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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

Medically reviewed by on Sep 27, 2021. Written by ASHP.


Rifamycin antibiotic; structural analog of rifampin.

Uses for Rifaximin

Hepatic Encephalopathy

Reduction of risk of recurrence of overt hepatic encephalopathy in adults. Comparative efficacy of rifaximin used alone or in conjunction with lactulose for prevention of hepatic encephalopathy recurrence not established.

Experts recommend rifaximin as an adjunct to lactulose for prevention of hepatic encephalopathy recurrence in patients who have had at least 1 episode of overt hepatic encephalopathy while receiving lactulose alone.

Not evaluated for prevention of overt hepatic encephalopathy recurrence in patients with model for end-stage liver disease (MELD) scores >25. Rifaximin systemic exposure is increased in patients with a history of hepatic encephalopathy who have severe hepatic impairment.

Has been used in the treatment of hepatic encephalopathy to reduce blood ammonia concentrations and decrease severity of neurologic manifestations; designated an orphan drug by FDA for treatment of this condition.

Information from the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) regarding the management of hepatic encephalopathy, including recommendations for treatment and prevention of recurrence, is available at [Web].

Irritable Bowel Syndrome with Diarrhea

Treatment of irritable bowel syndrome (IBS) with diarrhea in adults.

Travelers’ Diarrhea

Treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli in adults and adolescents ≥12 years of age.

Not effective in and should not be used for treatment of diarrhea complicated by fever or bloody stools.

Not effective 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).

Travelers' diarrhea caused by bacteria may be self-limited and often resolves within 3–7 days without anti-infective treatment. CDC and others recommend fluoroquinolones (ciprofloxacin, levofloxacin) as drugs of choice when anti-infective treatment, including self-treatment, indicated. Rifaximin can be considered an alternative when causative organism is enterotoxigenic E. coli; however, usefulness for empiric self-treatment of travelers' diarrhea remains to be determined.

Has been used for prevention of travelers’ diarrhea. CDC and others state that anti-infective prophylaxis for prevention of travelers' diarrhea not recommended for most travelers.

Rifaximin Dosage and Administration


Oral Administration

Administer orally without regard to meals.


Pediatric Patients

Travelers’ Diarrhea Caused by Noninvasive Strains of E. coli

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

If diarrhea worsens or persists >24–48 hours after drug initiated, discontinue and consider alternative anti-infective.


Hepatic Encephalopathy
Reduction of Risk of Recurrence of Overt Hepatic Encephalopathy

550 mg twice daily.

Treatment of Hepatic Encephalopathy†

600–1200 mg daily (usually in 3 divided doses) for 7–21 days has been used.

Irritable Bowel Syndrome with Diarrhea

550 mg 3 times daily for 14 days.

If symptoms recur, up to 2 additional courses may be given using the same 14-day regimen.

Travelers’ Diarrhea Caused by Noninvasive Strains of E. coli

200 mg 3 times daily for 3 days.

If diarrhea worsens or persists >24–48 hours after drug initiated, discontinue and consider alternative anti-infective.

Special Populations

Hepatic Impairment

Dosage adjustment not needed; use with caution in those with severe hepatic impairment (Child-Pugh class C). (See Hepatic Impairment under Cautions.)

Renal Impairment

Not specifically studied in renal impairment; clinically important changes in rifaximin elimination not expected.

Geriatric Patients

Not specifically studied in patients ≥65 years of age.

Cautions for Rifaximin


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


Sensitivity Reactions

Hypersensitivity reactions, including exfoliative dermatitis, rash, angioedema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus, and anaphylaxis, reported during postmarketing experience. Such reactions have occurred as soon as 15 minutes after a dose.

Precautions Related to Treatment of Travelers’ Diarrhea

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

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

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


Concomitant use of rifaximin with drugs that are P-glycoprotein (P-gp) transport inhibitors (e.g., cyclosporine) may substantially increase rifaximin systemic exposure. In patients with hepatic impairment, potential additive effect of reduced hepatic metabolism and concomitant use with P-gp inhibitors may further increase rifaximin systemic exposure. Use caution if concomitant use with a P-gp inhibitor necessary.

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including rifaximin, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible. Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

Not suitable for treatment of systemic bacterial infections because rifaximin plasma concentrations are low and variable following oral administration. (See Pharmacokinetics.)

To reduce development of drug-resistant bacteria and maintain effectiveness of rifaximin and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Specific Populations


Data not available regarding use in pregnant women. Teratogenic effects (e.g., ocular, oral and maxillofacial, cardiac, and lumbar spine malformations) observed in animal reproduction studies in rats and rabbits.


Not known whether distributed into human milk, affects human milk production, or affects breast-fed infant.

Consider benefits of breast-feeding and importance of rifaximin to the woman; also consider potential adverse effects on the breast-fed child from the drug or from underlying maternal condition.

Pediatric Use

Hepatic encephalopathy: Safety and efficacy not established in children and adolescents <18 years of age.

IBS with diarrhea: Safety and efficacy not established in children and adolescents <18 years of age.

Travelers' diarrhea: Safety and efficacy not established in children <12 years of age.

Geriatric Use

Hepatic encephalopathy: No overall differences in safety or effectiveness observed between patients ≥65 years of age and younger adults.

IBS with diarrhea: No overall differences in safety or effectiveness observed between patients ≥65 years of age and younger adults.

Travelers' diarrhea: Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger patients.

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Use with caution.

Although dosage adjustments not needed in patients with hepatic impairment, severe hepatic impairment results in increased rifaximin systemic exposure. (See Pharmacokinetics.)

Hepatic encephalopathy: Clinical trials did not include patients with MELD scores >25.

Renal Impairment

Not specifically studied in renal impairment. Clinically important changes in elimination not expected since the drug is poorly absorbed from GI tract and almost entirely excreted in feces.

Common Adverse Effects

Hepatic encephalopathy: Peripheral edema, nausea, dizziness, fatigue, ascites, muscle spasms, pruritus, abdominal pain, anemia, depression, nasopharyngitis, upper abdominal pain, arthralgia, dyspnea, pyrexia, rash.

IBS with diarrhea: Nausea, increased ALT concentrations.

Travelers' diarrhea: Headache.

Interactions for Rifaximin

Substrate of CYP3A4. Does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro. Has induced CYP3A4 in vitro, but clinically important effects on intestinal or hepatic CYP3A4 unlikely.

Substrate of P-gp transport in vitro. Inhibits P-gp in vitro, but effect in vivo unknown.

Substrate of organic anion transport polypeptides (OATP) 1A2, 1B1, and 1B3; not a substrate of OATP2B1. Inhibits OATP1B1, 1A2, and 1B3 in vitro, but effect in vivo unknown.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Pharmacokinetic interactions not expected in patients with normal hepatic function; not known whether interactions occur in those with hepatic impairment and increased rifaximin systemic exposure.

CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1 substrates: Pharmacokinetic interactions not expected.

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp inhibitors: Substantially increased rifaximin exposures may occur.

P-gp substrates: Possible effects in vivo unknown.

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

OATP1B1, 1A2, and 1B3 substrates: Possible effects in vivo unknown.

Specific Drugs





Substantially increased rifaximin concentrations and AUC

Clinical importance unknown

Hormonal contraceptives (ethinyl estradiol and norgestimate)

Decreased ethinyl estradiol and norgestimate concentrations

Clinical importance unknown


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

Dosage adjustment not needed

Rifaximin Pharmacokinetics



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

No evidence of accumulation following multiple doses.

History of hepatic encephalopathy (550 mg twice daily): Mean AUC approximately 12-fold higher compared with healthy adults.

IBS with diarrhea (rifaximin 550 mg 3 times daily for 14 days): AUC similar to healthy adults.


When administered 30 minutes after high-fat meal, time to peak plasma concentrations delayed from 0.75 hours to 1.5 hours after a dose, AUC increased twofold, peak plasma concentrations unchanged.

Plasma Concentrations

Healthy individuals (single or multiple doses of 550 mg): Peak plasma concentrations attained about 1 hour after dosing; mean peak plasma concentrations range from 2.4–4 ng/mL.

IBS with diarrhea (550 mg 3 times daily for 14 days): Peak plasma concentrations attained 1 hour after dosing; mean peak plasma concentrations similar to healthy individuals.


Plasma Protein Binding

Healthy individuals: 67.5%.

Hepatic impairment: 62%.



Systemically absorbed drug metabolized principally by CYP3A4.

Elimination Route

Approximately 97% of an oral dose excreted in feces (mostly as unchanged drug); 0.3% eliminated in urine (mostly as metabolites).


Healthy individuals: 5.6 hours.

IBS with diarrhea: 6 hours.

Special Populations

Pediatric patients: Pharmacokinetics not studied.

Geriatric patients: Pharmacokinetics not studied.

History of hepatic encephalopathy and with mild, moderate, or severe hepatic impairment: Systemic exposures approximately 10-, 14-, or 21-fold higher, respectively, compared with healthy individuals.

Renal impairment: Pharmacokinetics not studied.





20–25°C (may be exposed to 15–30°C).

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.

  • Escherichia coli: Active in vitro and in clinical infections (i.e., infectious diarrhea) against enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC). Although clinical importance unknown, also active in vitro against other E. coli strains, including enterohemorrhagic, enteroinvasive, enteropathogenic, and Hep-2 adherent strains.

  • Other bacteria: Although clinical importance unknown, has some in vitro activity against Aeromonas, Bacillus, Bacteroides, Bifidobacterium, Campylobacter jejuni, Enterobacter cloacae, Fusobacterium, Helicobacter, Klebsiella pneumoniae, Plesiomonas shigelloides, Peptostreptococcus, Prevotella, Salmonella, Shigella (including S. dysenteriae, S. flexneri, S. sonnei), Vibrio, and Yersinia enterocolitica.

  • Resistance to rifaximin has been produced in vitro in E. coli (ETEC and EAEC strains). Rifaximin resistance also reported in various clinical isolates of E. coli from patients with travelers' diarrhea or inflammatory bowel disease, including some patients who previously received the drug. Clinical isolates of Campylobacter, Salmonella, and Shigella with in vitro resistance to rifaximin also reported. Although some strains of Clostridium difficile susceptible to rifaximin in vitro, clinical isolates resistant to rifaximin (some with high-level resistance) reported.

  • Resistance generally is associated with mutations in the rpoB gene that change the binding site on DNA-dependent RNA polymerase and decrease rifaximin binding affinity. Presence of efflux pumps also appears to cause or contribute to development of rifaximin resistance in some organisms.

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

Advice to Patients

  • Advise patients that antibacterials (including rifaximin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

  • Importance of completing full course of therapy, even if feeling better after a few days.

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with rifaximin or other antibacterials in the future.

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

  • If used for treatment of travelers' diarrhea, advise patients of the importance of discontinuing rifaximin and seeking medical care if diarrhea worsens or persists for >24–48 hours after the drug is initiated or if fever and/or bloody diarrhea develop.

  • If used in patients with severe hepatic impairment (Child-Pugh class C), advise patients that rifaximin systemic exposure is increased. (See Hepatic Impairment under Cautions.)

  • Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

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

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

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


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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.



Dosage Forms


Brand Names




200 mg



550 mg



AHFS DI Essentials™. © Copyright 2022, Selected Revisions October 6, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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