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  • CLASSES

    Intestinal Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, non-systemically absorbed rifamycin antibiotic
    Approved to treat traveler's diarrhea (due to non-invasive strains of Escherichia coli), irritable bowel disease with diarrhea, and to reduce risk of hepatic encephalopathy recurrence
    No significant drug interactions since not systemically absorbed

    COMMON BRAND NAMES

    Xifaxan

    HOW SUPPLIED

    Xifaxan Oral Tab: 200mg, 550mg

    DOSAGE & INDICATIONS

    For the treatment of patients with traveler's diarrhea caused by noninvasive strains of Escherichia coli.
    Oral dosage
    Adults, Adolescents, and Children >= 12 years

    200 mg PO three times daily for 3 days.

    For reducing the risk of overt hepatic encephalopathy recurrence.
    Oral dosage
    Adults

    550 mg PO twice daily. In trials, 91% of patients used lactulose concomitantly; rifaximin has been shown to be as effective as neomycin, paromomycin or lactulose in the treatment of hepatic encephalopathys.

    For the treatment of irritable bowel syndrome (IBS) with diarrhea.
    Oral dosage
    Adults

    550 mg PO three times per day for 14 days. Patients experiencing a recurrence of symptoms may receive the same 14-day dosing regimen up to 2 additional times (maximum of 3 total treatment cycles). Data from two clinical trials showed more patients receiving rifaximin experienced adequate relief of IBS symptoms compared to placebo (41% vs. 31%, p= 0.0125 and 41% vs. 32%, p = 0.0263).  

    For the treatment of diverticulitis†.
    For recurrent acute diverticulitis† in combination with mesalamine.
    Oral dosage
    Adults

    Rifaximin 400 mg PO twice daily plus mesalamine (800 mg PO three times daily) for 7 days followed by rifaximin 400 mg PO twice daily plus mesalamine (800 mg PO twice daily) for 7 days per month.

    Geriatric

    See adult dosage.

    For symptomatic remission of uncomplicated diverticulitis† in combination with mesalamine.
    Oral dosage
    Adults

    Rifaximin 800 mg/day PO in divided doses plus mesalamine (2.4 g/day PO in divided doses) for 10 days, followed by mesalamine (1.6 g/day PO in divided doses) for 8 weeks.

    Geriatric

    See adult dosage.

    For the treatment of active Crohn's disease†.
    Oral dosage
    Adults

    In an open-label study, patients ranging in age from 18 to 80 years with active Crohn's disease received rifaximin 200 mg PO three times per day for 16 weeks. At the conclusion of the study, rifaximin was well tolerated and resulted in clinical improvement in patients with active Crohn's disease. Due to the open-label design, a randomized, double-blind, placebo-controlled study is needed to confirm the effectiveness of rifaximin in active Crohn's disease.

    Geriatric

    See adult dosage.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO for traveler's diarrhea; 1100 mg/day PO for hepatic encephalopathy; 1650 mg/day for irritable bowel syndrome with diarrhea.

    Geriatric

    600 mg/day PO for traveler's diarrhea; 1100 mg/day PO for hepatic encephalopathy; 1650 mg/day for irritable bowel syndrome with diarrhea.

    Adolescents

    600 mg/day PO for traveler's diarrhea.

    Children

    >= 12 years: 600 mg/day PO for traveler's diarrhea.
    < 12 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    There is increased systemic exposure in patients with severe hepatic impairment. Pharmacokinetic trials showed increased Cmax and AUC in patients with Child-Pugh Class A, B, and C (see Pharmacokinetics). Clinical trials were limited to patients with MELD (Model for End-Stage Liver Disease) scores < 25; therefore, caution should be exercised when administering rifaximin to patients with severe hepatic impairment (Child-Pugh class C).

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Rifaximin tablets may be taken with or without food.

    Extemporaneous Compounding-Oral

    Extemporaneous 20 mg/ml rifaximin oral suspension:
    NOTE: Rifaximin oral suspension is not an FDA approved formulation.
    With a mortar and pestle, crush six 200 mg rifaximin tablets into a fine powder.
    Mix 30 ml Ora-Plus with either 30 ml Ora-Sweet or 30 ml Ora-Sweet Sugar Free and stir vigorously.
    Levigate 30 ml of the Ora-Plus/Ora-Sweet mixture into the rifaximin powder via geometric dilution until a smooth suspension is formed.
    Transfer the mixture into a 2 ounce amber plastic bottle.
    Rinse the mortar with the remainder of the Ora-Plus/Ora-Sweet mixture and add to the amber plastic bottle to bring the final volume to 60 ml.
    Shake well before each use. This suspension is stable 60 days at room temperature (23—25 degrees C).

    STORAGE

    Xifaxan:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Rifamycin hypersensitivity

    Rifaximin should not be administered to patients with a previous reaction to rifaximin or to patient's with a rifamycin hypersensitivity.

    Colitis, diarrhea, dysentery, fever, GI bleeding, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Rifaximin should not be administered to patients with diarrhea complicated by fever or blood in the stool (melena, GI bleeding). Rifaximin was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than E.coli. During clinical trials, patients treated with rifaximin complicated by fever or blood in the stool had lower clinical cure rates. Subjects with fever or blood in the stool had invasive pathogens, primarily Campylobacter Jejuni, isolated in the baseline stool samples. Furthermore, the effectiveness of the use of rifaximin for diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. Therefore, rifaximin should not be used to treat dysentery caused by Campylobacter jejuni, Shigella spp., or Salmonella spp. Additionally, almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Pregnancy

    No data are available regarding use of rifaximin during pregnancy. However, because systemic absorption of rifaximin after oral administration is minimal, one study suggested rifaximin as an alternative agent for traveler's diarrhea in pregnant women, in whom quinolones are contraindicated. Pregnant women have a higher risk of experiencing traveler's diarrhea (due to decreased gastric acidity and increased GI transit time) and the consequences of fluid loss may be more severe (e.g., premature labor, shock). It is not known if rifaximin crosses the placenta. Animal studies have demonstrated rifaximin to be teratogenic in rats and rabbits. However, there are no adequate and well controlled studies of rifaximin in pregnant women. Based on the animal data, the safest course is not to administer rifaximin during the 1st trimester. Rifaximin should only be used in pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.

    Breast-feeding

    It is not known whether rifaximin is excreted in human milk. The manufacturer states that a decision should be made whether to discontinue breast feeding or discontinue the drug, taking into account the importance of the drug to the mother. However, after oral administration, rifaximin plasma concentrations and exposures are low and variable. There was no evidence of accumulation after repeated administration for 3 days (9 doses). Peak plasma concentrations after 3 and 9 consecutive doses ranged from 0.68—3.4 ng/mL. Additionally, oral absorption by the breast-feeding infant would also be expected to be minimal. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and effectiveness of rifaximin have not been established in neonates, infants, and children < 12 years of age. Rifaximin is approved for use in children and adolescents >= 12 years with traveler's diarrhea. It is not approved in pediatric patients for hepatic encephalopathy or irritable bowel syndrome.

    Geriatric

    Oral rifaximin is minimally absorbed and its action is concentrated in the gastrointestinal tract. Clinical trial and other reported clinical experience has generally not identified differences in responses between the geriatric and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    Hepatic disease

    There is increased rifaximin systemic exposure in patients with severe hepatic impairment (hepatic disease). Pharmacokinetic trials in patients with hepatic encephalopathy showed increased Cmax and AUC in patients with Child-Pugh Class A, B, and C (see Pharmacokinetics). Clinical trials were limited to patients with MELD (Model for End-Stage Liver Disease) scores < 25; therefore, caution should be exercised when administering rifaximin to patients with severe hepatic impairment (Child-Pugh class C).

    ADVERSE REACTIONS

    Severe

    proteinuria / Delayed / 0-2.0
    exfoliative dermatitis / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    angioedema / Rapid / 0-1.0

    Moderate

    peripheral edema / Delayed / 15.0-15.0
    ascites / Delayed / 11.0-11.0
    anemia / Delayed / 8.0-8.0
    depression / Delayed / 7.0-7.0
    dyspnea / Early / 6.0-6.0
    elevated hepatic enzymes / Delayed / 2.0-2.0
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    nausea / Early / 2.0-14.0
    dizziness / Early / 13.0-13.0
    fatigue / Early / 12.0-12.0
    headache / Early / 10.0-10.0
    abdominal pain / Early / 6.0-9.0
    pruritus / Rapid / 9.0-9.0
    pharyngitis / Delayed / 7.0-7.0
    arthralgia / Delayed / 6.0-6.0
    fever / Early / 6.0-6.0
    rash (unspecified) / Early / 5.0-5.0
    myalgia / Early / 0-5.0
    vertigo / Early / 0-5.0
    infection / Delayed / 0-5.0
    weight loss / Delayed / 0-2.0
    otalgia / Early / 0-2.0
    tinnitus / Delayed / 0-2.0
    flushing / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0
    anorexia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Afatinib: (Moderate) If the concomitant use of rifaximin and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of rifaximin. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and rifaximin is a weak in vitro P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Amiodarone: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and amiodarone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and clarithromycin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and lansoprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and clarithromycin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and omeprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Aprepitant, Fosaprepitant: (Major) Use caution if rifaximin and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Rifaximin is a moderate CYP3A4 inducer in vitro, and aprepitant is a CYP3A4 substrate. In patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
    Aspirin, ASA; Omeprazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and omeprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Atazanavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin and atazanavir may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. Rifaximin is a substrate for the drug transporter organic anion transporting polypeptide (OATP); atazanavir is an inhibitor of OATP1B1, During one in vitro study, coadministration with cyclosporine, another OATP1B1 inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and transporter inhibition may further increase exposure to rifaximin.
    Atazanavir; Cobicistat: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin and atazanavir may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. Rifaximin is a substrate for the drug transporter organic anion transporting polypeptide (OATP); atazanavir is an inhibitor of OATP1B1, During one in vitro study, coadministration with cyclosporine, another OATP1B1 inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and transporter inhibition may further increase exposure to rifaximin. (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with cobicistat, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Axitinib: (Major) Avoid the coadministration of axitinib with rifaximin in patients with hepatic impairment if possible; if concomitant use is necessary, be aware of a potential for decreased efficacy of axitinib. In patients without hepatic impairment, use with caution. Axitinib is a CYP3A4 substrate and rifaximin is a moderate CYP3A4 inducer in vitro. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Azithromycin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and azithromycin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Bepridil: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and bepridil, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering rifaximin with boceprevir due to potential alterations in the plasma concentration of both drugs. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of rifaximin and boceprevir. Since rifaximin and boceprevir are substrates and inhibitors of the drug efflux transporter P-glycoprotein (P-gp), coadministation may result in increased plasma concentrations of both drugs. However, because rifaximin is also a mild inducer of CYP3A4, and boceprevir is paritally metabolized by this enzyme, concurrent use may also result in reduced boceprevir exposure. In patients with hepatic impairment, reduced drug metabolism may increase the effects of P-gp inhibition/CYP induction, thereby resulting in further alterations in drug exposure. If these drugs are used in combination, monitor patients closely for adverse events and potential boceprevir treatment failure.
    Bosutinib: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and bosutinib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and rifaximin are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4. Rifaximin is a CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.
    Cabozantinib: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and rifaximin is necessary. Cabozantinib is primarily metabolized by CYP3A4. Rifaximin is a CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and rifaximin is a substrate of P-gp in vitro; plasma concentrations of rifaximin may be increased. However, the clinical relevance of this finding is unknown.
    Canagliflozin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and canagliflozin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Canagliflozin; Metformin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and canagliflozin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Clarithromycin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and clarithromycin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Clindamycin: (Moderate) Concomitant use of clindamycin and rifaximin may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; rifaximin is a CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Caution and close monitoring are advised if these drugs are used together.
    Cobicistat: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with cobicistat, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with cobicistat, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with cobicistat, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as rifaximin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: (Major) The manufacturer of cobimetinib recommends avoiding concurrent with rifaximin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and rifaximin is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer. In patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.
    Conivaptan: (Moderate) Use caution when administering conivaptan and rifaximin concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as rifaximin, can increase rifaximin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Crizotinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with crizotinib is necessary; this effect may be more significant in patients with hepatic impairment, where there may be an additive effect of reduced metabolism. Rifaximin is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. In vitro exposure to another P-gp inhibitor reduced the efflux ratio of rifaximin by greater than 50%. Coadministration with a P-gp inhibitor in a clinical trial increased the mean AUC of rifaximin by 124-fold.
    Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with rifaximin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifaximin can be a moderate CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Cyclosporine: (Moderate) Concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with cyclosporine, a P-gp and OATP inhibitor, increases the systemic exposure and maximum plasma concentration to rifaximin by 83- and 124-fold, respectively. The clinical significance of this increase in systemic exposure is unknown; thus, caution and close monitoring for adverse reactions is advised if these drugs must be administered together.
    Dabigatran: (Moderate) Coadministration of dabigatran and rifaximin may result in increased dabigatran serum concentrations, increasing the risk of dabigatran adverse effects. Coadministration of dabigatran and rifaximin should be avoided in patients with severe renal impairment (CrCl <= 30 ml/min). Dabigatran is a substrate of P-glycoprotein (P-gp); rifaximin is a mild P-gp inhibitor. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, may need to be increased to 90 mg PO once daily when administered in combination with rifaximin. Rifaximin is categorized as a moderate CYP3A4 inducer; however in patients with normal hepatic function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of rifaximin, a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP), may be increased by daclatasvir, a P-gp and OATP inhibitor.
    Darunavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and darunavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Darunavir; Cobicistat: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with cobicistat, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and darunavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ritonavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. (Moderate) Concurrent administration of rifaximin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated rifaximin and ombitasvir plasma concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a P-gp inhibitor. Although ritonavir's effect on rifaximin clearance is not defined, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in rifaximin Cmax and AUC, respectively. In patients with hepatic impairment, the reduced metabolism and P-gp inhibition may further increase rifaximin exposure. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are substrates of the hepatic isoenzyme CYP3A4. Rifaximin has been shown to be an inducer of CYP3A4, but enzyme induction is not expected when rifaximin is given at FDA-approved dosages in patients with normal liver function. It is not known whether rifaximin has a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with hepatic impairment. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of rifaximin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated rifaximin and ombitasvir plasma concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir and paritaprevir are P-gp inhibitors. Although ritonavir's effect on rifaximin clearance is not defined, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in rifaximin Cmax and AUC, respectively. In patients with hepatic impairment, the reduced metabolism and P-gp inhibition may further increase rifaximin exposure. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are substrates of the hepatic isoenzyme CYP3A4. Rifaximin has been shown to be an inducer of CYP3A4, but enzyme induction is not expected when rifaximin is given at FDA-approved dosages in patients with normal liver function. It is not known whether rifaximin has a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with hepatic impairment. Caution and close monitoring are advised if these drugs are administered together.
    Deflazacort: (Moderate) Monitor for decreased efficacy of deflazacort if concomitant use of deflazacort and rifaximin is necessary. Deflazacort is a CYP3A4 substrate. Rifaximin is a CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Dextromethorphan; Quinidine: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and quinidine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Dienogest; Estradiol valerate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Diltiazem: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and diltiazem, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Doxorubicin: (Major) In vitro, rifaximin is a moderate inducer CYP3A4 inducer and a mild inhibitor of P-glycoprotein (P-gp). With normal liver function and at normal doses, however, rifaximin is not expected to induce CYP3A4. Doxorubicin is a major substrate of CYP3A4 and P-gp. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of rifaximin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy and increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Oral rifaximin is largely unabsorbed and should not result in drug interactions.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with rifaximin is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate. Rifaximin is a moderate inducer of CYP3A4 in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and dronedarone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Drospirenone; Estradiol: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Drospirenone; Ethinyl Estradiol: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as rifaximin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Severe) Concurrent administration of elbasvir; grazoprevir with rifaximin is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Rifaximin is an inhibitor of the organic anion transporting polypeptide (OATP1B1/3); grazoprevir is an OATP1B1/3 substrate.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as rifaximin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as rifaximin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with rifaximin is necessary due to the risk of decreased erlotinib efficacy. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Rifaximin is a CYP3A4 inducer in vitro; the manufacturer of erlotinib recommends avoiding coadministration with CYP3A4 inducers, and increasing the dose if avoidance is not possible. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of erlotinib in patients with reduced liver function who may have elevated rifaximin concentrations. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with rifaximin in certain patient populations may also decrease erlotinib exposure.
    Erythromycin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and erythromycin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Erythromycin; Sulfisoxazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and erythromycin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Estradiol; Levonorgestrel: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Estradiol; Norethindrone: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Estradiol; Norgestimate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Desogestrel: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Etonogestrel: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Norelgestromin: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Norethindrone: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Norgestimate: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Ethinyl Estradiol; Norgestrel: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Etoposide, VP-16: (Minor) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with rifaximin. Etoposide, VP-16 is a CYP3A4 and P-gp substrate. Rifaximin is a weak in vitro P-glycoprotein (P-gp) inhibitor. Rifaximin can also induce CYP3A4; however, at the recommended dosing regimen, rifaximin is not expected to induce CYP3A4 in patients with normal liver function. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.
    Etravirine: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and etravirine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ezetimibe; Simvastatin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and simvastatin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Gefitinib: (Major) Monitor for clinical response of gefitinib if used concomitantly with rifaximin. Gefitinib is metabolized significantly by CYP3A4 and in vitro, rifaximin is a CYP3A4 inducer; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Gemfibrozil: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, an organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with gemfibrozil, an OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and rifaximin as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and rifaximin are both substrates and inhibitors of organic anion transporting polypeptide (OATP) 1B1/3 and P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and rifaximin as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Rifaximin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3; pibrentasvir is an inhibitor of these drug transporters. Additionally, pibrentasvir is a substrate of P-gp while rifaximin is an inhibitor of P-gp.
    Iloperidone: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and iloperidone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Irinotecan: (Major) In vitro, rifaximin is a moderate inducer of CYP3A4 and a mild P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    Itraconazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and itraconazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ivacaftor: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ivacaftor, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. In addition, rifaximin was shown to induce CYP3A in in vitro models; however, absorption after oral administration is low and in patients with normal liver function, rifaximin is not expected to induce CYP3A4.
    Ketoconazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ketoconazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Lansoprazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and lansoprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Lansoprazole; Naproxen: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and lansoprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Lapatinib: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and lapatinib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ledipasvir; Sofosbuvir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ledipsavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Leuprolide; Norethindrone: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Levonorgestrel: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be altered when administered concurrently with rifaximin, an inducer of CYP3A4 and a mild inhibitor of P-gp. If these drugs are used together, monitor for altered response to loperamide and loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be altered when administered concurrently with rifaximin, an inducer of CYP3A4 and a mild inhibitor of P-gp. If these drugs are used together, monitor for altered response to loperamide and loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin and lopinavir; ritonavir may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. Rifaximin is a substrate for the drug transporters P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP); lopinavir is an inhibitor of OATP1B1 and ritonavir is a P-gp inhibitor. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP1B1 inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and transporter inhibition may further increase exposure to rifaximin. (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ritonavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Lovastatin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and lovastatin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Lovastatin; Niacin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and lovastatin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Lumacaftor; Ivacaftor: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ivacaftor, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. In addition, rifaximin was shown to induce CYP3A in in vitro models; however, absorption after oral administration is low and in patients with normal liver function, rifaximin is not expected to induce CYP3A4.
    Maraviroc: (Minor) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and rifaximin as increased maraviroc concentrations may occur. Maraviroc is a substrate of CYP3A and P-glycoprotein (P-gp); rifaximin is a weak inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible. Additionally, rifaximin can be a moderate CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.
    Mefloquine: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and mefloquine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Mestranol; Norethindrone: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Midazolam: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A clinical drug-drug interaction study showed that rifaximin administered as 200 mg PO tid for 3 or 7 days did not alter the pharmacokinetics of IV or PO midazolam presystemically or systemically, demonstrating a lack of induction of intestinal or hepatic CYP 3A4 isoenzyme. Rifaximin was also administered as 550 mg PO bid for 7 or 14 days with oral midazolam in healthy subjects. The mean AUC of a single 2 mg oral dose of midazolam was 3.8 to 8.8% lower than when midazolam was administered alone. The mean Cmax of midazolam was decreased by 4 to 5% when administered for 7 to 14 days prior to midazolam administration. However, this degree of interaction was not considered clinically significant.
    Mifepristone, RU-486: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and mifepristone, RU-486, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Nelfinavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and nelfinavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Neratinib: (Moderate) Avoid concomitant use of rifaximin with neratinib in patients with hepatic impairment due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate. In patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. The effect of moderate CYP3A4 induction on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inducer decreased neratinib exposure by 87% and decreased exposure to active metabolites M6 and M7 by 37% to 49%. Because of the significant impact on neratinib exposure from strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers should be considered as they may also significantly decrease neratinib exposure.
    Niacin; Simvastatin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and simvastatin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Nicardipine: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and nicardipine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Nifedipine: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and nifedipine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Nintedanib: (Major) In vitro, rifaximin is a CYP3A4 inducer and a mild P-glycoprotein (P-gp) inhibitor; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with a CYP3A4 inhibitor could increase the concentration and clinical effect of nintedanib, while concomitant use of a CYP3A4 inducer could decrease exposure to nintedanib. Avoid coadministration of nintedanib with CYP3A4 inducers such as rifaximin as these drugs may compromise nintedanib efficacy.
    Norethindrone: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Norgestrel: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to rifaximin. Rifaximin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ritonavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. (Moderate) Concurrent administration of rifaximin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated rifaximin and ombitasvir plasma concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a P-gp inhibitor. Although ritonavir's effect on rifaximin clearance is not defined, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in rifaximin Cmax and AUC, respectively. In patients with hepatic impairment, the reduced metabolism and P-gp inhibition may further increase rifaximin exposure. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are substrates of the hepatic isoenzyme CYP3A4. Rifaximin has been shown to be an inducer of CYP3A4, but enzyme induction is not expected when rifaximin is given at FDA-approved dosages in patients with normal liver function. It is not known whether rifaximin has a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with hepatic impairment. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of rifaximin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated rifaximin and ombitasvir plasma concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir and paritaprevir are P-gp inhibitors. Although ritonavir's effect on rifaximin clearance is not defined, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in rifaximin Cmax and AUC, respectively. In patients with hepatic impairment, the reduced metabolism and P-gp inhibition may further increase rifaximin exposure. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are substrates of the hepatic isoenzyme CYP3A4. Rifaximin has been shown to be an inducer of CYP3A4, but enzyme induction is not expected when rifaximin is given at FDA-approved dosages in patients with normal liver function. It is not known whether rifaximin has a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with hepatic impairment. Caution and close monitoring are advised if these drugs are administered together.
    Omeprazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and omeprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Omeprazole; Sodium Bicarbonate: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and omeprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Oral Contraceptives: (Minor) Studies have shown rifaximin to be largely unabsorbed following oral administration with most of the drug recovered in feces. A study using rifaximin 200 mg PO tid for 3 days showed no alteration of presystemic metabolism of oral contraceptives containing 0.07 mg ethinyl estradiol and 0.50 mg norgestimate. No studies have been conducted with oral contraceptives and the 550 mg rifaximin dose used in hepatic encephalopathy.
    Paliperidone: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and paliperidone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Pantoprazole: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and pantoprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Posaconazole: (Moderate) Posaconazole and rifaximin should be coadministered with caution. Both posaconazole and rifaximin are substrates and inhibitors of the drug efflux protein, P-glycoprotein. This interaction may cause alterations in the plasma concentrations of both drugs, ultimately resulting in an increased risk of adverse events.
    Propafenone: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and propafenone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Quinidine: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and quinidine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ranolazine: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ranolazine, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Regorafenib: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and regorafenib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ritonavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ritonavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rivaroxaban: (Moderate) Rifaximin is a combined mild P-glycoprotein inhibitor and CYP3A4 inhibitor. The coadministration of rivaroxaban and rifaximin should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Based on simulated pharmacokinetic data, patients with renal impairment receiving rivaroxaban with drugs that are combined P-glycoprotein and weak or moderate CYP3A4 inhibitors such as rifaximin may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected. Because these increases may increase bleeding risk, only use rivaroxaban in this situation if the potential benefit justifies the potential risk. In addition, although rifaximin is an inhibitor of both CYP3A4 and P-glycoprotein, which may increase rivaroxaban exposure, the manufacturer of rivaroxaban states that clinical data suggest that the change in rivaroxaban exposure when coadministered with another CYP3A4/P-gp inhibitor, erythromycin, is unlikely to affect bleeding risk in patients with normal renal function.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Rifaximin is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and rifaximin as coadministration may result in increased systemic exposure of rifaximin. Rifaximin is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of rifaximin. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Saquinavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and saquinavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Simeprevir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with simeprevir, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Simvastatin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and simvastatin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Simvastatin; Sitagliptin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and simvastatin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Sofosbuvir; Velpatasvir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin with velpatasvir may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. Rifaximin is a substrate of the drug transporters P-glycoprotein (P-gp) and organic anion transporting polypeptides OATP1B1 and OATP1B3; velpatasvir is a P-gp, OATP1B1, and OATP1B3 inhibitor. During one in vitro study, coadministration with a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of voxilaprevir and rifaximin. Although not observed in patients with normal hepatic function, in patients with reduced liver function rifaximin may induce metabolism of CYP3A4 substrates, such as voxilaprevir. This interaction may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Conversely, by inhibiting the Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3), rifaximin may increase concentrations of voxilaprevir (a OATP1B1/1B3 substrate). In addition, voxilaprevir (a OATP1B1/1B3 and P-glycoprotein (P-gp) inhibitor) may increase concentrations of rifaximin (an OATP1B1/1B3 and P-gp substrate). Taking these drugs together may increase the risk for adverse events. (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin with velpatasvir may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. Rifaximin is a substrate of the drug transporters P-glycoprotein (P-gp) and organic anion transporting polypeptides OATP1B1 and OATP1B3; velpatasvir is a P-gp, OATP1B1, and OATP1B3 inhibitor. During one in vitro study, coadministration with a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and rifaximin; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and rifaximin is a CYP3A4 inducer in vitro. When given at the recommended dosage, rifaximin is not expected to induce the CYP3A4 isoenzyme in patients with normal liver function; however, it is not known whether rifaximin may induce metabolism of CYP3A4 substrates in patients with reduced hepatic function who may have elevated rifaximin concentrations. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    Sorafenib: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and sorafenib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Tamoxifen: (Major) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and tamoxifen, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. Additionally, in vitro, rifaximin is a CYP3A4 inducer. Tamoxifen and its metabolite, 4-hydroxytamoxifen, are metabolized in part by CYP3A4 to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Rifaximin may induce the CYP3A4 metabolism of tamoxifen to these metabolites; the clinical significance of this interaction is not known. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen as well as for rifaximin toxicity. In patients with normal liver function and at normal doses, rifaximin is not expected to induce 3A4; oral rifaximin is largely unabsorbed and should not result in any drug interactions.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering rifaximin with telaprevir due to potential alterations in the plasma concentration of both drugs. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of rifaximin and telaprevir. Since rifaximin and telaprevir are substrates and inhibitors of the drug efflux transporter P-glycoprotein (P-gp), coadministation may result in increased plasma concentrations of both drugs. However, because rifaximin is also a mild inducer of CYP3A4, and telaprevir is metabolized by this enzyme, concurrent use may also result in reduced telaprevir exposure. In patients with hepatic impairment, reduced drug metabolism may increase the effects of P-gp inhibition/CYP induction, thereby resulting in further alterations in drug exposure. If these drugs are used in combination, monitor patients closely for adverse events and potential telaprevir treatment failure.
    Telithromycin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) an organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with telithromycin, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Telotristat Ethyl: (Minor) Use caution if rifaximin is coadministered with telotristat ethyl, and monitor for an increase in telotristat ethyl-related adverse reactions. Telotristat, the active metabolite of telotristat ethyl, is a substrate of P-glycoprotein (P-gp) and rifaximin is a weak P-gp inhibitor in vitro. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Minor) Use caution if coadministration of temsirolimus with rifaximin is necessary, due to the possible effect on temsirolimus exposure or increased exposure to rifaximin. Temsirolimus is a CYP3A4 substrate as well as an in vitro substrate / inhibitor of P-glycoprotein (P-gp). Rifaximin is a moderate inducer of CYP3A4 inducer in vitro. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Additionally, rifaximin is an in vitro substrate / weak inhibitor of P-gp. Coadministration may affect temsirolimus exposure or increase exposure to rifaximin. The manufacturer of temsirolimus recommends a dose increase if coadministered with a strong CYP3A4 inducer, but recommendations are not available for concomitant use of moderate CYP3A4 or P-gp inducers or inhibitors. Coadministration of temsirolimus with rifampin, a strong CYP3A4/5 inducer, had no significant effect on the AUC or Cmax of temsirolimus, but decreased the sirolimus AUC and Cmax by 56% and 65%, respectively. Pharmacokinetic data are not available regarding the magnitude of effect of P-gp induction on temsirolimus exposure, or regarding the concomitant use of temsirolimus with P-gp substrates, but exposure to rifaximin is likely to increase.
    Tenofovir Alafenamide: (Moderate) Caution is advised when administering tenofovir alafenamide with rifaximin, as there is a potential for elevated tenofovir alafenamide plasma concentrations. Rifaximin is an in vitro inhibitor of P-glycoprotein (P-gp) and the orgainic anion transporting polypeptide (OATP1B1/1B3); tenofovir alafenamide is a P-gp and OATP1B1/1B3 substrate. Concurrent use may cause increased absorption of tenofovir resulting in adverse effects. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as rifaximin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Teriflunomide: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, an organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with teriflunomide, an OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, an OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively.
    Testosterone: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and testosterone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ticagrelor: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ticagrelor, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Tolvaptan: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and tolvaptan, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Topotecan: (Major) Avoid the concomitant use of rifaximin, an in vitro P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of rifaximin and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Trabectedin: (Minor) Use caution if coadministration of trabectedin and rifaximin is necessary, due to the potential risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, rifaximin is a CYP3A inducer; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A substrates in patients with reduced liver function who have elevated rifaximin concentrations. During pharmacokinetic studies, coadministration of a single dose of trabectedin with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Trandolapril; Verapamil: (Moderate) Rifaximin is a P-glycoprotein (P-gp) substrate. An in vitro study with the P-gp inhibitor verapamil showed that the efflux ratio of rifaximin was reduced more than 50%. Due to the potential for substantially increased systemic exposure to rifaximin, caution is advised when concurrent use of these drugs is required. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. The clinical significance of this interaction is unknown.
    Ulipristal: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ulipristal, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with rifaximin is necessary, due to a possibly unpredictable effect on vandetanib efficacy and toxicity; rifaximin-related adverse reactions may also increase. Rifaximin is a moderate inducer of CYP3A4 in vitro. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively. Additionally, rifaximin is an in vitro substrate of P-glycoprotein (P-gp); coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Vemurafenib: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and vemurafenib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Verapamil: (Moderate) Rifaximin is a P-glycoprotein (P-gp) substrate. An in vitro study with the P-gp inhibitor verapamil showed that the efflux ratio of rifaximin was reduced more than 50%. Due to the potential for substantially increased systemic exposure to rifaximin, caution is advised when concurrent use of these drugs is required. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. The clinical significance of this interaction is unknown.
    Vincristine Liposomal: (Moderate) In vitro, rifaximin is a CYP3A4 inducer and a mild P-glycoprotein (P-gp) inhibitor, and vincristine is a CYP3A and P-gp substrate. With normal liver function and at normal doses, rifaximin is not expected to induce CYP3A4. Oral rifaximin is largely unabsorbed and should not result in drug interactions. However, theoretically, coadministration may affect vincristine concentrations; monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together.
    Vincristine: (Moderate) In vitro, rifaximin is a CYP3A4 inducer and a mild P-glycoprotein (P-gp) inhibitor, and vincristine is a CYP3A and P-gp substrate. With normal liver function and at normal doses, rifaximin is not expected to induce CYP3A4. Oral rifaximin is largely unabsorbed and should not result in drug interactions. However, theoretically, coadministration may affect vincristine concentrations; monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together.
    Vinorelbine: (Moderate) Caution is warranted when rifaximin is administered with vinorelbine, as there is a potential for the metabolism of vinorelbine to be affected, decreasing drug efficacy. Patients receiving this drug concurrently with vincristine should be monitored for clinical effects. Vinorelbine is a substrate for cytochrome P450 (CYP) 3A4, and rifaximin is a CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    No data are available regarding use of rifaximin during pregnancy. However, because systemic absorption of rifaximin after oral administration is minimal, one study suggested rifaximin as an alternative agent for traveler's diarrhea in pregnant women, in whom quinolones are contraindicated. Pregnant women have a higher risk of experiencing traveler's diarrhea (due to decreased gastric acidity and increased GI transit time) and the consequences of fluid loss may be more severe (e.g., premature labor, shock). It is not known if rifaximin crosses the placenta. Animal studies have demonstrated rifaximin to be teratogenic in rats and rabbits. However, there are no adequate and well controlled studies of rifaximin in pregnant women. Based on the animal data, the safest course is not to administer rifaximin during the 1st trimester. Rifaximin should only be used in pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.

    It is not known whether rifaximin is excreted in human milk. The manufacturer states that a decision should be made whether to discontinue breast feeding or discontinue the drug, taking into account the importance of the drug to the mother. However, after oral administration, rifaximin plasma concentrations and exposures are low and variable. There was no evidence of accumulation after repeated administration for 3 days (9 doses). Peak plasma concentrations after 3 and 9 consecutive doses ranged from 0.68—3.4 ng/mL. Additionally, oral absorption by the breast-feeding infant would also be expected to be minimal. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Rifaximin inhibits bacterial and mycobacterial RNA synthesis. It binds to the beta-subunit of DNA-dependent RNA polymerase, thereby inhibiting the binding of the enzyme to DNA and blocking RNA transcription. Rifaximin does not bind to RNA polymerase in eukaryotic cells, so RNA synthesis in human cells is not affected.
     
    For use in the treatment of hepatic encephalopathy, the manufacturer suggests that rifaximin may have an effect on the gastrointestinal flora. Since oral rifaximin is minimally absorbed, it is concentrated in the gastrointestinal tract, where it exerts its effects. In general, oral antibiotics have been used for hepatic encephalopathy to reduce ammonia-producing enteric bacteria.

    PHARMACOKINETICS

    Rifaximin is administered orally. Although it is largely unabsorbed by the GI tract. Rifaximin is 67.5% bound to plasma proteins in healthy subjects and 62% bound to plasma proteins in patients with hepatic impairment. 
    Radiolabeled rifaximin given to healthy male subjects in clinical trials demonstrated that 0.32% of the dose to be excreted in urine mostly as metabolites with 0.03% as the unchanged drug. Therefore, since rifaximin is essentially unabsorbed via the GI tract, nearly all of an orally administered dose is recovered in the feces (96.63%). Additionally, rifaximin was detected in the bile after cholecystectomy patients with intact gastrointestinal mucosa, suggesting some biliary excretion.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP1A2, OAPT1B1, and OATP1B3)
    In vitro drug interaction studies of rifaximin show that it does not inhibit the human cytochrome P450 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 isoenzymes. Conversely, rifaximin was shown to induce cytochrome P450 3A4 isoenzymes in in vitro hepatocyte induction models. In patients with normal liver function, rifaximin given at normal doses is not expected to induce the CYP3A4 isoenzyme. It is unknown whether rifaximin may induce metabolism of CYP3A4 substrates in patients with reduced hepatic function who may have elevated rifaximin concentrations. In vitro data suggest the rifaximin is a substrate for the transporters P-gp, OATP1A2, OAPT1B1, and OATP1B3. Drugs that inhibit these transporters can substantially increase the systemic exposure of rifaximin. Rifaximin is also a weak inhibitor of P-gp, OATP1A2, OAPT1B1, and OATP1B3. The clinical significance of potential interaction with substrates of these transporters is unknown.

    Oral Route

    Unlike other rifamycins, rifaximin is largely unabsorbed by the GI tract in subjects with intact and damaged intestinal mucosa. Animal pharmacokinetic studies demonstrate that 80% to 90% of rifaximin is concentrated in the gut, less than 0.2% in the liver and kidneys, and less than 0.01% in other tissues following oral administration. Single doses of rifaximin 550 mg in healthy subjects resulted in peak plasma concentrations about 1 hour after the dose. Systemic absorption of oral rifaximin (200 mg three times daily) was evaluated in 13 shigellosis patients on days 1 and 3 of a 3-day treatment course. Rifaximin plasma concentrations were low and variable and there was no evidence of drug accumulation. Peak plasma concentrations on Day 1 and Day 3 ranged from 0.81—3.4 ng/ml and 0.68—2.26 ng/ml, respectively. AUC estimates were 6.95 +/- 5.15 ng X h/ml and 7.83 +/- 4.94 ng X h/ml, on Day 1 and Day 3 respectively. In patients with a history of hepatic encephalopathy, the pharmacokinetic parameters were associated with a high variability; the mean rifaximin AUC in these patients was 147 ng X h/ml, which was approximately 12-fold higher than that observed in healthy subjects (AUC = 12.3 +/- 4.8 ng X h/ml). In patients with Child-Pugh Class A, B, and C, the mean AUC was 10-fold (118 +/- 67/8 ng X h/ml), 13-fold (161 +/- 101 ng X h/ml), and 20-fold (246 +/- 120 ng X h/ml) higher, respectively, compared to healthy subjects. The Cmax was also increased from that in normal subjects (3.4 +/- 1.6 ng/ml) in Child-Pugh Class A (19.5 +/- 11.4 ng/ml), Class B (25.1 +/- 12.6 ng/ml), and Class C (35.5 +/- 12.5 ng/ml). In healthy subjects, a high-fat meal consumed 30 minutes before a 550 mg dose resulted in a delay in the mean peak plasma concentration from 0.75—0.8 hours to 1.5 hours and increased systemic AUC by 2-fold (11.1 +/- 4.2 ng X h/ml to 22.5 +/1 12 ng X ml/hg). The Cmax of rifaximin was unchanged in the fasting (4.1 +/1 1.5 ng/ml) vs the fed (4.8 +/- 4.3 ng/ml) state; however, the half-life increased from 1.8 +/- 1.4 hours in the fasting state to 4.8 +/- 1.3 hours in the fed state.