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Criteria for Outpatient Use Guidelines

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Rifaximin (Xifaxan®)

[Developed, September 2006; Revised, December 2006, April 2010]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Rifaximin is not indicated for treatment of systemic infections as less than 0.4% of drug is absorbed after oral administration.1

Adults
Rifaximin, a derivative of rifampin, is a nonsystemically absorbed antibiotic with bactericidal activity against aerobic and anaerobic gram-positive and gram-negative microorganisms.  Rifaximin is FDA-approved for use in managing travelers’ diarrhea due to noninvasive strains of Escherichia coli (E. coli) in adults and children 12 years of age and older, and should not be used in diarrhea due to pathogens     other than E. coli or complicated by fever or blood in the stool.1-4  The recommended oral dose is 200 mg three times daily for three days.1-8  Doses exceeding 600 mg/day for travelers’ diarrhea will be reviewed.

Rifaximin has recently gained FDA approval for reduction in risk of overt hepatic encephalopathy recurrence in patients 18 years of age and older.5-7, 9 In a randomized, double-blind, placebo-controlled trial over a six-month time period, Bass and cohorts10 evaluated rifaxamin safety and efficacy to maintain remission from hepatic encephalopathy (HE) episodes in 299 adult outpatients receiving concurrent lactulose therapy with a recent history of recurrent, overt hepatic encephalopathy. Results showed that the risk of a breakthrough HE episode was significantly lower with rifaxamin therapy compared to placebo [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.28 to 0.64; P< 0.001]. The risk of hospitalization was also significantly lower in rifaxamin-treated patients compared to those receiving placebo (HR, 0.50; 95% CI, 0.29 to 0.87; P = 0.01). The recommended oral rifaxamin dose for prevention of HE recurrence is 550 mg twice daily.1, 5-7, 10  Dosages exceeding 1100 mg daily for HE recurrence will be reviewed.

Although not FDA-approved, rifaximin has demonstrated some efficacy in hepatic encephalopathy treatment, irritable bowel syndrome, and  infectious diarrhea due to Salmonella, noninvasive Shigella and Campylobacter.8, 11-21  A few small studies have evaluated rifaximin use in irritable bowel syndrome/Crohn’s disease.  Gionchetti and cohorts17 assessed rifaximin efficacy compared to placebo in 26 ulcerative colitis patients unresponsive to steroid therapy and found that while overall clinical response was not significantly better than placebo, rifaximin-treated patients showed a significant reduction in stool frequency and rectal bleeding.  Prantera and colleagues18 evaluated rifaximin dosing and efficacy compared to placebo in 83 Crohn’s disease patients and found no statistical difference in clinical response or clinical remission but observed a significantly reduced number of treatment failures in rifaximin-treated patients.  Rifaximin efficacy in hepatic encephalopathy treatment has also been evaluated.  One small, open-label, randomized trial in 54 Korean patients with liver cirrhosis evaluated rifaximin therapy in hepatic encephalopathy and found rifaximin comparable to lactulose in improving blood ammonia, flapping tremor and mental status.19  Similarly, Mas et al20, in a randomized, double-blind, double-dummy trial, compared rifaximin to lactitol in 103 acute hepatic encephalopathy patients and found rifaximin as effective as lactitol in managing hepatic encephalopathy episodes.  Investigators found rifaximin significantly better than lactitol in improving ammonia levels and EEG grade, which led to better portal-systemic encephalopathy scores in rifaximin-treated patients.  Miglo and cohorts21 assessed rifaximin benefit and tolerability when compared to neomycin in 49 cirrhosis patients with hepatic encephalopathy and found rifaximin as effective as neomycin in improving neuropsychiatric signs and blood ammonia levels.

Pediatrics
Rifaximin is FDA-approved in children 12 years of age and older for use in managing travelers’ diarrhea due to noninvasive strains of E. coli.  The recommended oral rifaxamin dose for pediatric patients is 200 mg three times daily for three days.  Rifaximin should not be prescribed for use in diarrhea caused by pathogens other than E. coli or complicated by fever or blood in the stool.1, 5-7

The safety and efficacy of rifaximin 200 mg for travelers’ diarrhea in pediatric patients younger than 12 years of age or rifaxamin 550 mg for HE in pediatric patients younger than 18 years of age have not been established.1, 6, 7 

2. Duration of Therapy

The recommended treatment duration for rifaximin use in E. coli-mediated travelers’ diarrhea is a maximum of three days.1, 8, 11, 22, 23 Treatment regimens lasting greater than three days will be reviewed.

Rifaximin 550 mg tablets may be prescribed on a chronic basis (i.e., for at least 6 months) to reduce the risk of HE recurrence, based on results from the study by Bass and colleagues10.

3.* Duplicative Therapy

Concurrent administration of rifaximin with other approved antibiotic therapies for travelers’ diarrhea (i.e., azithromycin, fluoroquinolones, trimethoprim-sulfamethoxazole) is not recommended as these combinations do not provide additional therapeutic benefit and may result in enhanced adverse events.  Patient profiles containing concurrent prescriptions for rifaximin and additional travelers’ diarrhea antibiotic therapy will be reviewed.

References

  1. Rifaximin (Xifaxan®) package insert.  Salix Pharmaceuticals, 2010.
  2. DuPont HL. Ericsson CD. Mathewson JJ. Palazzini E. DuPont MW. Jiang ZD. Mosavi A. de la Cabada FJ. Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers' diarrhea. Digestion. 1998;59:708-14.
  3. DuPont HL. Jiang ZD. Okhuysen PC. Ericsson CD. de la Cabada FJ. Ke S. DuPont MW. Martinez-Sandoval F. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers' diarrhea.  Ann Intern Med. 2005;142:805-12.
  4. DuPont HL. Jiang ZD. Ericsson CD. Adachi JA. Mathewson JJ. DuPont MW. Palazzini E. Riopel LM. Ashley D. Martinez-Sandoval F. Rifaximin versus ciprofloxacin for the treatment of travelers’ diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis. 2001;33:1807-15.
  5. Drug Facts and Comparisons.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2010.  Available at:  http://clineguide.com.  Accessed April 14th, 2010.
  6. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2010. Available at: http://www.clinicalpharmacology.com. Accessed April 14th, 2010.
  7. Rifaximin (Drug Evaluation). In: DRUGDEX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.   Accessed April 14th, 2010.
  8. Pakyz AL.  Rifaximin:  a new treatment for travelers’ diarrhea.  Ann Pharmacother. 2005;39:284-9.
  9. U.S. Department of Health and Human Services.  U.S. Food and Drug Administration.  FDA news release (March 24, 2010).  FDA approves new use of Xifaxan for patients with liver disease.  Available at:  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm206104.htm.  Accessed April 14th, 2010.
  10. Bass NM, Mullen KD, Sanyal A, et al.  Rifaximin treatment in hepatic encephalopathy.  N Engl J Med. 2010;362:1071-81.
  11. Adachi JA, DuPont HL.  Rifaximin:  a novel nonabsorbed rifamycin for gastrointestinal disorders.  Clin Infect Dis. 2006;42:541-7.
  12. Taylor DN, McKenzie R, Durbin A, Carpenter C, Atzinger CB, Haake R, Bourgeois AL.  Rifaximin, a nonabsorbed oral antibiotic,
  13. Huang DB, DuPont HL.  Rifaximin – a novel antimicrobial for enteric infections. J Infect. 2005;50(2):97-106. 
  14. Taylor DN, Bourgeois AL, Ericsson CD, Steffen R, Jiang ZD, Halpern J, et al.  A randomized, double-blind, multicenter study of rifaximin compared with placebo and with ciprofloxacin in the treatment of travelers’ diarrhea.  Am J Trop Med Hyg. 2006;74:1060-6.
  15. Frisari L, Viggiano V, Pelagalli M.  An open, controlled study of two non-absorbable antibiotics for the oral treatment of paediatric infectious diarrhea.  Curr Med Res Opin. 1997;14:39-45.
  16. Vinci M, Gatto A, Giglio A, Racita T, D’Avola G, DiStefano B, et al.  Double-blind clinical trial on infectious diarrhea therapy: rifaximin versus placebo.  Curr Ther Res. 1984;36:92-9.
  17. Gionchetti P, Rizzello F, Ferrieri A, Venturi A, Brignola C, Ferretti M, et al.  Rifaximin in patients with moderate or severe ulcerative
  18. Prantera C, Lochs H, Campieri M, Scribano ML, Sturniolo GC, Castiglione F., Cottone M.  Antibiotic treatment of Crohn’s disease: results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin.  Aliment Pharmacol Ther. 2006;23:1117-25.
  19. Paik YH, Lee KS, Han KH, Song KH, Kim MH, Moon BS, et al.  Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study.  Yonsei Med J. 2005;46:399-407.
  20. Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V, et al.  Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial.  J Hepatol. 2003;38:51-8.
  21. Miglio F, Valpiani D, Rossellini SR, Ferrieri A.  Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy.  A double-blind, randomized trial.  Curr Med Res Opin. 1997;13:593-601.
  22. DuPont HL.  Travellers’ diarrhoea: contemporary approaches to therapy and prevention.  Drugs.  2006;66:303-14.
  23. Okhuysen PC. Current concepts in travelers' diarrhea: epidemiology, antimicrobial resistance and treatment. Curr Opin Infect Dis. 2005;18:522-6.

Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.