Rifaximin

Pronunciation

Class: Rifamycins
VA Class: AM900
Chemical Name: [2S - (2R*,16Z,18E,20R*,21R*,22S*,23S*,24S*,25R*,26S*,27R*,22E)] - 25 - acetyloxy) - 5,6,21,23 - tetrahydroxy - 27 - methoxy - 2,4,11,16,20,22,24,26 - octamethyl - 2,7 - (epoxypentadeca[1,11,13]trienimino)benzofuro[4,5 - e]pyrido[1,2 - a]benzimidazole - 1,15(2H) - dione
Molecular Formula: C43H51N3O11
CAS Number: 80621-81-4
Brands: Xifaxan

Introduction

Rifamycin antibiotic;11 12 structural analog of rifampin.1 11 12

Uses for Rifaximin

Travelers’ Diarrhea

Treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli in adults and adolescents ≥12 years of age.1 3 4 12 13 14 15 16

Slideshow: Foodborne Illness: The Thanksgiving Guest Nobody Invited

May be ineffective in and should not be used for treatment of diarrhea complicated by fever or bloody stools.1

May be ineffective in and should not be used for treatment of diarrhea known or suspected to be caused by pathogens other than E. coli (e.g., Campylobacter jejuni, Shigella, Salmonella).1

Has been used for prevention of travelers’ diarrhea, but safety and efficacy for such prophylaxis not established.2

Hepatic Encephalopathy

Has been used for adjunctive treatment of hepatic encephalopathy to reduce blood ammonia concentrations and decrease severity of neurologic manifestations.6 7 8 9 10 11 17 Designated an orphan drug by the FDA for use in this condition.5

Rifaximin Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1

Dosage

Pediatric Patients

Travelers’ Diarrhea Caused by Noninvasive Strains of E. coli
Treatment
Oral

Adolescents ≥12 years of age: 200 mg 3 times daily for 3 days.1

Adults

Travelers’ Diarrhea Caused by Noninvasive Strains of E. coli
Treatment
Oral

200 mg 3 times daily for 3 days.1

Hepatic Encephalopathy
Treatment
Oral

600–1200 mg daily (usually in 3 divided doses) for 7–21 days has been used.2 6 7 8 9 10 17

Special Populations

Hepatic Impairment

No specific dosage adjustments recommended.1

Renal Impairment

Not specifically studied in renal impairment, but clinically important differences in elimination not expected.1 2 11 12

Geriatric Patients

Not specifically studied in patients ≥65 years of age.1

Cautions for Rifaximin

Contraindications

  • Known hypersensitivity to rifaximin, other rifamycin anti-infectives, or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Treatment of Travelers’ Diarrhea

Do not use for treatment of diarrhea complicated by fever or bloody stools.1

Do not use for treatment of travelers’ diarrhea known or suspected to be caused by C. jejuni, Shigella, or Salmonella.1

If diarrhea worsens or persists >24–48 hours after initiating rifaximin, discontinue and consider use of another anti-infective.1

Superinfection/Clostridium difficile-associated Colitis

Overgrowth of nonsusceptible organisms may occur.1 If superinfection occurs, appropriate therapy should be instituted.1

Treatment with anti-infectives may permit overgrowth of clostridia.1 Consider Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) if diarrhea develops and manage accordingly.1

Some mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance alone.1 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) recommended if colitis is severe.1

Systemic Infections

Do not use for treatment of systemic bacterial infections since <0.4% of an oral dose is absorbed systemically.1 11 12

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1 2

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.1

Renal Impairment

Not specifically studied in renal impairment, but clinically important changes in elimination not expected since the drug is poorly absorbed from GI tract and almost entirely excreted in feces.1 2 11 12

Common Adverse Effects

GI effects (flatulence, abdominal pain, rectal tenesmus, defecation urgency, nausea, constipation, vomiting), headache, fever.1

Interactions for Rifaximin

Does not inhibit or induce CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1.1 Has induced CYP3A4 in vitro, but clinically important effects on intestinal or hepatic CYP3A4 unlikely; does not inhibit CYP3A4.1 2

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs metabolized by CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 unlikely.1

Specific Drugs

Drug

Interaction

Comments

Hormonal contraceptives (ethinyl estradiol and norgestimate)

No substantial changes in pharmacokinetics of ethinyl estradiol and norgestimate1

Dosage adjustment not necessary2

Midazolam

No substantial changes in pharmacokinetics of midolazam or its major metabolite (1′-hydroxymidazolam) 1 2

Dosage adjustment not necessary2

Rifaximin Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed from GI tract;1 11 12 <0.4% of an oral dose absorbed systemically.1 11 12

No evidence of accumulation following multiple doses.1

Food

Oral absorption not appreciably affected by food; systemic absorption remains low in the fasting state and when given within 30 minutes of a high-fat breakfast.1

Distribution

Extent

Animal studies indicate 80–90% of oral dose concentrated in the gut, <0.2% distributed into liver and kidney, and <0.01% into other tissues.1

Minimal or no hepatic distribution in patients receiving oral rifaximin (400 mg 4 times daily) for 2 days prior to cholescystectomy.11

Elimination

Metabolism

Does not appear to be metabolized.1

Elimination Route

Approximately 97% of an oral dose excreted in feces as unchanged drug;1 11 12 <0.4% eliminated in urine.1 11 12

Half-life

Approximately 6 hours.1

Special Populations

Pharmacokinetics not studied in pediatric patients or adults ≥65 years of age.1

Pharmacokinetics not studied in renal impairment.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Like other rifamycins, rifaximin inhibits RNA synthesis in susceptible bacteria by binding to the β subunit of bacterial DNA-dependent RNA polymerase.1 11

  • Escherichia coli: Active in vitro and in clinical infections (i.e., infectious diarrhea) against enterotoxigenic and enteroaggregative strains of E. coli.1 11 Also active in vitro against other E. coli strains, including enterohemorrhagic, enteroinvasive, enteropathogenic, and Hep-2 adherent strains.2 11

  • Other bacteria: Has in vitro activity against Acinetobacter, Aeromonas, Bacillus, Bacteroides, Bifidobacterium, Campylobacter jejuni, Clostridium difficile, Enterobacter cloacae, Fusobacterium, Helicobacter, Klebsiella pneumoniae, Plesiomonas shigelloides, Peptostreptococcus, Prevotella, Proteus, Pseudomonas aeruginosa, Salmonella (groups C1 and C2), Shigella (including S. dysenteriae, S. flexneri, S. sonnei), Serratia, Staphylococcus, Streptococcus, Vibrio, and Yersinia enterocolitica.2 11 Also active in vitro against Cryptosporidium and Giardia.2

  • Although clinical importance unclear, resistance to rifaximin has developed in E. coli in vitro.1 Further study needed to determine the resistance profile of rifaximin.2

  • Organisms with high rifaximin MICs also have elevated rifampin MICs;1 however, since rifaximin is not appreciably absorbed following oral administration and is present in high concentrations in the bowel lumen, a comparison of rifaximin MICs and MICs for well-absorbed drugs (e.g., rifampin) should be interpreted with caution.11 12 14 15

  • Cross-resistance between rifaximin and other classes of anti-infectives not evaluated.1

Advice to Patients

  • Advise patients and/or their caregivers that rifaximin may be taken with or without food.1

  • Importance of taking rifaximin exactly as prescribed and continuing therapy for entire treatment course.1

  • Importance of discontinuing rifaximin and seeking medical care if diarrhea persists for >24–48 hours or worsens or if fever and/or bloody diarrhea develop.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Rifaximin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg

Xifaxan

Salix

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Xifaxan 200MG Tablets (SALIX PHARMACEUTICALS): 30/$359.99 or 90/$1,060.02

Xifaxan 550MG Tablets (SALIX PHARMACEUTICALS): 60/$1,352.03 or 180/$3,801.18

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Salix Pharmaceuticals, Inc. Xifaxan tablets prescribing information. Raleigh, NC; 2004 Jun.

2. Salix Pharmaceuticals, Inc., Raleigh, NC: Personal communication.

3. Steffen R, Sack DA, Riopel L, et al. Therapy of traveler’s diarrhea with rifaximin on various continents. Am J Gastroenterol. 2003; 98:1073-8. [IDIS 502876] [PubMed 12809830]

4. Infante RM, Ericsson CD, Jiang Z, et al. Enteroaggregative Escherichia coli diarrhea in travelers: response to rifaximin therapy. Clin Gastroenterol Hepatol. 2003; 2:136-8.

5. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website (http: / / www.fda.gov / ForIndustry / DevelopingProductsforRareDiseasesConditions / HowtoapplyforOrphanProductDesignation / default.htm). Accessed 2004 Aug 19.

6. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997;337:473-9.

7. Williams R, James OF, Warnes TW et al. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study. Eur J Gastroenterol Hepatol. 2000;12:203-8.

8. Puxeddu A, Quartini M, Massimetti A et al. Rifaximin in the treatment of chronic hepatic encephalopathy. Curr Med Res Opin. 1995;13:274-81.

9. Pedretti G, Calzetti C, Missale G et al. Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial. Ital J Gastroenterol. 1991;23:175-8.

10. Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin. 1993;13:109-18.

11. Gillis JC, Brogden RN.. Rifaximin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential in conditions mediated by gastrointestinal bacteria. Drugs 1995;49:467-84.

12. Steffen R. Rifaximin: a nonabsorbed antimicrobial as a new tool for treatment of travelers’ diarrhea. J Travel Med. 2001;8:34-9.

13. DuPont HL, Ericsson CD, Mathewson JJ, et al. Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers’ diarrhea. Digestion. 1998;59:708-14.

14. DuPont HL. Treatment of travelers’ diarrhea. J Travel Med. 2001;8:31-3.

15. Lawler JV, Wallace MR. Diagnosis and treatment of bacterial diarrhea. Curr Gastroenterol Rep. 2003;5:287-94.

16. Ericsson CD. Travelers’ diarrhoea. Int J Antimicrob Agents. 2003;21:116-24.

17. Miglio F, Valpiani D, Rossellini SR, et al. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin. 1997;13:593-601.

18. Anon. Advice for travelers. Treat Guidelines Med Lett. 2004; 2:33-49.

19. Centers for Disease Control and Prevention. Health information for international travel, 2003–2004. Atlanta, GA: Department of Health and Human Services; 2003:184-91. From CDC website ()

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