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  • CLASSES

    Antibiotics for Tuberculosis
    Rifamycin Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Antimycobacterial agent; alternative to clarithromycin or azithromycin for MAC prophylaxis; alternative to rifampin for TB prophylaxis or treatment.

    COMMON BRAND NAMES

    Mycobutin

    HOW SUPPLIED

    Mycobutin/Rifabutin Oral Cap: 150mg

    DOSAGE & INDICATIONS

    For Mycobacterium avium complex (MAC) prophylaxis in persons with HIV.
    For primary Mycobacterium avium complex (MAC) prophylaxis.
    Oral dosage
    Adults

    300 mg PO once daily as an alternative therapy.[34362] [34696] Consider 150 mg PO twice daily for patients with a propensity for gastrointestinal upset.[29210] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Primary prophylaxis is only recommended for patients not on fully suppressive antiretroviral therapy (ART) with CD4 counts less than 50 cells/mm3 after ruling out disseminated MAC. Discontinue primary prophylaxis upon initiation of effective ART.[34362]

    Adolescents†

    300 mg PO once daily as an alternative therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Primary prophylaxis is only recommended for patients not on fully suppressive antiretroviral therapy (ART) with CD4 counts less than 50 cells/mm3 after ruling out disseminated MAC. Discontinue primary prophylaxis upon initiation of effective ART.[34362]

    Children 6 to 12 years†

    300 mg PO once daily as an alternative therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Primary prophylaxis is recommended in children 6 years and older with a CD4 count less than 50 cells/mm3. Primary prophylaxis may be discontinued after at least 6 months of ART and a CD4 count more than 100 cells/mm3 for at least 3 consecutive months. Restart primary prophylaxis if the CD4 count falls below these thresholds.[34361]

    For secondary Mycobacterium avium complex (MAC) prophylaxis in patients with disseminated disease, after treatment of the acute illness.
    Oral dosage
    Adults

    300 mg PO once daily plus clarithromycin or azithromycin and ethambutol. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. May consider addition of rifabutin as a third or fourth drug (or amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Consider discontinuing secondary prophylaxis in patients who have completed at least 12 months of MAC treatment, have no signs or symptoms of MAC, and have a sustained (more than 6 months) CD4 count more than 100 cells/mm3 in response to ART. Restart secondary prophylaxis if the CD4 count decreases to less than 100 cells/mm3.[34362]

    Adolescents†

    300 mg PO once daily plus clarithromycin or azithromycin and ethambutol. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. May consider addition of rifabutin as a third or fourth drug (or amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Consider discontinuing secondary prophylaxis in patients who have completed at least 12 months of MAC treatment, have no signs or symptoms of MAC, and have a sustained (more than 6 months) CD4 count more than 100 cells/mm3 in response to ART. Restart secondary prophylaxis if the CD4 count decreases to less than 100 cells/mm3.[34362]

    Children 6 to 12 years†

    5 mg/kg/dose (Max: 300 mg/dose) PO once daily plus clarithromycin or azithromycin and ethambutol for children older than 5 years who received rifabutin as part of the initial treatment regimen. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Consider discontinuing secondary prophylaxis in children who have received at least 12 months of MAC treatment, have no signs or symptoms of MAC, have been receiving stable antiretroviral therapy, and have a sustained (more than 6 months) CD4 count more than 100 cells/mm3. Restart secondary prophylaxis if the CD4 count falls below these thresholds.[34361]

    For the treatment of Mycobacterium avium complex infection† (MAC).
    For the treatment of disseminated Mycobacterium avium complex (MAC)†.
    NOTE: Rifabutin has been designated an orphan drug for this indication.
    Oral dosage
    Adults

    150 to 450 mg PO once daily plus clarithromycin or azithromycin and ethambutol. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Discontinue therapy with resolution of symptoms and reconstitution of cell-mediated immune function.[34696]

    For the treatment of Mycobacterium avium complex (MAC)† pulmonary disease.
    Oral dosage
    Adults

    150 to 300 mg PO once daily plus clarithromycin or azithromycin and ethambutol with consideration of 3-times weekly amikacin or streptomycin for the first 2 to 3 months for patients with fibrocavitary MAC lung disease or severe nodular or bronchiectatic disease. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Continue treatment until the patient is culture negative on therapy for 1 year. For macrolide-resistant MAC, consider 4-drug regimen including rifabutin plus isoniazid, ethambutol (for the first 2 months), and streptomycin or amikacin (for the first 3 to 6 months).[34696]

    For the treatment of Mycobacterium avium complex (MAC)† in persons with HIV.
    Oral dosage
    Adults

    300 mg PO once daily plus clarithromycin or azithromycin and ethambutol. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. May consider addition of rifabutin as a third or fourth drug (or amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Duration of treatment depends on clinical response but should continue for at least 12 months.[34362]

    Adolescents

    300 mg PO once daily plus clarithromycin or azithromycin and ethambutol. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. May consider addition of rifabutin as a third or fourth drug (or amikacin, streptomycin, levofloxacin, or moxifloxacin) for patients with high mycobacterial loads (more than 2 log CFU/mL of blood) or in the absence of effective antiretroviral therapy. Duration of treatment depends on clinical response but should continue for at least 12 months.[34362]

    Infants and Children

    10 to 20 mg/kg/dose (Max: 300 mg/dose) PO once daily plus clarithromycin or azithromycin and ethambutol for severe disease. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. If a fourth drug is needed for patients with more severe symptoms or disseminated disease, consider adding ciprofloxacin, levofloxacin, or amikacin. Duration of treatment depends on clinical response but should continue for at least 12 months.[34361]

    For the treatment of drug-susceptible tuberculosis infection† as part of combination therapy.
    Oral dosage
    Adults

    5 mg/kg/dose (Usual dose: 300 mg) PO once daily or 5 days/week. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Daily dosing is defined as 5- or 7 days/week. Rifabutin is generally recommended throughout the intensive and continuation phases of treatment as first-line therapy; duration is dependent on the site of involvement.

    Infants, Children, and Adolescents

    5 mg/kg/dose (Max: 300 mg/dose) PO given once daily or 5 days/week. [61094] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Daily dosing is defined as 5- or 7 days/week. Rifabutin is generally recommended throughout the intensive and continuation phases of treatment as first-line therapy; duration is dependent on the site of involvement. [61094]

    For the treatment of drug-resistant tuberculosis infection† as part of combination therapy.
    Oral dosage
    Adults

    5 mg/kg/dose (Max: 450 mg) PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Infants, Children, and Adolescents

    5 to 10 mg/kg/dose (Max: 300 mg) PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For tuberculosis prophylaxis† or latent tuberculosis infection† (LTBI) as an alternative to isoniazid and rifampin regimens.
    Oral dosage
    Adults

    5 mg/kg/dose (Usual dose: 300 mg/dose) PO once daily for 4 months.[34362] [61094] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Rifabutin may be used in place of 4 months of daily rifampin when rifampin is contraindicated due to drug-drug interactions and isoniazid cannot be used.[65588] There are no data demonstrating its efficacy as monotherapy.[34362]

    Infants, Children, and Adolescents

    5 mg/kg/dose (Max: 300 mg/dose) PO once daily once daily for 4 months.[34362] [61094] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Rifabutin may be used in place of 4 months of daily rifampin when rifampin is contraindicated due to drug-drug interactions and isoniazid cannot be used.[65588] There are no data demonstrating its efficacy as monotherapy.[34362]

    For Helicobacter pylori (H. pylori) eradication†.
    Oral dosage
    Adults

    300 mg PO once daily in combination with amoxicillin and a proton pump inhibitor for 10 days as a salvage regimen. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO is the FDA-approved maximum dosage; 450 mg/day PO has been used off-label.

    Geriatric

    300 mg/day PO is the FDA-approved maximum dosage; 450 mg/day PO has been used off-label.

    Adolescents

    Safety and efficacy have not been established; 5 mg/kg/day (Max: 300 mg/day) PO has been used off-label.

    Children

    Safety and efficacy have not been established; 20 mg/kg/day (Max: 300 mg/day) PO has been used off-label.

    Infants

    Safety and efficacy have not been established; 20 mg/kg/day PO has been used off-label.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

    CrCl 30 mL/minute or more: No dosage adjustment needed.
    CrCl less than 30 mL/minute: Consider reducing the dose by 50% if toxicity is suspected.[29210] [34362]
     
    Intermittent hemodialysis†
    No dosage adjustment needed.[32569]
     
    Peritoneal dialysis†
    No dosage adjustment needed.[32569]
     
    Continuous renal replacement therapy (CRRT)†
    NOTE: Various CRRT modalities include continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous high-flux hemodialysis (CVVHFD), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration (CAVHDF). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), type of infection, the duration of renal replacement therapy, the effluent flow rate, and the replacement solution administered.[42303]
     
    No dosage adjustment needed.[32569]

    ADMINISTRATION

     
    Tuberculosis
    Directly observed therapy (DOT) is recommended for all children as well as adolescents and adults with HIV.[34361] [34362] [61094]

    Oral Administration

    May be given with or without food, although administration with food reduces gastrointestinal irritation.
    If needed, the capsules may be opened and the contents mixed with food such as applesauce for administration.

    Extemporaneous Compounding-Oral

    NOTE: Extemporaneously compounded oral rifabutin suspension is not FDA-approved.[29210]
     
    Oral suspension using Ora-Sweet and Ora-Plus†
    Empty the powder from eight 150 mg rifabutin capsules in a glass mortar.
    Add 20 mL of 1:1 mixture of Ora-Sweet and Ora-Plus and mix to wet all the capsule contents.
    Pour the suspension into a 2-ounce bottle.
    Pour and additional 20 mL of the vehicle into the mortar and mix.
    Add this material to the 2-ounce bottle.
    Repeat with enough vehicle to fill the bottle to 60 mL.
    Shake well before use.
    Storage: The suspension is stable for 12 weeks at 4, 25, 30, or 40 degrees C.[65684]
     
    Oral suspension using cherry syrup†
    Empty the powder from eight 150 mg rifabutin capsules in a glass mortar.
    Add 20 mL of cherry syrup and mix to wet all the capsule contents.
    Pour the suspension into a 2-ounce bottle.
    Pour and additional 20 mL of the vehicle into the mortar and mix.
    Add this material to the 2-ounce bottle.
    Repeat with enough vehicle to fill the bottle to 60 mL.
    Shake well before use.
    Storage: The suspension is stable for 12 weeks at 4, 25, and 30 degrees C and for 8 weeks at 40 degrees C.[65684]

    STORAGE

    Mycobutin:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Rifamycin hypersensitivity

    Rifabutin is contraindicated in patients who have clinically significant rifabutin hypersensitivity or rifamycin hypersensitivity. Monitor patients receiving rifabutin therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue rifabutin.[29210]

    C. difficile-associated diarrhea, diarrhea, pseudomembranous colitis

    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. Almost all antibacterial agents, including rifabutin, 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.

    Renal failure, renal impairment

    In patients with severe renal impairment or renal failure, carefully monitor for rifabutin associated adverse events. A reduction in the dosage of rifabutin is recommended for patients with CrCl less than 30 mL/minute if toxicity is suspected.

    Geriatric

    In general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or drug therapy.[29210] 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.[60742]

    Contact lenses

    Rifabutin may produce a red-orange discoloration of body fluids. Contact lenses may become permanently stained due to rifabutin therapy.

    Laboratory test interference

    Administration of rifabutin may result in laboratory test interference. Antimicrobials are known to suppress H. pylori; thus, ingestion of these agents within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of rifabutin in the 4 weeks prior to the test.

    Tuberculosis

    Do not administer rifabutin for Mycobacterium avium complex (MAC) prophylaxis to patients with active tuberculosis (TB). Evaluate patients who develop complaints consistent with active TB while on prophylaxis with rifabutin immediately, so that those with active disease may be given an effective combination regimen of anti-TB medications. Administration of rifabutin as a single agent to patients with active TB is likely to lead to the development of TB that is resistant both to rifabutin and rifampin.[29210]

    Serious rash

    There have been reports of serious rash or severe cutaneous adverse reactions (SCAR) associated with rifabutin use. If patients develop a skin rash, monitor them closely and discontinue rifabutin if lesions progress.

    Pregnancy

    Use rifabutin during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies of rifabutin use in pregnant women. No teratogenicity was observed in animal studies at doses about 6 to 13 times the recommended human daily dose based on body surface area comparisons. However, fetal skeletal anomalies were observed in rats and rabbits after administration of a dose approximately equivalent and a dose 5 times the recommended human daily dose, respectively. At 6 times the recommended human daily dose, a decrease in fetal viability was observed in rats.[29210]

    Breast-feeding

    There are no adequate and well-controlled studies of rifabutin use in breast-feeding women. It is not known if rifabutin is excreted into breast milk. Because many drugs are excreted in human breast milk and because of the risk for serious adverse reactions in breast-feeding infants, discontinue breast-feeding or rifabutin, taking into consideration the importance of the drug to the mother.[29210] Previous American Academy of Pediatrics (AAP) recommendations generally considered another rifamycin, rifampin, as compatible for use in lactating women.[27500]

    ADVERSE REACTIONS

    Severe

    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    pancytopenia / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    seizures / Delayed / 0-1.0
    bronchospasm / Rapid / 0-1.0
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 25.0-25.0
    leukopenia / Delayed / 17.0-17.0
    elevated hepatic enzymes / Delayed / 0-9.0
    anemia / Delayed / 6.0-6.0
    thrombocytopenia / Delayed / 5.0-5.0
    eosinophilia / Delayed / 1.0-1.0
    hemolysis / Early / 0-1.0
    lymphopenia / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    chest pain (unspecified) / Early / 1.0-1.0
    confusion / Early / 0-1.0
    aphasia / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    ST-T wave changes / Rapid / 0-1.0
    pseudomembranous colitis / Delayed / 0-1.0
    conjunctivitis / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    superinfection / Delayed / Incidence not known

    Mild

    rash / Early / 11.0-11.0
    nausea / Early / 3.0-6.0
    abdominal pain / Early / 4.0-4.0
    diarrhea / Early / 3.0-3.0
    eructation / Early / 3.0-3.0
    vomiting / Early / 1.0-3.0
    dysgeusia / Early / 3.0-3.0
    dyspepsia / Early / 3.0-3.0
    headache / Early / 3.0-3.0
    anorexia / Delayed / 2.0-2.0
    flatulence / Early / 2.0-2.0
    myalgia / Early / 2.0-2.0
    fever / Early / 2.0-2.0
    skin discoloration / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    ocular pain / Early / 0-1.0
    asthenia / Delayed / 1.0-1.0
    insomnia / Early / 1.0-1.0
    paresthesias / Delayed / 0-1.0
    urine discoloration / Early / 30.0
    contact lens discoloration / Delayed / 10.0
    fatigue / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    weakness / Early / Incidence not known
    dizziness / Early / Incidence not known
    syncope / Early / Incidence not known
    cough / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
    Abemaciclib: (Major) Avoid coadministration of rifabutin with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29% respectively.
    Abiraterone: (Moderate) Concomitant use of abiraterone with rifabutin may result in decreased serum concentrations of abiraterone. Abiraterone is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of this enzyme. Caution and close monitoring for decreased efficacy are advised if these drugs are used together.
    Acetaminophen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Caffeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with rifamycins is necessary; consider increasing the dose of dihydrocodeine as needed. If the rifamycin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Rifamycins are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with rifamycins 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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Codeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Acetaminophen; Dextromethorphan: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Diphenhydramine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Hydrocodone: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Acetaminophen; Oxycodone: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin 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.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Pentazocine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Propoxyphene: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Pseudoephedrine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetohexamide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with rifamycins is necessary. If the rifamycin is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of CYP3A4 inducers like rifamycins with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Aliskiren; Amlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Alprazolam: (Moderate) Rifabutin could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and aminosalicylate sodium, aminosalicylic acid. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Amiodarone: (Major) Certain rifamycins, including rifampin, rifabutin, and rifapentine, may induce CYP3A4 metabolism of amiodarone, resulting in decreased serum concentrations of amiodarone and its active metabolite (desethylamiodarone) and potential decreased efficacy. A possible drug interaction has been reported with rifampin and amiodarone in one patient receiving therapy with ICD and amiodarone for history of atrial and ventricular arrhythmias; this patient had evidence of reduced serum amiodarone and metabolite levels, loss of antiarrhythmic efficacy, and required hospitalization.
    Amlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Amlodipine; Atorvastatin: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Amlodipine; Benazepril: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Amlodipine; Celecoxib: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Amlodipine; Olmesartan: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Amlodipine; Valsartan: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The combination of rifabutin and clarithromycin should be avoided. Clarithromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. The metabolism of rifabutin is inhibited by clarithromycin, possibly through inhibition of CYP3A4. Inhibition of rifabutin metabolism results in significant increases in rifabutin serum concentrations and adverse reactions. Also, rifabutin increases the metabolism of clarithromycin resulting in significant decreases in clarithromycin concentrations thereby reducing the antimicrobial efficacy of clarithromycin. As compared with the plasma concentration obtained with clarithromycin monotherapy, the clarithromycin plasma concentration was reduced by 63% when rifabutin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 2 +/- 1.5 mcg/ml when given in combination with rifabutin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups.
    Apalutamide: (Moderate) Monitor for decreased efficacy of rifabutin and potential issues of resistance if coadministration with apalutamide is necessary. Rifabutin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Aprepitant, Fosaprepitant: (Major) Use caution if rifabutin and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant as well as an increase in rifabutin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Rifabutin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of rifabutin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Additionally, Rifabutin is a moderate CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
    Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during coadministration of a CYP3A4 inducer, such as rifabutin. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. A dose adjustment of aripiprazole may be needed. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.
    Armodafinil: (Moderate) Armodafinil is partially metabolized via CYP3A4/5 isoenzymes. Drugs that exhibit significant induction of the CYP3A4 isoenzyme, such as rifabutin, may potentially increase the metabolism of armodafinil. Decreased serum levels of armodafinil could potentially result in decreased efficacy of the drug.
    Artemether; Lumefantrine: (Major) Rifabutin is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with rifamycins is necessary; consider increasing the dose of dihydrocodeine as needed. If the rifamycin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Rifamycins are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with rifamycins 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.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin 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.
    Aspirin, ASA; Pravastatin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Atazanavir: (Major) When coadministered with atazanavir, there is a clinically significant increase in rifabutin AUC, by 250%. If these drugs are used in combination, the manfuacturer recommends the adult dose of rifabutin should be reduced to 150 mg every other day or 150 mg three times per week. The CDC, however, recommends rifabutin 150 mg daily or 300 mg three times per week in patients receiving atazanavir (with or without ritonavir) in combination with rifabutin.
    Atazanavir; Cobicistat: (Major) Caution is recommended during coadministration of rifabutin with cobicistat. Concurrent use may result in elevated plasma concentrations of rifabutin. If these drugs are used together, the recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions, such as neutropenia and uveitis. (Major) When coadministered with atazanavir, there is a clinically significant increase in rifabutin AUC, by 250%. If these drugs are used in combination, the manfuacturer recommends the adult dose of rifabutin should be reduced to 150 mg every other day or 150 mg three times per week. The CDC, however, recommends rifabutin 150 mg daily or 300 mg three times per week in patients receiving atazanavir (with or without ritonavir) in combination with rifabutin.
    Atogepant: (Major) Use an atogepant dose of 30 or 60 mg PO once daily if coadministered with rifabutin. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
    Atovaquone: (Major) The administration of rifabutin with atovaquone is not recommended. Taking these drugs together reduces the average steady-state plasma concentrations of atovaquone and rifabutin by 34% and 19%, respectively. Dose adjustments have not been established. If these drugs are given together, instruct patient to take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.
    Atovaquone; Proguanil: (Major) The administration of rifabutin with atovaquone is not recommended. Taking these drugs together reduces the average steady-state plasma concentrations of atovaquone and rifabutin by 34% and 19%, respectively. Dose adjustments have not been established. If these drugs are given together, instruct patient to take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.
    Avacopan: (Major) Avoid concomitant use of avacopan and rifabutin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
    Avanafil: (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifabutin, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Avapritinib: (Major) Avoid coadministration of avapritinib with rifabutin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
    Axitinib: (Major) Avoid coadministration of axitinib with rifabutin 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 and rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of rifabutin could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
    Bedaquiline: (Major) Avoid concurrent use of bedaquiline with rifamycins (e.g., rifampin, rifapentine, and rifabutin). Rifamycins may induce the CYP3A4 metabolism of bedaquiline, resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. One study found bedaquiline AUC decreased by 52% when administered concurrently with rifampin 600 mg PO daily for 21 days.
    Benzhydrocodone; Acetaminophen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Concurrent use of benzhydrocodone with rifabutin may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of rifabutin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If rifabutin is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Rifabutin is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Bepridil: (Moderate) Rifabutin may induce the CYP3A4 metabolism of bepridil and thereby reduce its oral bioavailability. The dosage requirements of bepridil may be increased in patients receiving concurrent enzyme inducers.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Concomitant use of bictegravir and rifabutin is not recommended as coadministration may result in decreased bictegravir plasma concentrations, which may result in the loss of therapeutic efficacy and development of resistance. Bictegravir is a substrate of CYP3A4; rifabutin is an inducer of CYP3A4.
    Boceprevir: (Major) Coadministration of rifabutin and boceprevir is not recommended. If rifabutin and boceprevir are coadministered, close clinical monitoring is advised due to the increased potential for rifabutin-related adverse events and for the potential of decreased boceprevir efficacy. If rifabutin dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of rifabutin and boceprevir. Rifabutin is an inducer and substrate of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor and substrate of this isoenzyme. When used in combination, rifabutin plasma concentrations may be elevated and the plasma concentration of boceprevir may be deceased, resulting in an increased potential for rifabutin-related adverse events and boceprevir treatment failure.
    Bortezomib: (Minor) Agents that induce CYP3A4, such as rifabutin, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with CYP3A4 inducers is not known.
    Bosentan: (Minor) Theoretically, bosentan, a potent CYP3A4 inducer, may increase the hepatic clearance of rifampin, a CYP3A4 substrate and inducer. However, this interaction has not been studied.
    Brentuximab vedotin: (Moderate) Concomitant administration of brentuximab vedotin and rifabutin may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and rifabutin is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
    Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be doubled over 1 to 2 weeks when a strong CYP3A4 inducer, such as rifabutin, is added to brexpiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the brexpiprazole dose should be reduced to the original level over 1 to 2 weeks.
    Brigatinib: (Major) Avoid coadministration of brigatinib with rifabutin due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with rifabutin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of rifabutin, resume the brigatinib dose that was tolerated prior to initiation of rifabutin. Brigatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and rifabutin are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; rifabutin is a moderate inducer of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
    Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
    Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
    Butalbital; Acetaminophen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Butalbital; Acetaminophen; Caffeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Cabotegravir: (Contraindicated) Coadministration of rifabutin and cabotegravir; rilpivirine injection is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir and rilpivirine, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifabutin is an inducer of UGT. Coadministration with rifabutin decreased cabotegravir exposure by 33%. Rifabutin may be coadministered with cabotegravir monotherapy.
    Cabotegravir; Rilpivirine: (Contraindicated) Coadministration of rifabutin and cabotegravir; rilpivirine injection is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir and rilpivirine, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifabutin is an inducer of UGT. Coadministration with rifabutin decreased cabotegravir exposure by 33%. Rifabutin may be coadministered with cabotegravir monotherapy. (Major) Administration of rifabutin with rilpivirine may significantly decrease rilpivirine plasma concentrations; therefore, if these drugs are given concurrently, an additional dose of rilpivirine (25 mg PO once daily) is required and the drugs should be administered with a meal. Rifabutin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Use of these drugs together may result in HIV treatment failure or the development of rilpivirine or NNRTI resistance.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with rifabutin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with rifabutin 2 to 3 days after discontinuation of rifabutin. Cabozantinib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer.
    Capmatinib: (Major) Avoid coadministration of capmatinib and rifabutin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Capreomycin: (Moderate) Adverse hepatic effects have been associated with capreomycin, especially with concurrent use of other antituberculosis drugs known to alter hepatic function. Theoretically, coadministration of capreomycin and any of the rifamycins could increase the risk of hepatotoxicity. Monitor patients for changes in liver function if these drugs are coadministered.
    Carbamazepine: (Moderate) Inducers of the hepatic CYP3A4 isoenzyme, such as rifabutin, can increase the rate of carbamazepine metabolism, leading to subtherapeutic carbamazepine plasma concentrations.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as rifabutin or rifampin, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
    Carvedilol: (Moderate) Serum concentrations of carvedilol may be decreased if coadministered with rifabutin. Rifabutin is a known hepatic enzyme inducer, thus, it is not possible to stagger the administration times to avoid this interaction.
    Caspofungin: (Moderate) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving rifabutin. Coadministration of CYP450 enzyme inducers, such as rifabutin, with caspofungin may reduce the plasma concentrations of caspofungin.
    Ceritinib: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with ceritinib is necessary; a dosage adjustment may be necessary. Ceritinib is a strong CYP3A4 inhibitor and rifabutin is primarily metabolized by CYP3A4. Concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin.
    Cerivastatin: (Minor) Rifabutin may significantly increase the plasma clearance and decrease the serum concentrations of cerivastatin, with the potential for reduced antilipemic efficacy. To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifabutin with cerivastatin.
    Chlordiazepoxide: (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
    Chlordiazepoxide; Amitriptyline: (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
    Chlordiazepoxide; Clidinium: (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with rifamycins is necessary; consider increasing the dose of dihydrocodeine as needed. If the rifamycin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Rifamycins are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with rifamycins 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.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with rifamycins is necessary; consider increasing the dose of dihydrocodeine as needed. If the rifamycin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Rifamycins are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with rifamycins 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.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Chlorpropamide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Cisapride: (Moderate) Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. Inducers of CYP3A4, such as rifabutin, may increase the clearance of cisapride.
    Citalopram: (Moderate) Citalopram is metabolized by CYP2C19 and CYP3A4. Rifabutin can induce the metabolism of various CYP 450 isoenzymes, including those involved in citalopram metabolism. The possibility of an increase in the clearance of citalopram should be considered if coadministered with rifabutin.
    Clarithromycin: (Major) The combination of rifabutin and clarithromycin should be avoided. Clarithromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. The metabolism of rifabutin is inhibited by clarithromycin, possibly through inhibition of CYP3A4. Inhibition of rifabutin metabolism results in significant increases in rifabutin serum concentrations and adverse reactions. Also, rifabutin increases the metabolism of clarithromycin resulting in significant decreases in clarithromycin concentrations thereby reducing the antimicrobial efficacy of clarithromycin. As compared with the plasma concentration obtained with clarithromycin monotherapy, the clarithromycin plasma concentration was reduced by 63% when rifabutin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 2 +/- 1.5 mcg/ml when given in combination with rifabutin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups.
    Clonazepam: (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, such as clonazepam, leading to lower benzodiazepine concentrations.
    Clorazepate: (Moderate) Rifabutin is a hepatic inducers and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, such as clorazepate, leading to lower benzodiazepine concentrations.
    Clozapine: (Major) Concomitant use of clozapine, a CYP3A4 substrate, with strong CYP3A4 inducers, including rifampin or rifabutin, is not recommended. Rifampin is also a weak inducer of CYP1A2, which may further increase clozapine elimination. If these combinations are necessary, monitor for decreased effectiveness with consideration of increasing the clozapine dose if clinically warranted.
    Cobicistat: (Major) Caution is recommended during coadministration of rifabutin with cobicistat. Concurrent use may result in elevated plasma concentrations of rifabutin. If these drugs are used together, the recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions, such as neutropenia and uveitis.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with rifabutin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and rifabutin is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
    Codeine: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with rifabutin 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 rifabutin 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. Rifabutin is a moderate CYP3A4 inducer.
    Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as rifabutin. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with rifabutin is necessary. Dapsone is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). In a study of 16 HIV-infected patients, rifabutin decreased dapsone exposure by 27% to 40%.
    Darifenacin: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with rifamycins is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Rifamycins are CYP3A4 inducers and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Darunavir: (Major) Coadministration is expected to result in increased rifabutin and decreased darunavir plasma concentrations. If these drugs are coadministered, the manufacturer recommends the adult dose of rifabutin should be reduced by 75% (150 mg every other day), with appropriate monitoring and further dose reductions if necessary. The CDC recommends rifabutin 150 mg daily or 300 mg three times per week.
    Darunavir; Cobicistat: (Major) Caution is recommended during coadministration of rifabutin with cobicistat. Concurrent use may result in elevated plasma concentrations of rifabutin. If these drugs are used together, the recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions, such as neutropenia and uveitis. (Major) Coadministration is expected to result in increased rifabutin and decreased darunavir plasma concentrations. If these drugs are coadministered, the manufacturer recommends the adult dose of rifabutin should be reduced by 75% (150 mg every other day), with appropriate monitoring and further dose reductions if necessary. The CDC recommends rifabutin 150 mg daily or 300 mg three times per week.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Caution is recommended during coadministration of rifabutin with cobicistat. Concurrent use may result in elevated plasma concentrations of rifabutin. If these drugs are used together, the recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions, such as neutropenia and uveitis. (Major) Coadministration is expected to result in increased rifabutin and decreased darunavir plasma concentrations. If these drugs are coadministered, the manufacturer recommends the adult dose of rifabutin should be reduced by 75% (150 mg every other day), with appropriate monitoring and further dose reductions if necessary. The CDC recommends rifabutin 150 mg daily or 300 mg three times per week. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concurrent administration of rifabutin with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated rifabutin plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Rifabutin is a CYP3A4 substrate, and ritonavir is a potent CYP3A4 inhibitor. In addition, rifabutin is an inducer of CYP3A4, and ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Although rifabutin appears to induce the enzyme to a lesser degree than rifampin, the plasma concentrations of ritonavir, paritaprevir, and dasabuvir may be reduced. (Contraindicated) Concurrent administration of rifabutin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated rifabutin plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Rifabutin is a CYP3A4 substrate, and ritonavir is a potent CYP3A4 inhibitor. In addition, rifabutin is an inducer of CYP3A4, and ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Although rifabutin appears to induce the enzyme to a lesser degree than rifampin, the plasma concentrations of ritonavir, paritaprevir, and dasabuvir may be reduced. (Major) Coadministration of ritonavir and rifabutin results in clinically significant alterations of rifabutin pharmacokinetic parameters, with the rifabutin AUC being increased by 430%. In patients receiving any dosage of ritonavir, the dose of rifabutin should always be decreased to 150 mg every day or 300 mg three times per week.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and rifabutin. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; rifabutin is a moderate inducer of CYP3A4. 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.
    Delavirdine: (Contraindicated) The coadministration of rifabutin and delavirdine is contraindicated. Concurrent administration results in a 230% increase in rifabutin AUC. However, rifabutin significantly decreases delavirdine plasma concentrations. Clinical pharmacokinetic studies have shown an 82% reduction in delavirdine AUC when rifabutin was given concurrently.
    Dextromethorphan; Quinidine: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of quinidine.
    Diazepam: (Moderate) Rifabutin induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as diazepam, may require dosage adjustments when administered concurrently with rifabutin.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with rifamycins is necessary; consider increasing the dose of dihydrocodeine as needed. If the rifamycin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Rifamycins are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with rifamycins 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.
    Diltiazem: (Moderate) Diltiazem is a CYP3A4 substrate and inhibitor. Rifabutin is a CYP3A4 substrate and inducer. Coadministration of these drugs could lead to a complex interaction. Significant decreases in diltiazem concentrations could be seen, and significant increases in rifabutin concentrations could be seen. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure, as well as associated rifabutin side effects.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Disopyramide: (Moderate) Hepatic microsomal enzyme-inducing agents, such as rifabutin, have the potential to accelerate the hepatic metabolism of disopyramide, a CYP3A4 substrate. Patients should be monitored for loss of disopyramide activity if rifabutin is added.
    Dolutegravir; Rilpivirine: (Major) Administration of rifabutin with rilpivirine may significantly decrease rilpivirine plasma concentrations; therefore, if these drugs are given concurrently, an additional dose of rilpivirine (25 mg PO once daily) is required and the drugs should be administered with a meal. Rifabutin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Use of these drugs together may result in HIV treatment failure or the development of rilpivirine or NNRTI resistance.
    Doravirine: (Major) In patients who have taken rifabutin, a cessation period of at least 4-weeks is recommended prior to initiating doravirine. If doravirine and rifabutin must be coadministered, increase the doravirine adult dose to 100 mg by mouth twice daily (approximately 12 hours apart). Taking these drugs together decreases doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; rifabutin is a CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) In patients who have taken rifabutin, a cessation period of at least 4-weeks is recommended prior to initiating doravirine. If doravirine and rifabutin must be coadministered, increase the doravirine adult dose to 100 mg by mouth twice daily (approximately 12 hours apart). Taking these drugs together decreases doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; rifabutin is a CYP3A4 inducer.
    Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers, such as rifabutin, may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol.
    Doxorubicin Liposomal: (Major) Rifabutin is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifabutin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Doxorubicin: (Major) Rifabutin is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of rifabutin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with rifabutin is necessary, and monitor for a decrease in the efficacy of dronabinol. Concomitant use may result in decreased plasma concentrations of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; rifabutin is a moderate inducer of CYP3A4.
    Duvelisib: (Major) Avoid concomitant use of duvelisib with rifabutin. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib; rifabutin exposure may also be increased. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. Monitor for rifabutin-related adverse reactions. When rifabutin has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with rifabutin. Duvelisib is a CYP3A substrate and a moderate CYP3A4 inhibitor. Rifabutin is a CYP3A4 substrate and a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
    Efavirenz: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Major) If possible, avoid concurrent administration of elbasvir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of rifabutin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
    Elexacaftor; tezacaftor; ivacaftor: (Major) Administration of ivacaftor with strong CYP3A inducers, such as rifabutin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, another strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A, and rifabutin is metabolized by CYP3A. Co-administration may increase rifabutin exposure leading to increased or prolonged therapeutic effects and adverse events. (Major) Do not administer tezacaftor; ivacaftor and rifabutin together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of rifabutin, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
    Elvitegravir: (Major) Coadministration of rifabutin with elvitegravir may result in reduced elvitegravir concentrations and elevated rifabutin concentrations. If these drugs must be used concurrently, reduce the dose of rifabutin by at least 75% of the usual 300 mg/day dose (e.g., 150 mg every other day or 3x/week). If the rifabutin dose is reduced, no dose adjustment is required for elvitegravir. Monitor closely for rifabutin-associated adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Caution is recommended during coadministration of rifabutin with cobicistat. Concurrent use may result in elevated plasma concentrations of rifabutin. If these drugs are used together, the recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions, such as neutropenia and uveitis. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Coadministration of rifabutin with elvitegravir may result in reduced elvitegravir concentrations and elevated rifabutin concentrations. If these drugs must be used concurrently, reduce the dose of rifabutin by at least 75% of the usual 300 mg/day dose (e.g., 150 mg every other day or 3x/week). If the rifabutin dose is reduced, no dose adjustment is required for elvitegravir. Monitor closely for rifabutin-associated adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Caution is recommended during coadministration of rifabutin with cobicistat. Concurrent use may result in elevated plasma concentrations of rifabutin. If these drugs are used together, the recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions, such as neutropenia and uveitis. (Major) Coadministration of rifabutin with elvitegravir may result in reduced elvitegravir concentrations and elevated rifabutin concentrations. If these drugs must be used concurrently, reduce the dose of rifabutin by at least 75% of the usual 300 mg/day dose (e.g., 150 mg every other day or 3x/week). If the rifabutin dose is reduced, no dose adjustment is required for elvitegravir. Monitor closely for rifabutin-associated adverse events.
    Empagliflozin; Linagliptin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Administration of rifabutin with rilpivirine may significantly decrease rilpivirine plasma concentrations; therefore, if these drugs are given concurrently, an additional dose of rilpivirine (25 mg PO once daily) is required and the drugs should be administered with a meal. Rifabutin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Use of these drugs together may result in HIV treatment failure or the development of rilpivirine or NNRTI resistance. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Administration of rifabutin with rilpivirine may significantly decrease rilpivirine plasma concentrations; therefore, if these drugs are given concurrently, an additional dose of rilpivirine (25 mg PO once daily) is required and the drugs should be administered with a meal. Rifabutin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Use of these drugs together may result in HIV treatment failure or the development of rilpivirine or NNRTI resistance.
    Emtricitabine; Tenofovir alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Enalapril; Felodipine: (Moderate) Concomitant use of felodipine and rifabutin may decrease the exposure and therapeutic efficacy of felodipine. If used together, monitor blood pressure closely; the dosage requirements of felodipine may be increased. Felodipine is a CYP3A substrate. Rifabutin is a CYP3A inducer.
    Encorafenib: (Major) Avoid coadministration of encorafenib and rifabutin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. 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 rifabutin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of rifabutin and potential issues of resistance if coadministration with enzalutamide is necessary. Rifabutin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Erdafitinib: (Major) If coadministration of erdafitinib and rifabutin 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 rifabutin must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If rifabutin is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with rifabutin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Erythromycin: (Moderate) Caution is warranted when erythromycin is administered with rifabutin as rifabutin concentrations may be elevated. Monitor for adverse events of rifabutin, such as neutropenia and rash. Erythromycin is an inhibitor of CYP3A4, and rifabutin is a substrate of CYP3A4.
    Erythromycin; Sulfisoxazole: (Moderate) Caution is warranted when erythromycin is administered with rifabutin as rifabutin concentrations may be elevated. Monitor for adverse events of rifabutin, such as neutropenia and rash. Erythromycin is an inhibitor of CYP3A4, and rifabutin is a substrate of CYP3A4.
    Escitalopram: (Moderate) CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. Rifabutin can induce the metabolism of escitalopram via induction of CYP3A4. Given the enzyme-inducing properties rifabutin, the possibility that the drug may increase the clearance of escitalopram should be considered if the 2 drugs are coadministered.
    Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and rifamycins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifamycins. In some cases, it may be advisable for patients to change to non-hormonal methods of birth control during rifamycin therapy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of rifamycins. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifamycins, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and rifamycins are a CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
    Ethambutol: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Ethionamide: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Ethotoin: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
    Etravirine: (Moderate) If a patient's antiretroviral treatment regimen contains etravirine and a protease inhibitor boosted with ritonavir (i.e., either darunavir or saquinavir with ritonavir), then rifabutin should not be coadministered due to the potential for significant reductions in etravirine exposure. However, if the antiretroviral regimen does not contain a protease inhibitor boosted with ritonavir, then rifabutin may be used (at a dose of 300 mg daily).
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with rifabutin is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Ezetimibe; Simvastatin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Fedratinib: (Major) Avoid coadministration of fedratinib with rifabutin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Felodipine: (Moderate) Concomitant use of felodipine and rifabutin may decrease the exposure and therapeutic efficacy of felodipine. If used together, monitor blood pressure closely; the dosage requirements of felodipine may be increased. Felodipine is a CYP3A substrate. Rifabutin is a CYP3A inducer.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of rifabutin is necessary. If rifabutin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like rifabutin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Finerenone: (Major) Avoid concurrent use of finerenone and rifabutin due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased overall exposure to finerenone by 80%.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and rifabutin, a strong CYP3A4 inducer, is not recommended.
    Fluconazole: (Moderate) Monitor for rifabutin-associated adverse effects with concomitant fluconazole use. Reduce the rifabutin dose or discontinue rifabutin if toxicity is suspected. Carefully monitor for uveitis when rifabutin is given concomitantly with fluconazole. If uveitis is suspected, refer the patient to an ophthalmologist, and if considered necessary, discontinue rifabutin. Coadministration of fluconazole increased the rifabutin AUC by 82% and Cmax by 88%.
    Flurazepam: (Moderate) Several hepatic inducers, including rifabutin, can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
    Fluvastatin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with rifabutin. Rifabutin is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with rifabutin, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be increased. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Major) Coadministration with fosamprenavir results in clinically significant increases in rifabutin and rifabutin metabolite plasma concentrations. There are no clinically significantly alterations in fosamprenavir pharmacokinetics. If these drugs are coadministered, the CDC recommends the adult rifabutin dose be reduced to 150 mg daily or 300 mg three times per week. When fosamprenavir is given (i.e., 'boosted') with ritonavir, the manufacturer recommends the rifabutin dose be further decreased to 150 mg every other day or 150 mg three times per week. A complete blood count should be performed weekly and as indicated in order to monitor for neutropenia.
    Fosphenytoin: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
    Glasdegib: (Major) Avoid coadministration of glasdegib and rifabutin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, 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). Resume the previous dose of glasdegib after rifabutin has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
    Glecaprevir; Pibrentasvir: (Major) When possible, avoid concurrent administration of glecaprevir and rifabutin; consider use of an alternative hepatitis C treatment. Use of these drugs together may decrease the plasma concentration of glecaprevir. Use of another rifamycin with glecaprevir resulted in an 88% decrease in the plasma concentration of glecaprevir. (Major) When possible, avoid concurrent administration of pibrentasvir and rifabutin; consider use of an alternative hepatitis C treatment. Use of these drugs together may decrease the plasma concentration of pibrentasvir. Use of another rifamycin with pibrentasvir resulted in an 87% decrease in the plasma concentration of pibrentasvir.
    Glimepiride: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Glimepiride; Rosiglitazone: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Glipizide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Glipizide; Metformin: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Glyburide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Glyburide; Metformin: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Guanfacine: (Major) Rifabutin may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if rifabutin is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If rifabutin is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and rifabutin is a moderate CYP3A4 inducer.
    Haloperidol: (Major) Significant reductions in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and CYP3A4 enzyme-inducing drugs such as carbamazepine or rifampin. Rifabutin is an inducer and a substrate of CYP3A4. Haloperidol dosage adjustments should be made as needed when rifabutin is added or discontinued.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Hydantoins: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ribabutin 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 ribabutin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and ribabutin is a moderate CYP3A4 inducer.
    Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with rifabutin. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
    Ibrutinib: (Moderate) Use ibrutinib and rifabutin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin 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.
    Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with rifabutin, a CYP3A substrate, as rifabutin toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with rifabutin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; rifabutin is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Indinavir: (Major) The coadministration of indinavir and rifabutin results in clinically significant alterations in each drug's pharmacokinetic parameters; rifabutin AUC is increased by more than 200% and indinavir AUC is decreased by 32%. If rifabutin and indinavir are used together the dose of indinavir should be increased to 1000 mg every 8 hours and the adult dose of rifabutin should be decreased to 150 mg daily or 300 mg three times per week.
    Infigratinib: (Major) Avoid concurrent use of infigratinib and rifabutin. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
    Isavuconazonium: (Major) Caution and close monitoring are warranted when isavuconazonium is administered with rifabutin as there is a potential for elevated rifabutin concentrations and decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Rifabutin is a substrate and inducer of the hepatic isoenzyme CYP3A4. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme.
    Isoniazid, INH: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isradipine: (Moderate) Because isradipine is a substrate of CYP3A4, the concomitant use of drugs that induce CYP3A4 such as rifabutin, may cause a reduction in the bioavailability and thus decreased therapeutic effect of isradipine. Until more data are available, patients should be monitored for potential loss of therapeutic effect when hepatic enzyme inducers are added to isradipine therapy.
    Ivabradine: (Major) Avoid coadministration of ivabradine and rifabutin. Ivabradine is primarily metabolized by CYP3A4; rifabutin is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ivacaftor: (Major) Administration of ivacaftor with strong CYP3A inducers, such as rifabutin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, another strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A, and rifabutin is metabolized by CYP3A. Co-administration may increase rifabutin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate and concomitant use with strong CYP3A4 inducers such as rifabutin may lead to reduced and subtherapeutic concentrations of ixabepilone. Caution should be utilized when CYP3A4 inducers are coadministered with ixabepilone, and alternative therapies with low enzyme induction potential should be considered.
    Ixazomib: (Major) Avoid the concomitant use of ixazomib and rifabutin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and rifabutin is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
    Ketoconazole: (Major) Concurrent use of ketoconzole with rifabutin is not recommended. Taking these drug together may result in increased exposure to rifabutin and decreased exposure to ketoconazole. Both drugs are substrates for CYP3A4, while rifabutin is also a CYP3A4 inducer and ketoconazole is a potent inhibitor of CYP3A4.
    Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) The combination of rifabutin and clarithromycin should be avoided. Clarithromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. The metabolism of rifabutin is inhibited by clarithromycin, possibly through inhibition of CYP3A4. Inhibition of rifabutin metabolism results in significant increases in rifabutin serum concentrations and adverse reactions. Also, rifabutin increases the metabolism of clarithromycin resulting in significant decreases in clarithromycin concentrations thereby reducing the antimicrobial efficacy of clarithromycin. As compared with the plasma concentration obtained with clarithromycin monotherapy, the clarithromycin plasma concentration was reduced by 63% when rifabutin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 2 +/- 1.5 mcg/ml when given in combination with rifabutin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups.
    Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with rifabutin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Lefamulin: (Major) Avoid coadministration of lefamulin with rifabutin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
    Lemborexant: (Major) Avoid coadministration of lemborexant and rifabutin as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of rifabutin; monitor for potential reduction in efficacy. Rifabutin is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of rifabutin; monitor for potential reduction in efficacy. Rifabutin is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Major) Concurrent administration of letermovir and rifabutin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, an increase in the plasma concentration of rifabutin may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rifabutin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levamlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Levobupivacaine: (Minor) Levobupivacaine is metabolized by cytochrome P450 isoenzymes 3A4 and 1A2. Inducers of these isoenzymes, such as rifabutin, may decrease the efficacy of levobupivacaine.
    Levomethadyl: (Major) Agents that induce hepatic cytochrome P450 CYP3A4, such as rifamycins, may reduce serum levels of levomethadyl leading to symptoms of withdrawal in stabilized patients. Dosage adjustments of levomethadyl may be required if given with rifamycins.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and rifabutin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; rifabutin induces CYP3A4.
    Linagliptin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with rifabutin may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; rifabutin is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and rifabutin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Rifabutin exposure and the risk for rifabutin-related adverse effects may also be increased; rifabutin dosage adjustments may be required if concomitant use is necessary. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor and rifabutin is a CYP3A4 substrate and moderate CYP3A4 inducer.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with rifabutin. Loperamide is metabolized by the hepatic enzyme CYP3A4; rifabutin is an inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with rifabutin. Loperamide is metabolized by the hepatic enzyme CYP3A4; rifabutin is an inducer of this enzyme.
    Lopinavir; Ritonavir: (Major) Coadministration of ritonavir and rifabutin results in clinically significant alterations of rifabutin pharmacokinetic parameters, with the rifabutin AUC being increased by 430%. In patients receiving any dosage of ritonavir, the dose of rifabutin should always be decreased to 150 mg every day or 300 mg three times per week. (Major) If lopinavir and rifabutin are administered concurrently, the manufacturer recommends a rifabutin dose reduction of at least 75% of the usual dose (i.e., a maximum dose of 150 mg every other day or 3 times per week). In addition, increase monitoring for adverse reactions is recommended. Use of these drugs together increases the AUC of rifabutin and it's metabolites.
    Lorlatinib: (Major) Avoid concomitant use of lorlatinib and rifabutin due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
    Lovastatin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Lovastatin; Niacin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Lumacaftor; Ivacaftor: (Major) Administration of ivacaftor with strong CYP3A inducers, such as rifabutin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, another strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A, and rifabutin is metabolized by CYP3A. Co-administration may increase rifabutin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of rifabutin and lumacaftor; ivacaftor is not recommended. Rifabutin may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Lumacaftor; ivacaftor may also decrease the therapeutic effect of rifabutin. Rifabutin is a substrate and potent inducer (per FDA-approved labeling for lumacaftor; ivacaftor) of CYP3A. Ivacaftor is a substrate of CYP3A and lumacaftor is a potent inducer of CYP3A; although the enzyme induction effects of lumacaftor are already accounted for in fixed-combination dosing, ivacaftor exposure is further decreased when given together with other CYP3A inducers. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure (AUC) by 57%, with minimal effect on the exposure of lumacaftor. Rifabutin may be expected to have a similar effect on some drugs that are affected by coadministration with rifampin. Rifabutin appears to be a less potent hepatic enzyme inducer than rifampin; however, the clinical significance of this finding has not been determined.
    Lumateperone: (Major) Avoid coadministration of lumateperone and rifabutin as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4. Concurrent use of lurasidone and CYP3A4 inducers, such as rifabutin, may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more).
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and rifabutin due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with rifabutin is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and rifabutin is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Mebendazole: (Moderate) Mebendazole is metabolized by hepatic cytochrome P450 enzymes and other enzymes. Rifamycins induce hepatic microsomal enzymes and may increase the metabolism of mebendazole if given concomitantly.
    Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Rifabutin is an inducer of CYP3A4, and may increase the metabolism of mefloquine and reduce mefloquine plasma concentrations if coadministered.
    Metformin; Repaglinide: (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer, such as rifabutin, should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
    Midazolam: (Moderate) Rifabutin is an inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving rifabutin may require higher doses of midazolam to achieve the desired clinical effect.
    Mitotane: (Major) Use caution if mitotane and rifabutin are used concomitantly, and monitor for decreased efficacy of rifabutin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rifabutin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rifabutin.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and rifabutin. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
    Modafinil: (Moderate) Drugs that exhibit significant induction of the hepatic microsomal CYP3A4 isoenzyme may potentially increase the metabolism of modafinil. These medications include rifabutin. Decreased serum levels of modafinil could potentially result in decreased efficacy of modafinil.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with rifabutin is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Concurrent use of sirolimus with strong inducers of CYP3A4 and/or P-glycoprotein, such as rifabutin, should be avoided. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Agents that induce CYP3A4 and/or P-glycoprotein may affect absorption and elimination of sirolimus leading to decreased blood concentrations. In patients where rifabutin is indicated, alternative agents with less enzyme induction should be considered (e.g., rifapentine). Enzyme induction may still occur with the alternative agents (e.g., rifapentine); however, the degree should be less. Rifapentine is known to decrease sirolimus concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Nelfinavir: (Major) Rifabutin may be used as an alternative to rifampin in tuberculosis treatment regimens for HIV-infected patients who remain on nelfinavir. While coadministration of nelfinavir 750 mg every 8 hours with rifabutin resulted in a 32% decrease in nelfinavir plasma AUC and a 207% increase in rifabutin plasma AUC, the coadministration of nelfinavir 1250 mg every 12 hours with rifabutin resulted in no pharmacokinetic alteration. If rifabutin and nelfinavir are coadministered, the dose of nelfinavir should be 1250 mg twice daily and the dose of rifabutin should be 150 mg daily or 300 mg three times per week.
    Neratinib: (Major) Avoid concomitant use of rifabutin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Niacin; Simvastatin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Nicardipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as nicardipine and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent enzyme inducers.
    Nifedipine: (Contraindicated) Nifedipine is a substrate of the CYP3A4 isoenzyme and its use is contraindicated with potent inducers of CYP3A4, such as rifabutin. Potent CYP3A4 inducers reduce the bioavailability and efficacy of nifedipine.
    Nimodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as nimodipine and thereby reduce their oral bioavailability. The dosage requirements of nimodipine may be increased in patients receiving concurrent enzyme inducers.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with rifabutin due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Olaparib: (Major) Avoid coadministration of olaparib with rifabutin due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and rifabutin is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concurrent administration of rifabutin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated rifabutin plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Rifabutin is a CYP3A4 substrate, and ritonavir is a potent CYP3A4 inhibitor. In addition, rifabutin is an inducer of CYP3A4, and ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Although rifabutin appears to induce the enzyme to a lesser degree than rifampin, the plasma concentrations of ritonavir, paritaprevir, and dasabuvir may be reduced. (Major) Coadministration of ritonavir and rifabutin results in clinically significant alterations of rifabutin pharmacokinetic parameters, with the rifabutin AUC being increased by 430%. In patients receiving any dosage of ritonavir, the dose of rifabutin should always be decreased to 150 mg every day or 300 mg three times per week.
    Ondansetron: (Minor) Monitor for altered response to ondansetron during coadministration of rifabutin. Rifabutin may increase the clearance and decrease blood concentrations of ondansetron. However, no dosage adjustment for ondansetron is recommended during coadministration.
    Oritavancin: (Moderate) Rifabutin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of rifabutin may be reduced if these drugs are administered concurrently.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of oxycodone as needed. If rifabutin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and rifabutin 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.
    Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including rifabutin.
    Panobinostat: (Major) Avoid the concomitant use of panobinostat and rifabutin; panobinostat levels may be significantly decreased and its efficacy reduced. Rifabutin is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
    Pazopanib: (Major) Avoid administering pazopanib in patients who require chronic treatment with a strong CYP3A4 inducer, such as rifabutin. The concomitant use of pazopanib, a weak CYP3A4 inhibitor and a substrate for CYP3A4, and rifabutin, a substrate for and a strong CYP3A4 inducer, may result in altered pazopanib and/or rifabutin concentrations.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and rifabutin due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with rifabutin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of rifabutin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Rifabutin is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Perindopril; Amlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Phenothiazines: (Major) Rifamycins can increase the metabolism or reduce the bioavailability of phenothiazines. Dosage increases of phenothiazines may be necessary following the addition of rifampin or another rifamycin.
    Phenytoin: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as rifabutin. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Pioglitazone; Glimepiride: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Posaconazole: (Major) The concurrent use of posaconazole and rifabutin should be avoided, if possible, due to the potential for decreased posaconazole efficacy as well as increased risk of rifabutin related adverse events. If used in combination, closely monitor for breakthrough fungal infections and rifabutin adverse events, such as uveitis and leukopenia. Rifabutin induces UDP-glucuronidase resulting in decreased posaconazole plasma concentrations. When posaconazole (200 mg PO daily) was administered with rifabutin (300 mg PO daily), the mean reductions in Cmax were 43% and the mean reductions in AUC were 49% for posaconazole. Additionally, posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rifabutin. Coadministration of posaconazole (200 mg PO daily) with rifabutin (300 mg PO daily) increased the mean rifabutin Cmax (by 31%) and AUC (by 72%). The concomitant use of rifabutin with posaconazole should be avoided unless the benefits outweigh the risks; dosage adjustment recommendations are not available.
    Pravastatin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with rifabutin, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Propafenone: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of propafenone.
    Propranolol: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Rifamycins are inducers of hepatic enzymes, and may alter the pharmacokinetics of beta-blockers including propranolol. Patients should be monitored for loss of propranolol effects if rifamycins are added.
    Pyrazinamide, PZA: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Quazepam: (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
    Quetiapine: (Moderate) Increased doses of quetiapine may be required to maintain symptom control if rifabutin is used concomitantly. Rifabutin is a less potent inducer of CYP3A4 than rifampin, a potent inducer. However, increased doses of quetiapine up to 5 fold may be required to maintain control of symptoms in patients receiving quetiapine and known potent CYP3A4 inducers. There are no specific recommendations for moderate inducers. When rifabutin is discontinued, the dose of quetiapine should be reduced to the original level within 7 to 14 days.
    Quinidine: (Moderate) Rifabutin is an inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of quinidine.
    Quinine: (Major) Rifabutin is an inducer of hepatic metabolism and may significantly accelerate quinine clearance and reduce its half-life. Higher doses of quinine may be required in patients receiving rifabutin.
    Ramelteon: (Moderate) Administration of rifabutin, a CYP1A2 enzyme inducer, may theoretically result in decreased exposure to ramelteon. Monitor the patient closely if rifabutin therapy is initiated or stopped in patients receiving ramelteon.
    Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifabutin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
    Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inducers can theoretically reduce the effectiveness of HMG-CoA reductase activity via induction of CYP3A4 metabolism. Examples of CYP3A4 inducers include rifabutin.
    Repaglinide: (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer, such as rifabutin, should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
    Ribociclib: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin.
    Rilpivirine: (Major) Administration of rifabutin with rilpivirine may significantly decrease rilpivirine plasma concentrations; therefore, if these drugs are given concurrently, an additional dose of rilpivirine (25 mg PO once daily) is required and the drugs should be administered with a meal. Rifabutin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Use of these drugs together may result in HIV treatment failure or the development of rilpivirine or NNRTI resistance.
    Rimegepant: (Major) Avoid coadministration of rimegepant with rifabutin; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
    Ripretinib: (Major) Avoid coadministration of ripretinib with rifabutin. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of rifabutin. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and rifabutin is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
    Ritonavir: (Major) Coadministration of ritonavir and rifabutin results in clinically significant alterations of rifabutin pharmacokinetic parameters, with the rifabutin AUC being increased by 430%. In patients receiving any dosage of ritonavir, the dose of rifabutin should always be decreased to 150 mg every day or 300 mg three times per week.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and rifabutin may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Rifabutin is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs lack of efficacy of rivaroxaban.
    Roflumilast: (Major) Coadminister rifabutin and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Rifabutin is a CYP3A4 inducer and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide. Specific pharmacokinetic study of this potential interaction has not been conducted.
    Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and rifabutin, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
    Saquinavir: (Major) Systemic exposure (AUC) of rifabutin is increased by 60% when administered concurrently with saquinavir boosted with ritonavir. To compensate, the manufacturer recommends reducing the adult rifabutin dose by at least 75% (i.e., 150 mg every other day or three times weekly) during times of coadministration. The CDC guidelines suggest decreasing the adult dose of rifabutin to 150 mg daily or 300 mg three times per week when coadministered with ritonavir boosted protease inhibitors, such as saquinavir. No dosage adjustment is necessary for saquinavir/ritonavir. Monitor patients carefully when this combination is used.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and rifabutin due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease selpercatinib exposure by 40% to 70%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and rifabutin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
    Sildenafil: (Minor) Sildenafil is metabolized principally by cytochrome P450 3A4 and 2C9 enzymes. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as rifabutin, will decrease plasma levels of sildenafil, however, no interaction studies have been performed.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
    Simvastatin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Simvastatin; Sitagliptin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Siponimod: (Moderate) Concomitant use of siponimod and rifabutin 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; rifabutin is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
    Sirolimus: (Major) Concurrent use of sirolimus with strong inducers of CYP3A4 and/or P-glycoprotein, such as rifabutin, should be avoided. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Agents that induce CYP3A4 and/or P-glycoprotein may affect absorption and elimination of sirolimus leading to decreased blood concentrations. In patients where rifabutin is indicated, alternative agents with less enzyme induction should be considered (e.g., rifapentine). Enzyme induction may still occur with the alternative agents (e.g., rifapentine); however, the degree should be less. Rifapentine is known to decrease sirolimus concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of CYP3A4, such as rifabutin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of CYP3A4, such as rifabutin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate. (Major) Avoid coadministration of voxilaprevir with moderate to potent inducers of CYP3A4, such as rifabutin. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Voxilaprevir is metabolized by CYP3A4.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and rifabutin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and rifabutin is a strong CYP3A4 inducer. The sonidegib geometric mean Cmax and AUC were decreased by 54% and 72%, respectively when coadministered with a strong inducer in a drug interaction study.
    Sorafenib: (Major) Avoid coadministration of sorafenib with rifabutin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if rifabutin must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with rifabutin is necessary; consider increasing the dose of sufentanil injection as needed. If rifabutin is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. 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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. sulfamethoxazole; trimethoprim, SMX-TMP did not alter the pharmacokinetics of rifabutin.
    Sulfonylureas: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Tacrolimus: (Major) Coadministration with strong CYP3A4-inducers such as rifabutin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and rifabutin. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inducers, such as rifabutin, may reduce the efficacy of tasimelteon.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with rifabutin as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
    Telaprevir: (Major) Coadministration of rifabutin and telaprevir is not recommended. If rifabutin and telaprevir are coadministered, close clinical monitoring is advised due to the increased potential for rifabutin-related adverse events and for the potential of decreased telaprevir efficacy. If rifabutin dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of rifabutin and telaprevir. Rifabutin is an inducer and substrate of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor and substrate of this isoenzyme. When used in combination, rifabutin plasma concentrations may be elevated and the plasma concentration of telaprevir may be deceased, resulting in an increased potential for rifabutin-related adverse events and telaprevir treatment failure.
    Telmisartan; Amlodipine: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
    Temsirolimus: (Major) Avoid coadministration of temsirolimus with rifabutin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifabutin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of rifabutin. Temsirolimus is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Tenofovir Alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Tenofovir Alafenamide: (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Terbinafine: (Moderate) Due to the risk for breakthrough fungal infections, caution is advised when administering terbinafine with rifabutin. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may decrease the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; rifabutin induces this enzyme. Monitor patients for breakthrough fungal infections.
    Tezacaftor; Ivacaftor: (Major) Administration of ivacaftor with strong CYP3A inducers, such as rifabutin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, another strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A, and rifabutin is metabolized by CYP3A. Co-administration may increase rifabutin exposure leading to increased or prolonged therapeutic effects and adverse events. (Major) Do not administer tezacaftor; ivacaftor and rifabutin together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of rifabutin, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
    Thiothixene: (Major) Limited data suggest that rifampin can increase the metabolism or reduce the bioavailability of thiothixene. Dosage adjustments of thiothixene may be necessary following the addition of rifampin or another rifamycin (e.g., rifabutin, rifapentine).
    Tipranavir: (Major) Coadministration with tipranavir (in the FDA approved dosage regimen) results in an increase in rifabutin AUC. If coadministered, the manufacturer recommends the adult dose of rifabutin should be reduced by 75% (150 mg every other day), with appropriate monitoring and further dose reductions if necessary. The CDC recommends rifabutin 150 mg daily or 300 mg three times per week.
    Tolazamide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Tolbutamide: (Moderate) Monitor for decreased efficacy of sulfonylureas during coadministration of rifamycins as plasma concentrations of sulfonylureas may be decreased; dosage adjustments made be necessary. Sulfonylureas are CYP2C9 substrates and rifamycins are CYP2C9 inducers.
    Toremifene: (Major) Avoid coadministration of rifabutin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Tramadol; Acetaminophen: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Trandolapril; Verapamil: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as verapamil and thereby reduce their oral bioavailability. The dosage requirements of verapamil may be increased in patients receiving concurrent enzyme inducers.
    Tretinoin, ATRA: (Moderate) Rifabutin may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and rifabutin, however, patients should be closely monitored for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy.
    Trimethoprim: (Moderate) Concomitant administration of rifabutin and sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole (double-strength) in 12 HIV-infected patients decreased the AUC of SMX-TMP by about 15 to 20%. Rifabutin decreased the AUC and Cmax of trimethoprim by 14% and 6%, respectively, when rifabutin was given with trimethoprim alone. sulfamethoxazole; trimethoprim, SMX-TMP did not alter the pharmacokinetics of rifabutin.
    Trimetrexate: (Minor) Drugs such as rifabutin, rifampin, and rifapentine can increase the metabolism of trimetrexate by induction of the cytochrome P-450 system. This can lead to lower plasma concentrations of trimetrexate.
    Tucatinib: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with tucatinib is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin.
    Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with rifabutin as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and rifabutin is a CYP3A4 inducer. Concomitant use is expected to decrease the plasma concentration of ulipristal and may decrease its effectiveness.
    Vemurafenib: (Major) Concomitant administration of rifabutin and vemurafenib may decrease concentrations of both agents. Both rifabutin and vemurafenib are CYP3A4 substrates and inducers. Avoid using these agents together if possible.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and rifabutin; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and rifabutin is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Verapamil: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as verapamil and thereby reduce their oral bioavailability. The dosage requirements of verapamil may be increased in patients receiving concurrent enzyme inducers.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifabutin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including rifabutin. Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Voclosporin: (Major) Avoid coadministration of voclosporin with rifabutin. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and rifabutin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with rifabutin, a CYP3A inducer.
    Voriconazole: (Contraindicated) Concurrent administration of rifabutin and voriconazole is contraindicated. In one study, the maximum plasma concentration (Cmax) and systemic exposure (AUC) of voriconazole were decreased by an average of 67% and 79%, respectively, when given with rifabutin. Another study, found concurrent administration caused the Cmax and AUC of rifabutin to be increased by an average of 3-times and 4-times, respectively. Rifabutin induces the CYP2C9, CYP2C19 and CYP3A4 metabolism of voriconazole. Voriconazole inhibits the CYP3A4 metabolism of rifabutin.
    Voxelotor: (Major) Avoid coadministration of voxelotor and rifabutin 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; rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 60%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with rifamycins is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Rifamycins may induce the hepatic metabolism of warfarin through induction of CYP3A4, CYP2C9, and CYP1A2. A 2- to 3-fold increase in the daily dose of warfarin may be needed within a week of starting rifamycins to maintain appropriate anticoagulation. Once the rifamycin is discontinued, the dose of warfarin will need to be decreased.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and rifabutin. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. The AUC of zanubrutinib is predicted to decrease by 60% when coadministered with another moderate CYP3A4 inducer.
    Zidovudine, ZDV: (Minor) Rifabutin may accelerate the metabolism of zidovudine. However the effectiveness of zidovudine against HIV does not appear to be altered and no dosage adjustments are required. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifamycins, including rifampin, rifabutin and rifapentine.
    Ziprasidone: (Moderate) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme. A decrease in ziprasidone plasma levels could potentially occur if the drug is used concurrently with inducers of CYP3A4, such as rifabutin. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone.
    Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as rifabutin. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
    Zonisamide: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as rifabutin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.

    PREGNANCY AND LACTATION

    Pregnancy

    Use rifabutin during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies of rifabutin use in pregnant women. No teratogenicity was observed in animal studies at doses about 6 to 13 times the recommended human daily dose based on body surface area comparisons. However, fetal skeletal anomalies were observed in rats and rabbits after administration of a dose approximately equivalent and a dose 5 times the recommended human daily dose, respectively. At 6 times the recommended human daily dose, a decrease in fetal viability was observed in rats.[29210]

    There are no adequate and well-controlled studies of rifabutin use in breast-feeding women. It is not known if rifabutin is excreted into breast milk. Because many drugs are excreted in human breast milk and because of the risk for serious adverse reactions in breast-feeding infants, discontinue breast-feeding or rifabutin, taking into consideration the importance of the drug to the mother.[29210] Previous American Academy of Pediatrics (AAP) recommendations generally considered another rifamycin, rifampin, as compatible for use in lactating women.[27500]

    MECHANISM OF ACTION

    Mechanism of Action: Rifabutin appears to inhibit DNA-dependent RNA polymerase in susceptible strains of E. coli and B. subtilis, thereby suppressing RNA synthesis. It is unknown if this mechanism is responsible for activity against M. avium or M. intracellulare. There is also some evidence that it interferes with DNA synthesis in M. tuberculosis. Rifabutin exhibits bactericidal or bacteriostatic action, depending on the drug concentrations reached within an infected site and the susceptibility of the organism.In general, the following organisms are susceptible to rifabutin: M. avium-intracellulare and some strains of M. tuberculosis, and M. leprae. Rifabutin has similar in vitro actions to rifampin against gram-positive and gram-negative organisms.

    PHARMACOKINETICS

    Rifabutin is administered orally. Due to its lipophilicity, it is widely distributed with substantial intracellular accumulation. Lung concentrations are approximately 5—10 times higher than serum concentrations. The half-life averages 45 hours. With multiple dosing, systemic concentrations decreased by 38%, but the elimination half-life remained the same. The primary metabolites are 31-hydroxy and 25-O-desacetyl rifabutin. The latter compound exhibits comparable activity to the parent drug, contributing about 10% to the total antimicrobial action. Approximately 53% of a dose is excreted in the urine, primarily as metabolites, and 5% through biliary clearance. Approximately 30% is excreted in the feces.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    Rifabutin may be expected to have a similar effect on some drugs that are affected by coadministration with rifampin. Rifabutin is an inducer and a substrate of the CYP3A4 isoenzyme. Rifabutin appears to be a less potent hepatic enzyme inducer than rifampin; however, the clinical significance of this finding has not been determined. Unlike with rifampin, acetylation of isoniazid by rifabutin is not affected. The overall potency of rifabutin induction is variable among substrates and rifabutin may alter drug metabolizing enzymes in a dose-dependant manner. Additionally, plasma concentrations at standard doses of rifabutin are lower compared to other rifamycins with may explain the lower induction potential clinically.
     

    Oral Route

    Rifabutin is rapidly absorbed from the GI tract following oral administration. Roughly 53% of a dose is absorbed, but bioavailability is only 12—20% in HIV-positive patients. High-fat content food delays the rate of absorption. Peak plasma concentrations are attained in 1—4 hours.