Change condition: IBS-D
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Efficacy

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In this section:

In adults with IBS-D

2 weeks of XIFAXAN provided significant relief of abdominal pain and diarrhea1,2,*

Percentage of composite efficacy responders† in TARGET 1 and 2 during the month following 2 weeks of treatment (pooled analysis)

Target 1 and Target 2 Target 1 and Target 2

*Patients who experience recurrence can be retreated up to 2 times.1

†Efficacy responder defined as a ≥30% decrease from baseline in abdominal pain, with a weekly mean stool consistency score of <4 (loose stool) for ≥2 weeks during the month following 2 weeks of treatment.1

‡P<0.001, represents pooled data.

TARGET 1 and 2 study design

Two identical phase 3, randomized, double-blind, placebo-controlled trials were conducted over a 3-month period. A total of 1258 patients meeting Rome II criteria for IBS-D were to receive XIFAXAN 550 mg 3 times a day (n=624) or placebo (n=634) for 14 days.

Primary endpoint: Adequate relief of IBS-D signs and symptoms for at least 2 of 4 weeks during the month following 14 days of treatment, with adequate relief defined as a response of “yes” to the weekly Subject Global Assessment (SGA) question: “In regards to your IBS-D symptoms, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS-D symptoms? [Yes/No].”

Primary endpoint results: 41% of patients (254 of 624) in the XIFAXAN 550 mg group, 31% of TARGET 1 placebo group (98 of 314), and 32% of TARGET 2 placebo group (103 of 320) experienced adequate relief of IBS-D signs and symptoms.

Secondary endpoint: In both studies, more patients in the XIFAXAN 550 mg group had adequate relief of global IBS-D symptoms (see primary endpoint for definition) within the first month compared with the placebo group. Relief continued during the first 2 months and throughout all 3 months in both studies. TARGET 1 odds ratio: 1.35 (95% CI: 1.00-1.82). TARGET 2 odds ratio: 1.52 (95% CI: 1.13-2.03).

Composite endpoint: Responder defined by a ≥30% decrease from baseline in abdominal pain, with a weekly mean stool consistency score of <4 (loose stool) for ≥2 weeks during the month following 2 weeks of treatment.

XIFAXAN provided relief of bloating and urgency2,3

Percentage of BLOATING responders based on weekly
responses in TARGET 1 & 22

Key secondary endpoint Key secondary endpoint

§Represents pooled analysis.

Key secondary endpoint

The proportion of patients who achieved adequate relief of IBS-D–related bloating (ie, responders) for at least 2 of 4 weeks during the month following 14 days of treatment.2

A bloating responder was defined as a patient who responded “yes” to the weekly question: “In regards to your IBS-D symptom of bloating, compared to the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS-D symptom of bloating? [Yes/No].”2,¶

Responses were given during the first 4 weeks of the treatment-free period following 2 weeks of active treatment (primary evaluation period).2

Percentage of URGENCY responders based on weekly responses in
TARGET 1, 2, and 3 in a pooled post hoc analysis4

Secondary endpoint Secondary endpoint

Secondary endpoint

Change from baseline to each week during the 12-week study duration for sense of urgency.5,6

An urgency responder was defined as a patient with a ≥30% decrease from baseline in the percentage of days with urgency for at least 2 of 4 weeks during the month following 14 days of treatment. Urgency was determined based on patient response of “yes” to the daily question: “Have you felt or experienced a sense of urgency today? [Yes/No]”4

Stool frequency (number of bowel movements per day) was assessed as a secondary endpoint, but there was no meaningful difference between XIFAXAN and placebo.5,6

Efficacy and safety evaluation of TARGET 3:
an extended retreatment trial1,7

TARGET 3 study design1 TARGET 3 study design1

TARGET 3 study design

This trial included an open-label phase followed by a randomized, placebo-controlled phase, with the aim of determining the efficacy and safety of repeat treatment with XIFAXAN in patients with IBS-D who had responded to a 2-week course of XIFAXAN and subsequently experienced IBS-D symptom recurrence.

A responder was defined as a patient experiencing a ≥30% improvement from baseline in the weekly average abdominal pain score (based on daily self-reports) and a ≥50% reduction in the number of days in a week with a daily stool consistency of Bristol Stool Form Scale type 6 or 7 (mushy or watery) for ≥2 of the 4 weeks after treatment.

Recurrence was defined as the return of abdominal pain or lack of stool consistency for 3 weeks of a rolling 4-week period.

Primary endpoint: The proportion of patients who were responders to repeat treatment in both IBS-D–related abdominal pain and stool consistency during the 4 weeks following the first repeat treatment course.

With repeated treatment, recurring symptoms
were less severe than baseline1,7,#

Repeated treatmentTARGET 3 study design1

Change from baseline in mean daily global IBS-D symptom score during the first and second repeat treatment double-blind phases. Global daily IBS-D symptom score is based on a 6-question patient assessment related to bowel movements, urgency, abdominal pain, bloating, and severity of symptoms. All patients in the XIFAXAN arm of this study were given second retreatment/third treatment regardless of symptom recurrence status.7

#Baseline defined as study entry into open-label phase.7

XIFAXAN Strong Recommendation Seal

XIFAXAN was given a strong recommendationll to treat global IBS-D symptoms in the 2020 ACG Clinical Guideline on Managing IBS8,**

**Based on a moderate quality of evidence. ††

ACG, American College of Gastroenterology.

llStrength of recommendation: Strong=Most patients should receive the recommended course of action; Conditional=Many patients should have this recommended course of action, but different choices may be appropriate for some patients.

††Summary of quality of evidence: High=The estimate of effect is unlikely to change with new data. Moderate=The estimate of effect is uncertain.

Questions and statements used to provide recommendations were based on response to global IBS-D symptoms.

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XIFAXAN has a proven
safety profile1

Compare to placebo

IBS-D, irritable bowel syndrome with diarrhea.

References: 1. XIFAXAN. Prescribing information. Salix Pharmaceuticals; 2023. Accessed January 4, 2024. https://shared.salix.com/globalassets/pi/xifaxan550-pi.pdf 2. Pimentel M, Lembo A, Chey WD, et al; TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364(1):22-32. doi:10.1056/NEJMoa1004409 3. Pimentel M, Cash BD, Lacy BE, Heimanson Z, Lembo A. Assessing the efficacy of rifaximin in diarrhea-predominant irritable bowel syndrome: a post hoc analysis of two phase 3, randomized, placebo-controlled trials. Poster presented at: World Congress of Gastroenterology; October 13-18, 2017; Orlando, FL. 4. Schoenfeld PS, Brenner DM, Pichetshote N, Heimanson Z, Lacy BE. Rifaximin significantly improves bowel movement urgency in patients with irritable bowel syndrome with diarrhea: a pooled analysis of three phase 3 trials. Poster presented at: Digestive Disease Week; May 21-23, 2021; virtual. 5. Data on file. Target 1 CSR May 2010. Salix Pharmaceuticals, Bridgewater, NJ. 6. Data on file. Target 2 CSR May 2010. Salix Pharmaceuticals, Bridgewater, NJ. 7. 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. doi:10.1053/j.gastro.2016.08.003 8. Lacy BE, Pimentel M, Brenner DM, et al. ACG clinical guideline: management of irritable bowel syndrome. Am J Gastroenterol. 2021;116(1):17-44. doi:10.14309/ajg.0000000000001036

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INDICATIONS

XIFAXAN® (rifaximin) 550 mg tablets are indicated for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults and for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

XIFAXAN® (rifaximin) 550 mg tablets are indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

IMPORTANT SAFETY INFORMATION

  • XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, 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. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
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INDICATIONS

XIFAXAN® (rifaximin) 550 mg tablets are indicated for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults and for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

IMPORTANT SAFETY INFORMATION

  • XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, 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. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
  • There is an increased systemic exposure in patients with severe (Child-Pugh Class C) hepatic impairment. Caution should be exercised when administering XIFAXAN to these patients.
  • Caution should be exercised when concomitant use of XIFAXAN and P-glycoprotein (P-gp) and/or OATPs inhibitors is needed. Concomitant administration of cyclosporine, an inhibitor of P-gp and OATPs, significantly increased the systemic exposure of rifaximin. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin.
  • In clinical studies, the most common adverse reactions for XIFAXAN (alone or in combination with lactulose) were:
    – HE (≥10%): Peripheral edema (17%), constipation (16%), nausea (15%), fatigue (14%), insomnia (14%), ascites (13%), dizziness (13%), urinary tract infection (12%), anemia (10%), and pruritus (10%)
    – IBS-D (≥2%): Nausea (3%), ALT increased (2%)
  • INR changes have been reported in patients receiving rifaximin and warfarin concomitantly. Monitor INR and prothrombin time. Dose adjustment of warfarin may be required.
  • XIFAXAN may cause fetal harm. Advise pregnant women of the potential risk to a fetus.

To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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