General Information

Xifaxan (rifaximin) is a non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived from rifamycin. Rifaximin exerts its antimicrobial effect by inhibiting bacterial RNA synthesis.

Xifaxan is indicated for the treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coli in patients 12 years old and older.

Xifaxan is specifically indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults.

Xifaxan is specifically indicated for the treatment of  irritable bowel syndrome (IBS) with diarrhea (IBS-D) in adults.

Mechanism of Action

Rifaximin, the active ingredient in Xifaxan, is a rifamycin derivative and non-systemic, gastrointestinal site-specific antibiotic.

Side Effects

Adverse events associated with the use of Xifaxan for TD may include (but are not limited to) the following:

• Flatulence
• Headache
• Abdominal pain
• Rectal tenesmus
• Defecation urgency
• Nausea
• Constipation
• Pyrexia
• Vomiting

Adverse events associated with the use of Xifaxan for HE may include, but are not limited to, the following:

• Peripheral edema
• Nausea
• Dizziness
• Fatigue
• Ascites
• Flatulence
• Headache

Adverse effects associated with the use of Xifaxan for IBS-D may include, but are not limited to, the following:

• ALT increased
• Nausea

Dosing/Administration

For the treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli in patients 12 years old and older, the recommended dosage of Xifaxan is one 200 mg tablet taken three times a day for three days.

For reduction in risk of overt hepatic encephalopathy recurrence in adults, Xifaxan is supplied as 550 mg tablet for oral administration. The recommended dose is one 550 mg tablet taken orally two times a day, with or without food.

For the treatment of  IBS-D in adults, Xifaxan is supplied as a tablet for oral administration. The recommended dose is one 550-mg tablet taken orally three times a day for 14 days. Patients who experience a recurrence of symptoms can be retreated up to two times with the same dosage regimen.

Clinical Trial Results

Travelers’ diarrhea: FDA approval of Xifaxan was based on two randomized, multicenter, double-blind, placebo-controlled studies in adult subjects with travelers’ diarrhea. The studies enrolled 320 subjects at multiple sites in Mexico, Peru, India, Guatemala and Kenya. Subject’s stool specimens were collected before and after the end of treatment to identify enteric pathogens, which was predominantly Escherichia coli. The primary efficacy end point was time to last unformed stool (TLUS), which is defined as the time to the last unformed stool passed, after which clinical cure was declared.

Results showed that the duration of diarrhea was significantly shorter in patients treated with rifaximin (32.5 hours) than in the placebo group (58.6 hours). In addition, more subjects treated with rifaximin (99) were classified as being clinical cured than subjects treated with placebo (78). Although rifaximin had microbiologic activity similar to placebo, it demonstrated a clinically significant reduction in duration of diarrhea and a higher clinical cure rate than placebo.

The majority of the rifaximin-treated subjects who had Campylobacter jejuni isolated as a sole pathogen at baseline failed treatment with a clinical cure rate of 23.5 percent (4/17). These results were no different from placebo and the microbiologic eradication rates for subjects with Campylobacter jejuni isolated at baseline were much lower than the eradication rates seen for Escherichia coli.

The FDA approval of Xiaxan for hepatic encephalopathy was based on a randomized, placebo-controlled, double-blind, multicenter, six-month trial in adults across the U.S., Canada and Russia. All subjects were defined as being in remission from hepatic encephalopathy and had at least two episodes of HE associated with chronic liver disease in the previous six months. A total of 299 subjects were randomized to receive either Xifaxan or placebo. The primary end point 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. Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22 percent) in the Xifaxan group and by 73 of 159 subjects (46 percent) in the placebo group during the six-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves showed Xifaxan significantly reduced the risk of HE breakthrough by 58 percent during the six-month treatment period.

The FDA approval of Xifaxan for IBS-D was based on three phase 3 randomized, multicenter, double-blind, placebo-controlled trials, TARGET-1, -2 and -3. 

TARGET-1 and -2

These two trials enrolled  1,258 patients meeting Rome II criteria for IBS who 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 primary endpoint for both trials was the proportion of patients who achieved adequate relief of IBS signs and symptoms for at least two of four weeks during the month following 14 days of treatment. Adequate relief of IBS symptoms was experienced by more patients receiving Xifaxan than those receiving placebo during the month following two weeks of treatment (SGA-IBS weekly results: 41 percent vs. 31 percent, p=0.0125; 41 percent vs. 32 percent, p=0.0263).

TARGET-3

This trial enrolled 2,579 patients who were scheduled to receive an initial 14-day course of open-label Xifaxan followed by four weeks of treatment-free follow-up. At the end of the follow-up period, patients were assessed for response to treatment. 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 three weeks of a rolling four-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. Overall, 1,257 of 2,579 patients (49 percent) were nonresponders in the open-label phase and per the study protocol were withdrawn from the study. There were 1,074 (44 percent) of 2,438 evaluable patients who responded to initial treatment with improvement in abdominal pain and stool consistency. The response rate for each IBS symptom during the open-label phase of Trial 3 is similar to the rates seen in Trials 1 and 2. A total of 636 patients subsequently had sign and symptom recurrence and were randomized to the repeat treatment phase. Patients who responded to treatment with Xifaxan 550 mg but experienced recurrent symptoms responded to repeat treatment in the FDA composite end point versus placebo.