Xifaxan Drug Information

Travelers’ Diarrhea

The efficacy of XIFAXAN given as 200 mg orally taken three times a day for 3 days was evaluated in 2 randomized, multi‑center, double-blind, placebo-controlled studies in adult subjects with travelers’ diarrhea. One study was conducted at clinical sites in Mexico, Guatemala, and Kenya (Study 1). The other study was conducted in Mexico, Guatemala, Peru, and India (Study 2).

Stool specimens were collected before treatment and 1 to 3 days following the end of treatment to identify enteric pathogens. The predominant pathogen in both studies was Escherichia coli. The clinical efficacy of XIFAXAN was assessed by the time to return to normal, formed stools, and resolution of symptoms.

The primary efficacy endpoint was time to last unformed stool (TLUS) which was defined as the time to the last unformed stool passed, after which clinical cure was declared. Table 5 displays the median TLUS and the number of patients who achieved clinical cure for the intent to treat (ITT) population of Study 1. The duration of diarrhea was significantly shorter in patients treated with XIFAXAN than in the placebo group.

More patients treated with XIFAXAN were classified as clinical cures than were those in the placebo group. Table 3. Escherichia coli was the only pathogen with sufficient numbers to allow comparisons between treatment groups.

Even though XIFAXAN had microbiologic activity similar to placebo, it demonstrated a clinically significant reduction in duration of diarrhea and a higher clinical cure rate than placebo. Therefore, patients should be managed based on clinical response to therapy rather than microbiologic response. Table 4.

In addition, this study provided evidence that subjects treated with XIFAXAN with fever and/or blood in the stool at baseline had prolonged TLUS. These subjects had lower clinical cure rates than those without fever or blood in the stool at baseline. Many of the patients with fever and/or blood in the stool (dysentery-like diarrheal syndromes) had invasive pathogens, primarily Campylobacter jejuni, isolated in the baseline stool.

Also in this study, the majority of the subjects treated with XIFAXAN who had Campylobacter jejuni isolated as a sole pathogen at baseline failed treatment and the resulting clinical cure rate for these patients was 23.5% (4/17). In addition to not being different from placebo, the microbiologic eradication rates for subjects with Campylobacter jejuni isolated at baseline were much lower than the eradication rates seen for Escherichia coli. Although this open-label challenge trial was not adequate to assess the effectiveness of XIFAXAN in the treatment of shigellosis, the following observations were noted: eight subjects received rescue treatment with ciprofloxacin either because of lack of response to XIFAXAN treatment within 24 hours, or because they developed severe dysentery, or because of recurrence of Shigella flexneri 2a in the stool; five of the 13 subjects received ciprofloxacin although they did not have evidence of severe disease or relapse.

Hepatic Encephalopathy Trial 1

The efficacy of XIFAXAN 550 mg taken orally two times a day was evaluated in a randomized, placebo-controlled, double-blind, multi-center 6-month trial of adult subjects from the U.S., Canada, and Russia who were defined as being in remission (Conn score of 0 or 1) from hepatic encephalopathy (HE). Eligible subjects had ≥2 episodes of HE associated with chronic liver disease in the previous 6 months. A total of 299 subjects were randomized to receive either XIFAXAN (N=140) or placebo (N=159) in this study.

Patients had MELD scores of either at baseline. No patients were enrolled with a MELD score of >25. Nine percent of the patients were Child-Pugh Class C.

Lactulose was concomitantly used by 91% of the patients in each treatment arm of the study. Per the study protocol, patients were withdrawn from the study after experiencing a breakthrough HE episode. The primary endpoint was the time to first breakthrough overt HE episode.

A breakthrough overt HE episode was defined as a marked deterioration in neurological function and an increase of Conn score to Grade ≥2. In patients with a baseline Conn score of 0, a breakthrough overt HE episode could also be defined as an increase in Conn score of 1 and asterixis grade of 1. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE breakthrough by 58% during the 6-month treatment period.

Presented below in Figure 1 is the Kaplan-Meier event-free curve for all subjects (n=299) in the study. Note: Open diamonds and open triangles represent censored subjects. ¹ Event-free refers to non-occurrence of breakthrough HE ² 91% of subjects were taking concomitant lactulose When the results were evaluated by the following demographic and baseline characteristics, the treatment effect of XIFAXAN 550 mg in reducing the risk of breakthrough overt HE recurrence was consistent for: sex, baseline Conn score, duration of current remission, and diabetes. The differences in treatment effect could not be assessed in the following subpopulations due to small sample size: non-White (n=42), baseline MELD >19 (n=26), Child-Pugh Class C (n=31), and those without concomitant lactulose use (n=26).

Comparison of Kaplan-Meier estimates of event-free curves is shown in Figure 2. Note: Open diamonds and open triangles represent censored subjects. ¹ Event-free refers to non-occurrence of HE-related hospitalization ² 91% of subjects were taking concomitant lactulose Trial 2 - Risk Reduction of Hepatic Encephalopathy (XIFAXAN + lactulose vs. XIFAXAN monotherapy) The efficacy of XIFAXAN monotherapy to reduce the risk of recurrence of overt hepatic encephalopathy was evaluated in an open-label, active-controlled, multi-center, 6-month trial of adult subjects (Trial 2).

Sixty-five percent of subjects received lactulose at enrollment. Subjects randomized to XIFAXAN monotherapy who received lactulose at enrollment (N=76) discontinued lactulose on the day of randomization. Comparison of Kaplan-Meier estimates of event-free curves showed that XIFAXAN monotherapy compared with the combination of XIFAXAN + lactulose, increased the risk of HE breakthrough by 98% during the 6-month treatment period (see Figure 3).

Figure 3. In these trials, a total of 1,258 patients meeting Rome II criteria for IBS* were randomized to receive XIFAXAN 550 mg three times a day (n=624) or placebo (n=634) for 14 days and then followed for a 10-week treatment-free period. The Rome II criteria further categorizes IBS patients into 3 subtypes: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), or alternating IBS (bowel habits alternating between diarrhea and constipation).

Patients with both IBS-D and alternating IBS were included in Trials 1 and 2. XIFAXAN is recommended for use in patients with IBS-D. *Rome II Criteria: At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features: 1. Relieved with defecation; and/or 2.

Onset associated with a change in frequency of stool; and/or 3. Onset associated with a change in form (appearance) of stool. Symptoms that Cumulatively Support the Diagnosis of Irritable Bowel Syndrome: –Abnormal stool frequency (for research purposes “abnormal” may be defined as greater than 3 bowel movements per day and less than 3 bowel movements per week); Abnormal stool form (lumpy/hard or loose/watery stool); Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); Passage of mucus; Bloating or feeling of abdominal distension.

Trial 3 - Design Trial 3 evaluated repeat treatment in adults with IBS-D meeting Rome III criteria* for up to 46 weeks. A total of 2,579 patients were enrolled to receive open-label XIFAXAN for 14 days. A total of 636 patients had symptom recurrence and were randomized into the double-blind phase of the study.

These patients were scheduled to receive XIFAXAN 550 mg three times a day (n=328) or placebo (n=308) for two additional 14-day repeat treatment courses separated by 10 weeks (see Figure 4). Improvement with defecation; 2. The primary endpoint for both trials was the proportion of patients who achieved adequate relief of IBS signs and symptoms for at least 2 of 4 weeks during the month following 14 days of treatment.

Adequate relief was defined as a response of “yes” to the following weekly Subject Global Assessment (SGA) question: “ In regards to your IBS 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 symptoms?.” Adequate relief of IBS symptoms was experienced by more patients receiving XIFAXAN than those receiving placebo during the month following 2 weeks of treatment SGA-IBS Weekly Results: (see Table 7). Table 5. Adequate Relief of IBS Symptoms During the Month Following Two Weeks of Treatment The trials examined a composite endpoint which defined responders by IBS-related abdominal pain and stool consistency measures.

Patients were monthly responders if they met both of the following criteria: • experienced a ≥30% decrease from baseline in abdominal pain for ≥2 weeks during the month following 2 weeks of treatment • had a weekly mean stool consistency score <4 (loose stool) for ≥2 weeks during the month following 2 weeks of treatment More patients receiving XIFAXAN were monthly responders for abdominal pain and stool consistency in Trials 1 and 2 (see Table 8). Table 6. Efficacy Responder Rates in Trial 1 and 2 During the Month Following Two Weeks of Treatment ª Confidence Interval ᵇ The p -value for the composite endpoint for Trial respectively.

At the end of the follow-up period, patients were assessed for response to treatment. Patients were considered a responder if they achieved both of the following: • ≥30% improvement from baseline in the weekly average abdominal pain score based on the daily question: “ In regards to your specific IBS symptoms of abdominal pain, on a scale of 0-10, what was your worst IBS-related abdominal pain over the last 24 hours? ‘Zero’ means you have no pain at all; ‘Ten’ means the worst possible pain you can imagine”. • at least a 50% reduction in the number of days in a week with a daily stool consistency of Bristol Stool Scale type 6 or 7 compared with baseline where 6=fluffy pieces with ragged edges, a mushy stool; 7=watery stool, no solid pieces; entirely liquid. Responders were then followed for recurrence of their IBS-related symptoms of abdominal pain or mushy/watery stool consistency for up to 20 treatment-free weeks.

When patients experienced recurrence of their symptoms of abdominal pain or mushy/watery stool consistency for 3 weeks of a rolling 4-week period, they were randomized into the double-blind, placebo-controlled repeat treatment phase. Of 1,074 patients who responded to open-label XIFAXAN, 382 experienced a period of symptom inactivity or decrease that did not require repeat treatment by the time they discontinued, including patients who completed the 22 weeks after initial treatment with XIFAXAN (see Figure 3). Overall, 1,257 of 2,579 patients (49%) were nonresponders in the open-label phase and per the study protocol were withdrawn from the study.

There were 1,074 (44%) of 2,438 evaluable patients who responded to initial treatment with improvement in abdominal pain and stool consistency. A total of 636 patients subsequently had sign and symptom recurrence and were randomized to the repeat treatment phase. The median time to recurrence for patients who experienced initial response during the open-label phase with XIFAXAN was 10 weeks (range 6 to 24 weeks).

The XIFAXAN (rifaximin) and placebo treatment groups had similar baseline IBS symptom scores at the time of recurrence and randomization to the double-blind phase, but symptom scores were less severe than at study entry into the open-label phase. Patients were deemed to have recurrent signs and symptoms by the following criteria: a return of abdominal pain or lack of stool consistency for at least 3 weeks during a 4-week follow-up period. The primary endpoint in the double-blind, placebo-controlled portion of the trial was the proportion of patients who were responders to repeat treatment in both IBS-related abdominal pain and stool consistency as defined above during the 4 weeks following the first repeat treatment with XIFAXAN.

The primary analysis was performed using the worst case analysis method where patients with <4 days of diary entries in a given week are considered as non-responders for that week. More patients receiving XIFAXAN were monthly responders for abdominal pain and stool consistency in the primary analysis in Trial 3 (see Table 9). Table 7.