical Response
ORLANDO, FLA., October 6, 2008 – Salix Pharmaceuticals, Ltd. (NASDAQ:SLXP) today announced findings from two analyses of a Phase II clinical trial that demonstrate the utility of rifaximin, a non–absorbed, gut–selective antibiotic, in the treatment of patients with diarrhea–predominant irritable bowel syndrome (IBS). Data presented at the annual meeting of the American College of Gastroenterology (ACG) showed that patients treated with rifaximin demonstrated that the severity of baseline IBS symptoms of abdominal pain and bloating predicted clinical response to rifaximin and demonstrated statistically greater clinical improvement in quality of life compared with placebo.
"The latest findings, along with previously reported data, suggest a potential therapeutic role for rifaximin – a non–absorbed and gut–selective antibiotic – in patients with irritable bowel syndrome," said William D. Chey, MD, professor of medicine in the Division of Gastroenterology at the University of Michigan, and director of the Gastrointestinal (GI) Physiology Laboratory at the University of Michigan Medical Center. "The evidence in support of rifaximin will be discussed in a forthcoming evidence-based review from the American College of Gastroenterology on the management of IBS."
Improvements in Quality of Life
In a poster presentation at ACG, Dr. Chey and colleagues reported that a 2-week course of rifaximin (1100 mg/day) significantly improved quality of life (QOL) measures, compared with placebo. In a Phase II multi–center, double–blind, placebo–controlled trial, 191 adult patients diagnosed with diarrhea-predominant IBS (IBS-D) by Rome II criteria were randomized to receive rifaximin 550 mg twice daily (b.i.d.) and 197 patients were randomized to placebo. Following a 2-week initial treatment period, both groups of patients received placebo for an additional 14 days. Quality of life was assessed via the 34-item IBS-QOL questionnaire at baseline and 4 weeks after initiating treatment. Each item was scored on a 5-point scale (1=not at all; 2=slightly; 3=moderately; 4=quite a bit; 5=extremely or a great deal); results for composite and subscale scores were converted to a scale ranging from 0 to 100, with higher scores indicating better QOL.
At Week 4, the mean improvement from baseline in the overall QOL score was significantly greater with rifaximin compared with placebo (20.4 vs. 15.8, respectively; p=0.020). Patients in the rifaximin group also reported significantly greater mean improvement from baseline in QOL subscale scores for dysphoria (restlessness or agitation, 24.8 vs. 19.8; p=0.027), body image (20.1 vs. 14.6; p=0.012), health worry (16.0 vs. 12.2; p=0.047), social reaction (17.3 vs. 13.2; p=0.047), and relationships (14.9 vs. 10.7; p=0.030), compared with placebo. Rifaximin was well tolerated in the study, with a similar incidence of adverse events compared with placebo.
Severity of Baseline Symptoms as Predictor of Clinical Response
In a separate poster presentation from the same study, Mark Pimentel, MD, and colleagues reported that the severity of baseline symptoms of abdominal pain and bloating influenced the response to rifaximin treatment. The co-primary endpoints in this analysis assessed weekly yes/no responses to questions regarding adequate relief of global IBS symptoms and IBS-associated bloating. Clinical response was defined as adequate relief for at least 2 of the final 3 treatment weeks (Week 2, 3 or 4). Severity of baseline IBS symptoms was evaluated as a potential confounder of clinical response and was categorized as mild/moderate or severe based on a mean score of ≤4 vs. >4 (on a 7-point scale [0=not bothersome; 6=very bothersome]) for bloating and abdominal pain.
A significantly larger percentage of patients treated with rifaximin reported adequate relief of global IBS symptoms (52% vs. 44% for placebo; p=0.03) and bloating (46% vs. 40%; p=0.04), compared with placebo-treated patients. In patients with mild/moderate abdominal pain, rifaximin produced a greater degree of improvement, compared with placebo, in global symptoms of IBS (50% vs. 39%, respectively; p=0.04) and bloating (44% vs. 35%; p=0.09). Similarly, in patients with mild/moderate bloating, rifaximin treatment was associated with greater improvement, compared with placebo, in global IBS symptoms (56% vs. 41%, respectively; p=0.006) and bloating (47% vs. 36%; p=0.03). However, rifaximin was not significantly superior to placebo in improving global IBS symptoms or bloating in patients who had severe baseline abdominal pain or bloating.
"The symptom-based criteria that are used for enrolling patients with IBS in clinical trials are overly broad and often lead to enrollment of individuals ranging from mild to severe, despite the possibility that patients with severe IBS symptoms may respond differently to treatment compared with individuals with moderate complaints," commented Dr. Pimentel, who is director of the Gastrointestinal Motility Program and Laboratory at Cedars-Sinai Medical Center, and associate professor in residence for the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). "Our data demonstrate that patients with mild/moderate IBS symptoms are more likely than those with severe disease to achieve symptomatic relief with rifaximin. Clinical trials evaluating the efficacy of IBS therapies should therefore account for baseline symptom severity because of the potential impact of these symptoms on therapeutic efficacy. Additionally, incorporating severity assessments into clinical practice may improve treatment success in patients with IBS."
Rifaximin, which Salix markets in the United States under the trade name XIFAXAN® (rifaximin), currently is approved for the treatment of patients, 12 years of age or older, with travelers' diarrhea caused by non–invasive strains of Escherichia coli.
XIFAXAN® (rifaximin) is a gut–selective antibiotic with negligible systemic absorption (<0.4%) and broad–spectrum activity in vitro against both gram–positive and gram–negative pathogens. Rifaximin has a similar tolerability profile to that of placebo and has activity against the most common TD pathogens. XIFAXAN is under investigation in the United States as a treatment for irritable bowel syndrome. In the United States, the FDA granted marketing clearance for XIFAXAN tablets 200 mg indicated for the treatment of patients (≥12 years of age) with travelers' diarrhea caused by noninvasive strains of Escherichia coli. XIFAXAN should not be used in patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than Escherichia coli. XIFAXAN should be discontinued if diarrhea symptoms get worse or persist more than 24–48 hours and alternative antibiotic therapy should be considered. In clinical trials, XIFAXAN was generally well tolerated. The most common side effects (vs. placebo) were flatulence 11.3% (versus 19.7%), headache 9.7% (versus 9.2%), abdominal pain 7.2% (versus 10.1 %) and rectal tenesmus 7.2% (versus 8.8%).
Rifaximin has been used in Italy for 23 years and is approved in 23 countries. Salix acquired rights to market rifaximin in North America from Alfa Wassermann S.p.A. in Bologna, Italy. Alfa Wassermann markets rifaximin in Italy under the trade name Normix®.
XIFAXAN® (rifaximin) 550 mg tablets
XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age. In the trials of XIFAXAN for HE, 91 percent of the patients were using lactulose concomitantly. XIFAXAN has not been studied in patients with MELD scores > 25, and only 8.6 percent of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child–Pugh C).
XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.
Clostridium difficile–associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
The most common adverse reactions occurring in more than 8 percent of patients in the clinical study were edema peripheral (15 percent), nausea (14 percent), dizziness (13 percent), fatigue (12 percent), ascites (11 percent), muscle spasms (9 percent), pruritus (9 percent), and abdominal pain (9 percent).
Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription pharmaceutical products for the treatment of gastrointestinal diseases. Salix's strategy is to in–license late–stage or marketed proprietary therapeutic drugs, complete any required development and regulatory submission of these products, and market them through the Company's 150–member gastroenterology specialty sales and marketing team.
What are Phases?
Treatment trials or studies are in phases:
- Phase 1 tests a new drug or treatment in a small group to evaluate its safety, determine a safe dosage range, and identify side effects;
- Phase 2 expands the study to a larger group of people to see if it is effective and to further evaluate its safety;
- Phase 3 expands the study to an even larger group of people to confirm its effectiveness, monitor side effects, and collect information that will allow the drug or treatment to be used safely.