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  • CLASSES

    Antibiotics for IBS-D
    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), to reduce risk of hepatic encephalopathy recurrence, and treatment of irritable bowel syndrome with diarrhea (IBS-D)
    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 traveler's diarrhea due to noninvasive strains of E. coli.
    Oral dosage
    Adults

    200 mg PO 3 times daily for 3 days. Rifaximin is an alternative treatment for severe, nondysenteric diarrhea in areas where invasive pathogens are not common. May reserve use for patients unable to take a quinolone or azithromycin. Antibiotic treatment is not recommended for mild cases, may be considered for moderate cases, and should be used for severe cases.

    Children 12 years and Adolescents

    200 mg PO 3 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 traveler's diarrhea prophylaxis†.
    Oral dosage
    Adults

    200 to 1,100 mg/day PO in 1 to 3 divided doses for travelers at high risk of health-related complications of traveler's diarrhea.

    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.

    For the treatment of pseudomembranous colitis† due to C. difficile infection†.
    Oral dosage
    Adults

    400 mg PO 3 times daily for 20 days after 10 days of oral vancomycin for patients with second or subsequent recurrences.

    †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 is contraindicated in patients with a history of rifamycin hypersensitivity, rifaximin hypersensitivity, or hypersensitivity to any of the components of rifaximin.

    Diarrhea, fever, pseudomembranous colitis

    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. Discontinue rifaximin if diarrhea symptoms get worse or persist more than 24 to 48 hours and consider alternative antibiotic therapy. Do not use rifaximin in patients where Campylobacter jejuni, Shigella sp., or Salmonella sp. may be suspected as causative pathogens. Rifaximin is not effective in cases of travelers' diarrhea due to Campylobacter jejuni. The effectiveness of rifaximin in travelers' diarrhea caused by Shigella sp. and Salmonella sp. has not been proven. Almost all antibacterial agents, including rifaximin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.

    Hepatic disease

    Use caution when administering rifaximin to patients with severe hepatic disease (Child-Pugh class C). There is increased rifaximin systemic exposure in patients with severe hepatic impairment. Clinical trials were limited to patients with MELD (Model for End-Stage Liver Disease) scores less than 25.

    Geriatric

    Clinical studies with rifaximin for travelers' diarrhea did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    Pregnancy

    There are no available data on rifaximin use in human pregnancy to inform any drug associated risks. However, because systemic absorption of rifaximin after oral administration is minimal, rifaximin is suggested as an alternative agent for travelers' diarrhea in pregnant women in whom quinolones are contraindicated. Pregnant women have a higher risk of experiencing travelers' 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). Teratogenic effects were observed in animal reproduction studies after administration of rifaximin to pregnant rats and rabbits during organogenesis at doses approximately 0.9 to 5 times and 0.7 to 33 times, respectively of the recommended human doses of 600 to 1,650 mg/day. In rabbits, ocular, oral and maxillofacial, cardiac, and lumbar spine malformations were observed. Ocular malformations were observed in both rats and rabbits at doses that caused reduced maternal body weight gain. Advise pregnant women of the potential risk to a fetus.

    Breast-feeding

    There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breast-fed infant, or the effects of rifaximin on milk production. Consider the development and health benefits of breast-feeding along with the mother's clinical need for rifaximin and any potential adverse effects on the breast-fed infant from rifaximin or from the underlying maternal condition.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known

    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
    pseudomembranous colitis / Delayed / 0-5.0
    elevated hepatic enzymes / Delayed / 2.0-2.0

    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 / Early / 5.0-5.0
    myalgia / Early / 0-5.0
    weight loss / Delayed / 0-2.0
    anorexia / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with rifaximin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If rifaximin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. 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.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifaximin is necessary; consider increasing the dose of oxycodone as needed. If rifaximin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifaximin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Amiodarone: (Moderate) Concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and amiodarone, a P-gp inhibitor, may increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During an 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.
    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.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with rifaximin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If rifaximin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. 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.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifaximin is necessary; consider increasing the dose of oxycodone as needed. If rifaximin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifaximin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin and atazanavir may 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-gp and organic anion transporting polypeptide (OATP); atazanavir is an inhibitor of OATP1B1. During one in vitro study, coadministration with a combined P-gp and OATP1B1 inhibitor resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively.
    Atazanavir; Cobicistat: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin and atazanavir may 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-gp and organic anion transporting polypeptide (OATP); atazanavir is an inhibitor of OATP1B1. During one in vitro study, coadministration with a combined P-gp and OATP1B1 inhibitor resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. (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.
    Avapritinib: (Minor) Avoid coadministration of avapritinib with rifaximin in patients with hepatic impairment due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate. In vitro, rifaximin is a CYP3A4 inducer. In patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. However, it is unknown whether rifaximin can have a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Coadministration with a moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
    Axitinib: (Moderate) In patients with hepatic impairment, avoid coadministration of axitinib with rifaximin if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate. In patients with normal hepatic function, rifaximin is not expected to induce CYP3A4 at the recommended dosing regimen. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.
    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 increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During an 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.
    Berotralstat: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with berotralstat is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and berotralstat is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with a P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Boceprevir: (Moderate) Rifaximin is a substrate of P-gp and boceprevir is a P-gp inhibitor. Coadministation may result in increased plasma concentrations of rifaximin; use caution. In patients with hepatic impairment, reduced drug metabolism may increase the effects of P-gp inhibition.
    Brigatinib: (Moderate) In patients with hepatic impairment, avoid coadministration of brigatinib with rifaximin due to decreased plasma exposure to brigatinib which may result in decreased efficacy; brigatinib may be administered with rifaximin in patients with normal hepatic function. If concomitant use is unavoidable in patients with hepatic impairment, after 7 days of concomitant treatment with rifaximin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of rifaximin, resume the brigatinib dose that was tolerated prior to initiation of rifaximin. Brigatinib 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. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Cabozantinib: (Moderate) Rifaximin is a substrate of P-gp and cabozantinib is a P-gp inhibitor. Coadministation may result in increased plasma concentrations of rifaximin; use caution. In patients with hepatic impairment, reduced drug metabolism may increase the effects of P-gp inhibition.
    Cannabidiol: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cannabidiol is necessary. Rifaximin is a P-gp substrate and cannabidiol is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with rifaximin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If rifaximin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. 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.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with rifaximin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If rifaximin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. 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.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    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.
    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.
    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.
    Codeine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with rifaximin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If rifaximin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. 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.
    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.
    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; 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.
    Darunavir; Cobicistat; 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.
    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 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. (Moderate) Monitor for an increase in adverse reactions related to either therapy if coadministration is necessary. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Monitor for an increase in adverse reactions related to either therapy if coadministration is necessary. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. 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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with rifaximin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If rifaximin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. 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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Doravirine: (Moderate) Concurrent administration of doravirine and rifaximin may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate. 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.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and rifaximin may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate. 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.
    Doxorubicin: (Major) Avoid coadministration of rifaximin and doxorubicin if possible. If not possible, monitor doxorubicin closely for increased side effects including myelosuppression and cardiotoxicity. Oral rifaximin is largely unabsorbed and should not result in drug interactions. In vitro, rifaximin is a mild inhibitor of P-glycoprotein (P-gp). Doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Dronabinol: (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.
    Elagolix: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with elagolix is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and elagolix is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with elagolix is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and elagolix is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold. (Moderate) Monitor for rifaximin-related adverse reactions during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of rifaximin. Rifaximin is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3.
    Elvitegravir; Cobicistat; 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.
    Elvitegravir; Cobicistat; 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.
    Enasidenib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with enasidenib is necessary. Rifaximin is a P-gp substrate and enasidenib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Encorafenib: (Major) Avoid coadministration of encorafenib and rifaximin due to decreased encorafenib exposure and potential loss of efficacy. Although not observed in patients with normal hepatic function, in patients with reduced liver function rifaximin may induce metabolism of CYP3A4 substrates, such as encorafenib. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Entrectinib: (Major) Avoid coadministration of entrectinib with rifaximin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifaximin is a moderate CYP3A4 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. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Erdafitinib: (Major) If coadministration of erdafitinib and rifaximin is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If rifaximin must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21) in patients with hepatic impairment, increase the dose of erdafitinib up to 9 mg. If rifaximin is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib 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.
    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.
    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.
    Fedratinib: (Moderate) Avoid coadministration of fedratinib with rifaximin in patients with hepatic dysfunction as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate. 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 hepatic dysfunction who have elevated rifaximin concentrations. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    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.
    Glasdegib: (Major) Avoid coadministration of glasdegib and rifaximin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, consider an increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily) for select patients. Resume the previous dose of glasdegib after rifaximin has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; 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 CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
    Glecaprevir; Pibrentasvir: (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. (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with glecaprevir is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and glecaprevir is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rifaximin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifaximin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone 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.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifaximin is necessary; consider increasing the dose of oxycodone as needed. If rifaximin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifaximin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    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) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    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; Amoxicillin; 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.
    Lapatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lapatinib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    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.
    Lefamulin: (Major) Avoid coadministration of lefamulin with rifaximin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; rifaximin is a moderate CYP3A4 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.
    Lemborexant: (Moderate) Avoid coadministration of lemborexant and rifaximin as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate. 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.
    Lonafarnib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lonafarnib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Loperamide: (Moderate) If coadministration is necessary, monitor closely for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be altered when administered concurrently with rifaximin, a mild inhibitor of P-gp.
    Loperamide; Simethicone: (Moderate) If coadministration is necessary, monitor closely for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be altered when administered concurrently with rifaximin, a mild inhibitor of P-gp.
    Lopinavir; Ritonavir: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin and lopinavir may 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); lopinavir is an inhibitor of OATP1B1. 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.
    Lumacaftor; Ivacaftor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and rifaximin if possible as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate. 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.
    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 P-glycoprotein (P-gp); rifaximin is a mild 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.
    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.
    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.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with rifaximin is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate. Rifaximin is a moderate CYP3A4 inducer, although in patients with normal liver function, rifaximin at the recommended dosage regimen is not expected to induce CYP3A4.
    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) Monitor for an increase in rifaximin-related adverse reactions if coadministration with neratinib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    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.
    Olaparib: (Minor) Monitor for a decrease in the efficacy of olaparib if coadministration with rifaximin is necessary in patients with hepatic insufficiency. Olaparib is a CYP3A substrate. In patients with normal liver function, rifaximin is not expected to induce CYP3A4 at the recommended dosing regimen. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who may have elevated rifaximin concentrations.
    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 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. (Moderate) Monitor for an increase in adverse reactions related to either therapy if coadministration is necessary. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.
    Osimertinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with osimertinib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifaximin is necessary; consider increasing the dose of oxycodone as needed. If rifaximin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifaximin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    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.
    Rimegepant: (Major) Avoid coadministration of rimegepant with rifaximin; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant 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.
    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) If coadministration is necessary, monitor closely for rivaroxaban-associated adverse reactions, such as increased bleeding risk. The plasma concentration of rivaroxaban, a P-glycoprotein (P-gp) substrate, may be altered when administered concurrently with rifaximin, a mild inhibitor of P-gp.
    Romidepsin: (Moderate) Coadministration of romidepsin, a substrate for P-glycoprotein (P-gp) with rifaximin, a P-gp inhibitor may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    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.
    Selumetinib: (Major) Avoid coadministration of selumetinib and rifaximin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifaximin is a moderate CYP3A4 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. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
    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.
    Siponimod: (Moderate) Concomitant use of siponimod and rifaximin is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; rifaximin is a moderate CYP3A4 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. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
    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: (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. (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with voxilaprevir is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and voxilaprevir is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    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) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sorafenib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Sotorasib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sotorasib is necessary. Rifaximin is a P-gp substrate and sotorasib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if rifaximin must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with rifaximin is necessary; consider increasing the dose of sufentanil injection as needed. If rifaximin is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil 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. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with rifaximin as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and rifaximin is a moderate CYP3A4 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.
    Telaprevir: (Moderate) 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. If these drugs are used in combination, monitor patients closely for adverse events.
    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.
    Temsirolimus: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with temsirolimus is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased the mean rifaximin Cmax by 83-fold and the mean AUC by 124-fold. The effect may be greater in patients with hepatic impairment.
    Tepotinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with tepotinib is necessary. Rifaximin is a P-gp substrate and tepotinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    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.
    Tezacaftor; Ivacaftor: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    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.
    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.
    Tucatinib: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with tucatinib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Ubrogepant: (Major) Consider increasing the initial and second dose of ubrogepant to 100 mg if coadministered with rifaximin in patients with reduced liver function as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate. 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.
    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) Monitor patients for vincristine toxicity if coadministration of rifaximin, a mild P-glycoprotein (P-gp) inhibitor and vincristine, a P-gp substrate is necessary.
    Vincristine: (Moderate) Monitor patients for vincristine toxicity if coadministration of rifaximin, a mild P-glycoprotein (P-gp) inhibitor and vincristine, a P-gp substrate is necessary.
    Voclosporin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with voclosporin is necessary. Rifaximin is a P-gp substrate and voclosporin is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Voxelotor: (Major) Avoid coadministration of voxelotor and rifaximin as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily. Voxelotor is a substrate of CYP3A4; rifaximin is a moderate CYP3A4 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. Coadministration with another moderate CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 60%.
    Warfarin: (Moderate) Monitor the INR if warfarin is coadministered with rifaximin; concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A4 substrate. Rifaximin is a moderate CYP3A4 inducer; however, at the recommended dosing regimen in patients with normal liver function, rifaximin is not expected to induce CYP3A4.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and rifaximin. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; rifaximin is a moderate CYP3A4 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. The AUC of zanubrutinib is predicted to decrease by 60% when coadministered with another moderate CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no available data on rifaximin use in human pregnancy to inform any drug associated risks. However, because systemic absorption of rifaximin after oral administration is minimal, rifaximin is suggested as an alternative agent for travelers' diarrhea in pregnant women in whom quinolones are contraindicated. Pregnant women have a higher risk of experiencing travelers' 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). Teratogenic effects were observed in animal reproduction studies after administration of rifaximin to pregnant rats and rabbits during organogenesis at doses approximately 0.9 to 5 times and 0.7 to 33 times, respectively of the recommended human doses of 600 to 1,650 mg/day. In rabbits, ocular, oral and maxillofacial, cardiac, and lumbar spine malformations were observed. Ocular malformations were observed in both rats and rabbits at doses that caused reduced maternal body weight gain. Advise pregnant women of the potential risk to a fetus.

    There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breast-fed infant, or the effects of rifaximin on milk production. Consider the development and health benefits of breast-feeding along with the mother's clinical need for rifaximin and any potential adverse effects on the breast-fed infant from rifaximin or from the underlying maternal condition.

    MECHANISM OF ACTION

    Rifaximin is a semi-synthetic derivative of rifampin and acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase thereby blocking 1 of the steps in transcription. This results in inhibition of bacterial protein synthesis and consequently inhibits bacterial growth.
     
    Resistance to rifaximin is caused primarily by mutations in the rpoB gene. This changes the binding site on DNA-dependent RNA polymerase and decreases rifaximin binding affinity, thereby reducing efficacy.
     
    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. In an in vitro study, rifaximin was metabolized mainly by CYP3A4. Rifaximin accounted for 18% of radioactivity in plasma suggesting that the absorbed rifaximin undergoes extensive metabolism. After administration of radiolabeled rifaximin to healthy volunteers, 96.62% of the administered radioactivity was recovered in the feces mostly as unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Biliary excretion of rifaximin was suggested in a study in which rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa. The mean half-life in healthy subjects at steady-state is 5.63 hours and 6.08 hours in patients with irritable bowel syndrome with diarrhea.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp, OATP1A2, OAPT1B1, and OATP1B3
    In vitro studies show that rifaximin is a substrate of CYP3A4, P-gp, and OATP1A2, OAPT1B1, and OATP1B3. In vitro drug interaction studies of rifaximin show that it does not inhibit the CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 isoenzymes. In vitro studies show rifaximin is an inhibitor of P-gp, OATP1A2, OAPT1B1, and OATP1B3. The clinical significance of potential interaction with substrates of these drug transporters is unknown.

    Oral Route

    In healthy volunteers treated with rifaximin 550 mg 3 times daily for 14 days, the median Tmax was 1 hour. The mean Cmax was 4.04 ng/mL after a single dose on day 1 and 2.39 ng/mL on day 14. The mean AUC was 10.4 ng x hour/mL after a single dose on day 1 and 9.3 ng x hour/mL on day 14. A high-fat meal consumed 30 minutes before a 550 mg dose resulted in a delay in the mean Cmax from 0.75 to 0.8 hours to 1.5 hours and increased systemic AUC by 2-fold. The Cmax of rifaximin was unchanged in the fasting vs. the fed state.
     
    After oral administration of rifaximin 200 mg, 400 mg, and 600 mg, systemic exposure increased dose-dependently by approximately 2-fold for both AUC and Cmax from 200 to 400 mg, but with a less than dose-proportional increase of 1.3-fold for both AUC and Cmax from 400 to 600 mg.
     
    In patients with irritable bowel syndrome with diarrhea treated with rifaximin 550 mg 3 times daily for 14 days, the median Tmax was 1 hour. The mean Cmax was 3.49 ng/mL after a single dose on day 1 and 4.22 ng/mL on day 14. The mean AUC was 9.69 ng x hour/mL after a single dose on day 1 and 16 ng x hour/mL on day 14.
     
    Systemic absorption of rifaximin 200 mg 3 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 after repeated administration for 3 days. Peak plasma concentrations (Cmax) on day 1 and day 3 ranged from 0.81 to 3.4 ng/mL and 0.68 to 2.26 ng/mL, respectively. The AUC estimates were 6.95 +/- 5.15 ng x hour/mL and 7.83 +/- 4.94 ng x hour/mL, on day 1 and day 3 respectively. Rifaximin is not suitable for treating systemic bacterial infections because of the limited systemic exposure after oral rifaximin administration.