Xifaxan (Rifaximin)

Brand name¹:  Xifaxan

Generic name¹:  rifaximin

Manufacturer¹:  Salix Pharmaceuticals

Drug Class¹:  non-systemic antibiotic

Uses^1,2: 

Labeled use-  The treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli in patients twelve years old and up.

Unlabeled uses-  Surgical antibiotic prophylaxis when added to cefotaxime, diarrhea, symptomatic relief of diverticular disease, enterocolitis, and hepatic encephalopathy in combination with lactulose.

Rifaximin 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.

Mechanism of action^1,2:  Rifaximin’s antibacterial properties arise through its ability to inhibit bacterial RNA synthesis through binding to the beta-subunit of bacterial DNA-dependent RNA polymerase.

Pharmacokinetics^1,2:

Metabolism^1,3:  Since this drug is absorbed systemically in such a small amount most of the drug is not metabolized.  This drug has not been shown to inhibit or induce CYP 450 isozymes at clinical plasma concentrations.  An in vitro hepatocyte induction model was shown to induce CYP 3A4.

Excretion^1,2:  Rifaximin is largely excreted in the feces.  97% of rifaximin is excreted in the feces, while 0.32% is excreted in the urine.  Rifaximin is excreted almost entirely as unchanged drug.

Steffen R, Sack DA, Riopel L, et. al.  Therapy of Travelers’ Diarrhea with Rifaximin on Various Continents.  The American Journal of Gastroenterology 2003; 98(5): 1073-1078.³

This was an 8 day multicenter, randomized, double-blind, placebo-controlled study.  380 people were enrolled.  To be enrolled the patients had to be nonindigenous travelers who were affected by acute diarrhea.  3 or more unformed stools within 24 hours of enrollment qualified as diarrhea.  The patient also had to have an additional sign of infection, such as abdominal pain or cramps, nausea, vomiting, a fever of 100 F or more, macroscopic blood in the stools, fecal urgency, excessive gas or flatulence, or tenesmus.  The major exclusion criteria was the use of medication that could effect the results of the study.  Subjects were randomized to receive a placebo, rifaximin 600 mg/day, or 1200 mg/day for 3 days.  The medication was taken three times daily.  Follow-up lasted 5 days.  The median time to the last unformed stool was 60.0 hours in the placebo group, 32.5 hours in the rifaximin 600 mg group, and 32.9 hours in the 1200 mg group.  There was a significant difference between the rifaximin and placebo groups.  Patients were clinically cured within 120 hours in 79.2% of patients in the 600 mg/day rifaximin group, 81.0% of patients in the 1200 mg/day rifaximin group, and 60.5% of the patients in the placebo group.  This was a significant difference.  The medication was found to be safe in the study and not associated with any severe adverse effects.  A study enrolling more subjects having fecal leukocyte-positive diarrhea would give a better idea as to the effectiveness of rifaximin against invasive or inflammatory pathogens.  Rifaximin should be included in a travel kit for the treatment of travelers’ diarrhea.  The use of the drug could help prevent the overuse and resistance of quinolones.  Also since the drug is poorly absorbed the drug should be safe in children and pregnant women.

DuPont HL, Jiang Z, Ericsson CD, et al. Rifaximin versus Ciprofloxacin for the Treatment of Travelers’ Diarrhea: A Randomized, Double-Blind Clinical Trial. Clinical Infectious Disease 2001;33: 1807-1815.⁴

This was an 8 day double-blind, randomized clinical trial.  187 patients were enrolled. To be eligible patients had to be at least 18 years old and have diarrhea.  Adult students from the Untied States in Mexico and international tourists in Jamaica took part in the study.  The major exclusion criteria was the use of medication that could effect the results of the study.  Patients were randomized to receive either 2 tablets of rifaximin (200 mg each) plus 1 tablet of ciprofloxacin placebo twice a day for 3 days or 2 tablets of rifaximin placebo plus 1 tablet of ciproflaxacin (500 mg) twice a day for 3 days.  The median time to last unformed stool was 25.7 hours (95% CI, 20.9-38.0) in the rifaximin group and 25.0 hours (95% CI, 18.5-35.2) in the ciprofloxacin group.  The two groups showed no significant difference in the number of unformed stools passed.  87% of the patients in the rifaximin group and 88% of the patients in the ciprofloxacin group were considered well after the study.  The adverse effect profile was similar between the groups and did not include severe adverse effects.  The effectiveness of rifaximin on invasive pathogens, such as shigella, salmonella, and campylobacter could not be determined because not enough patients were infected with these bacteria.  Also its use in children is unknown from this study.  In conclusion rifaximin is effective for travelers’ diarrhea and may have less side effects and drug interactions than drugs that are absorbed to a greater extent.  Ciprofloxacin may have a more rapid effect.  Rifaximin may possibly be useful in quinolone resistant infections.

DuPont HL, Ericsson CD, Mathewson JJ, et al.  Rifaximin: A Nonabsorbed Antimicrobial in the Therapy of Travelers’ Diarrhea.  Digestion 1998;59:708-714.⁵

This was a five day, randomized, prospective, double-blind, clinical trial.  The data of this study were compared to two placebo groups from previous trials.  72  adult students attending universities in Mexico completed the trial.  The main exclusion criteria was the use of medication that could affect the outcome of the study.  All patients enrolled had acute diarrhea.  Three or more unformed stools in the 24 hours period prior to enrollment in addition to one of the signs or symptoms of enteric infections is considered acute diarrhea.  These signs and symptoms include: nausea, vomiting, abdominal pain/cramps, tenesmus, or fecal urgency with diarrhea having lasted no loner than 72 hours.  The patients were randomized to receive either 200 mg of rifaximin given three times a day for five days, 400 mg of rifaximin given three times a day for five days, 600 mg of rifaximin given three times a day for five days, or trimethoprim/sulfamethoxaxole 160 mg/ 800 mg twice a day for five 5 days.  The mean and median time from initiation of therapy until the passage of the last unformed stool was examined among the treatment groups.  The median and mean times respectively were: rifaximin 200 mg (26.3 and 36.9 hours), rifaximin 400 mg (40.5 and 38.6 hours), rifaximin 600 mg (35.0 and 53.0 hours), all rifaximin patients (35.0 and 43.1 hours), and TMP/SMX (47.0 and 55.7 hours).  No significant differences exist among the groups, but the rifaximin 200 mg group had the shorest median and mean durations.  The percentage of patients experiencing improvement of diarrhea after 24 hours are: 200 mg rifaximin 56%, 400 mg rifaximin 44%, 600 mg rifaximin 53%, and TMP/SMX 65%.  The rate of clinical failure was 11% for the rifaximin group as a whole and 29% for the TMP/SMX group, but this difference was not significant.  The rifaximin group has significantly less unformed stools passed during the first 24 hours of treatment when compared to the two placebo groups.  Also a significant difference was seen in the groups with regards to the time until the passage of the last unformed stool.  The rifaximin group had a shorter time to the passage of the last unformed stool.   No adverse effects experience in the rifaximin group could be found to be related to the drug.  The sample size used in the study was too small to show statistically significant differences between the rifaximin and TMP/SMX groups.  Further study is needed to examine its use as a self-treatment used by travelers’.  In conclusion, 200 mg three times a day appears to be the most effective dose.  It may be useful due to the increasing resistance to TMP/SMX and fluoroquinolones.  It may be considered as a medication travelers may take with themselves to other countries, so that they may self-treat diarrhea.  The drug is well tolerated.  Because it is poorly absorbed it may be safe in children and pregnant women, but more studies are needed.  Rifaximin is at least as effective as TMP/SMX in the treatment of travelers’ diarrhea.        

Adverse effects (with an incidence > 2%)¹:

None of these adverse effects were found to be significantly greater in rifaximin than in placebo.

Drug Interactions¹:  None have been reported.

Dosing/Administration²:  For travelers’ diarrhea an oral dose of 200 mg of rifaximin three times a day for 3 days should be administered in persons older than 12 years old.

Unlabeled uses:  Infection Prophylaxis Colonic Surgery: 600 mg –800 mg daily for 3 to 5 days preceding surgery.  This is given in combination with 3 grams of intravenous cefotaxime daily.

Diverticular Disease:  400 mg twice a day for 7 days every month for 12 months.

Gastrointestinal Infection:  10 mg-15 mg/kg/day

Hepatic Encephalopathy:  1200 mg daily for 15 to 21 days given with or without lactulose.

Pyogenic Skin Infection:  apply 0.5 to 3 centimeters of cream 3 times a day for 4 to 10 days.

Enterocolitis or intestinal inflammatory diseases: 400 mg suspended in 200 to 400 mL of sterile water administered via a nasogastric tube for 2 hours. 

In special populations

Geriatric²:  An oral dose of 200 mg of rifaximin three times a day for 7 days is recommended.

Pediatric¹:  unkown

Renal Impairment^1,2:  unkown

Hepatic Impairment^1,2:  No dosing adjustments are needed, because a small amount of the drug is absorbed systemically.

Contraindications¹:  Patients with a hypersensitivity to rifaximin or any rifamycin antibiotics should not take Xifaxan.

Warnings¹:  Rifaximin has not been shown to be effective against diarrhea caused by pathogens other than Escherichia coli or diarrhea complicated by fever and/or blood in the stool.  A different antibiotic should be used if diarrhea worsens or lasts for more than 24 to 48 hours.  Xifaxan may cause Pseudomembranous colitis.  Clostridium difficile overgrowth may result from alterations to the normal flora caused by Xifaxan.

Conclusions^3,4,5:  Rifaximin is has been shown to be an effective treatment for travelers’ diarrhea.  It is at least as effective as ciprofloxacin and TMP/SMX, so the use of rifaximin may be beneficial because of the increasing bacterial resistance to ciprofloxacin and TMP/SMX which are the current treatments for travelers’ diarrhea.  Rifaximin may be safe to use in children and pregnant women, because it is not well absorbed systemically.  However, further studies need to be done to examine its safety in children and pregnant woman.  Rifaximin has not been shown to produce more adverse effects than placebo.  Rifaximin could be considered for placement in a travelers’ kit for self treatment of travelers diarrhea.  Further studies are needed to determine its effectiveness against invasive pathogens.

Recommended References: 

1.      Xifaxan (rifaximin)-Prescribing information. Salix Pharmaceuticals. Raleigh, NC. May 2004.

2.      Rifaximin (Drug Evaluation). In: Hutchinson TA & Shahan DR (Eds):  DRUGDEX System. MICROMEDEX, Greenwood Village, Colorado (Edition expires 12/04).

3.      Steffen R, Sack DA, Riopel Lise, et. al. Therapy of Travelers’ Diarrhea With Rifaximin on Various Continents. The American Journal of Gastroenterology 2003;98(5):1073-1078.

4.      DuPont HL, Jiang Z, Ericsson CD, et. al. Rifaximin versus Ciprofloxacin for the Treatment of Traveler’s Diarrhea: A Randomized, Double-Blind Clinical Trial. Clinical Infectious Disease 2001;33:1807-1815.

5.      DuPont HL, Ericsson CD, Mathewson JJ, et. al. Rifaximin: A Nonabsorbed Antimicrobial in the Therapy of Travelers’ Diarrhea. Digestion 1998;59:708-714.