([Web])

Introduction

Rifamycin antibiotic; structural analog of rifampin.

Uses for rifAXIMin (Systemic)

Hepatic Encephalopathy

Reduction of risk of recurrence of overt hepatic encephalopathy in adults.

Guidelines generally 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.

Has been used in the treatment of hepatic encephalopathy^{† [off-label]} 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]. Treatment of overt hepatic encephalopathy first includes lactulose, while rifaximin is recommended as add-on therapy to prevent recurrence.

Irritable Bowel Syndrome with Diarrhea

Treatment of irritable bowel syndrome (IBS) with diarrhea in adults. Guidelines for diarrhea-predominant IBS generally include use of rifaximin for treating global symptoms. Rifaximin is also recommended for retreatment in those who had a response to rifaximin and develop recurrent symptoms.

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. Guidelines generally consider rifaximin an alternative to fluoroquinolones or azithromycin for noninvasive moderate-to-severe travelers’ diarrhea.

Has been used for prevention of travelers’ diarrhea^{† [off-label]}. CDC and others state that anti-infective prophylaxis for prevention of travelers' diarrhea is not recommended for most travelers.

Other Uses

Has been used in some adults as treatment for the prevention of recurrence following standard treatment for Clostridioides difficile infection (CDI) in patients with multiple recurrences^{† [off-label]}.

Has been used in combination therapy for patients with refractory acute pouchitis,^{† [off-label]} although safety and efficacy have not been established.

Has been used for treatment of small intestinal bacterial overgrowth,^{† [off-label]} although safety and efficacy have not been established.

rifAXIMin (Systemic) Dosage and Administration

General

Patient Monitoring

• Monitor for signs and symptoms of hypersensitivity reactions to rifaximin.

• Monitor for worsening or persistence of travelers’ diarrhea for more than 24–48 hours after initiation of rifaximin. Discontinue rifaximin if either occurs, and consider treatment with an alternative anti-infective.

Administration

Oral Administration

Administer orally without regard to meals.

Dosage

Pediatric Patients

Travelers’ Diarrhea

Treatment

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

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

Adults

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.

Irritable Bowel Syndrome with Diarrhea

Oral

550 mg three times daily for 14 days.

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

Travelers’ Diarrhea

Treatment

200 mg three times daily for 3 days.

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

Prevention†

200–1100 mg daily, divided into 1–3 doses.

Clostridioides difficile Infection - Patients With Multiple Recurrences†

Oral

400 mg three times daily for 20 days or 400 mg three times daily for 14 days, followed by 200 mg three times daily for an additional 14 days.

Refractory Acute Pouchitis†

Oral

400 mg three times daily for 4 weeks or 1 gram twice daily for 15 days.

Small Intestinal Bacterial Overgrowth†

Oral

400 mg three times daily for 10 days.

Special Populations

Hepatic Impairment

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

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time.

Contraindications

• Hypersensitivity to rifaximin, other rifamycin anti-infectives, or any ingredient in the formulation. Hypersensitivity reactions such as exfoliative dermatitis, angioedema, and anaphylaxis have been reported, some occurring within 15 minutes of a dose of rifaximin.

Warnings/Precautions

Travelers’ Diarrhea Not Caused by Escherichia Coli

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. Rifaximin was not effective for diarrhea due to pathogens other than E. coli.

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

Clostridium difficile-associated Diarrhea (CDAD)

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. CDI and CDAD (also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) are 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, anti-infective therapy directed against C. difficile, and surgical evaluation as clinically indicated.

Development of Drug-Resistant Bacteria

Use for travelers’ diarrhea in absence of bacterial infection or a prophylactic indication is unlikely to provide benefit and increases risk of drug-resistant bacteria.

Severe (Child-Pugh Class C) Hepatic Impairment

Systemic exposure increased in severe hepatic impairment. Exercise caution when administering rifaximin to patients with severe hepatic impairment (Child-Pugh Class C).

Concomitant Use With P-glycoprotein Inhibitors

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

Specific Populations

Pregnancy

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.

Lactation

Not known whether distributed into human milk; effects on human milk production or effects on breast-fed infant are not known.

Consider benefits of breast-feeding and importance of rifaximin to the female; also consider potential adverse effects on the breast-fed child from the drug or from the 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

Although dosage adjustments are not needed in patients with hepatic impairment, severe hepatic impairment (Child-Pugh class C) results in increased rifaximin systemic exposure and additional awareness and monitoring for rifaximin-related adverse effects would be suggested.

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

Renal Impairment

Not specifically studied in renal impairment.

Common Adverse Effects

Hepatic encephalopathy: Adverse effects (≥10%): peripheral edema, nausea, dizziness, fatigue, ascites.

IBS with diarrhea: Adverse effects (≥2%): nausea, increased ALT concentration.

Travelers' diarrhea: Adverse effects (≥2%): headache.

General

Patient Monitoring

• Monitor for signs and symptoms of hypersensitivity reactions to rifaximin.

• Monitor for worsening or persistence of travelers’ diarrhea for more than 24–48 hours after initiation of rifaximin. Discontinue rifaximin if either occurs, and consider treatment with an alternative anti-infective.

Administration

Oral Administration

Administer orally without regard to meals.

Dosage

Pediatric Patients

Travelers’ Diarrhea

Treatment

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

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

Adults

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.

Irritable Bowel Syndrome with Diarrhea

Oral

550 mg three times daily for 14 days.

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

Travelers’ Diarrhea

Treatment

200 mg three times daily for 3 days.

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

Prevention†

200–1100 mg daily, divided into 1–3 doses.

Clostridioides difficile Infection - Patients With Multiple Recurrences†

Oral

400 mg three times daily for 20 days or 400 mg three times daily for 14 days, followed by 200 mg three times daily for an additional 14 days.

Refractory Acute Pouchitis†

Oral

400 mg three times daily for 4 weeks or 1 gram twice daily for 15 days.

Small Intestinal Bacterial Overgrowth†

Oral

400 mg three times daily for 10 days.

Special Populations

Hepatic Impairment

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

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time.

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 is unknown.

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

Drugs Affected 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 resulting in increased rifaximin systemic exposure.

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

Drugs Affecting or Affected by Transport Systems

P-gp inhibitors: Substantially increased rifaximin exposures may occur. Exercise caution with concomitant use; impaired hepatic function may further increase exposure to rifaximin.

P-gp substrates: Possible effects in vivo are unknown.

Specific Drugs