Rifabutin (Monograph)

Brand name: Mycobutin
Drug class: Antituberculosis Agents
- Antimycobacterial Agents

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Antimycobacterial agent; semisynthetic ansamycin antibiotic; spiropiperidyl derivative of rifamycin S.

Uses for Rifabutin

Mycobacterium avium Complex (MAC) Infections

Primary prevention (primary prophylaxis) of disseminated MAC infection in adults, adolescents, and children^{† [off-label]} with advanced HIV infection; designated an orphan drug by FDA for this use. The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the IDSA (USPHS/IDSA) recommend monotherapy with azithromycin or clarithromycin for primary prevention of MAC in HIV-infected individuals and consider rifabutin (with or without azithromycin) an alternative.

Prevention of recurrence (secondary prophylaxis) of disseminated MAC infections^{† [off-label]} in HIV-infected adults, adolescents, and children^{† [off-label]}; designated an orphan drug by FDA for this use. USPHS/IDSA, CDC, NIH, IDSA, and others recommend clarithromycin (or azithromycin) given with ethambutol (with or without rifabutin) for secondary prophylaxis after the initial infection has been treated.

Treatment of pulmonary MAC infections^{† [off-label]} in conjunction with other antimycobacterials. For initial treatment of nodular/bronchiectatic pulmonary disease caused by macrolide-susceptible MAC, ATS and IDSA recommend a 3-times weekly regimen of clarithromycin (or azithromycin), ethambutol, and rifampin in most patients. For initial treatment of fibrocavitary or severe nodular/bronchiectatic pulmonary disease caused by macrolide-susceptible MAC, ATS and IDSA recommend a daily regimen of clarithromycin (or azithromycin), ethambutol, and rifampin (or rifabutin) and state that consideration can be given to adding amikacin or streptomycin during the first 2–3 months of treatment for extensive (especially fibrocavitary) disease or when previous therapy has failed.

Treatment of disseminated MAC infections^{† [off-label]} in conjunction with other antimycobacterials, including infections in HIV-infected adults, adolescents, and children^†; designated an orphan drug by FDA for this use. ATS, CDC, NIH, and IDSA recommend a regimen of clarithromycin (or azithromycin) and ethambutol with or without rifabutin.

Although either rifampin or rifabutin can be used in multiple-drug regimens for treatment of MAC infections, rifampin may be the preferred rifamycin for most patients with pulmonary MAC infections since it may be better tolerated (e.g., in older patients). Rifabutin may be the preferred rifamycin for treatment of disseminated MAC disease (especially in HIV-infected individuals) since it appears to be more active in vitro against MAC and is associated with fewer drug interactions. (See Specific Drugs under Interactions.)

Treatment of MAC infections is complicated and should be directed by clinicians familiar with mycobacterial diseases; consultation with a specialist is particularly important when the patient cannot tolerate first-line drugs or when the infection has not responded to prior therapy or is caused by macrolide-resistant MAC. In addition, specialized references should be consulted for guidance on the use of rifabutin in HIV-infected patients receiving HIV protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). (See Specific Drugs under Interactions.)

Other Mycobacterial Infections

Treatment of infections caused by M. xenopi^† in conjunction with other antimycobacterials. Optimum regimens not established; in vivo response may not correlate with in vitro susceptibility. ATS and IDSA state that a regimen of clarithromycin, rifampin, and ethambutol has been used, although the rate of relapse is high. A regimen of isoniazid, rifampin (or rifabutin), ethambutol, and clarithromycin (with or without streptomycin during initial treatment) also has been suggested.

Tuberculosis

Treatment of active (clinical) tuberculosis^† (TB) in conjunction with other antituberculosis agents.

First-line agent for treatment of all forms of TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug when rifampin cannot be used.

Usually reserved for patients who cannot receive rifampin because of intolerance or because they are receiving other drugs that have clinically important interactions with rifampin (e.g., HIV patients receiving certain antiretroviral agents). Used in both the initial intensive treatment phase and continuation treatment phase.

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months). Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months, ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy. A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.

Latent Tuberculosis Infection

Treatment of latent tuberculosis infection^† (LTBI), including in HIV-infected adults and adolescents.

LTBI is asymptomatic infection with M. tuberculosis; usually defined as a positive tuberculin skin test (TST) or Quantiferon-TB gold test (QFT-G) with no evidence of active (clinical) TB. LTBI is treated to decrease the risk of progression to active TB.

Regimen of choice for treatment of LTBI is isoniazid monotherapy, unless the patient has been in contact with an individual with drug-resistant TB. Rifampin monotherapy is the preferred alternative and is especially useful in adults, adolescents, or children who have been exposed to isoniazid-resistant M. tuberculosis and those who cannot tolerate isoniazid. Rifabutin is used in those who cannot receive rifampin because of intolerance or because they are receiving other drugs that have clinically important interactions with rifampin (e.g., HIV patients receiving certain antiretroviral agents).

Treatment of LTBI in patients who have been exposed to a source case with drug-resistant TB, including MDR TB or XDR TB, should be managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.

Prior to initiating treatment of LTBI, clinical (active) TB must be excluded using appropriate testing (e.g., radiographs).

Rifabutin Dosage and Administration

Administration

Oral Administration

Administer orally.

May be administered without regard to meals, but administration with food may minimize adverse GI effects.

In patients unable to swallow capsules, the drug may be mixed with food (e.g., applesauce). Alternatively, it has been suggested that an oral suspension containing 10 mg/mL can be prepared extemporaneously using the contents of the commercially available capsules and cherry or simple syrup.

Dosage

May be used alone for primary prophylaxis of MAC infections in HIV-infected patients; must be used in conjunction with other antimycobacterials for treatment of pulmonary or disseminated MAC infections^† in HIV-infected or immunocompetent patients or prevention of MAC recurrence^† (secondary prophylaxis) in HIV-infected patients.

May be used alone for treatment of LTBI^†; must be used in conjunction with other antimycobacterials for treatment of active TB^†.

If used for treatment of active TB^†, can be used in daily or intermittent (2 or 3 times weekly) multiple-drug regimens.

If used for treatment of TB^† in HIV-infected patients, rifabutin should be given at least 3 times weekly in those with CD4⁺ T-cell counts <100/mm³.

If used in HIV-infected patients receiving certain PIs or NNRTIs, adjustment in the treatment regimen recommended. (See Specific Drugs under Interactions.)

Pediatric Patients

Mycobacterium avium Complex (MAC) Infections

Primary Prevention of MAC in Children ≥6 Years of Age with Advanced HIV Infection†

Oral

300 mg once daily.

USPHS/IDSA recommends initiation of primary prophylaxis against MAC if CD4⁺ T-cell count is <750/mm³ in those <1 year, <500/mm³ in those 1–2 years, <75/mm³ in those 2–6 years, or <50/mm³ in those ≥6 years of age.

The safety of discontinuing primary MAC prophylaxis in HIV-infected infants and children receiving potent antiretroviral therapy has not been extensively studied.

Primary Prevention of MAC in Adolescents with Advanced HIV Infection

Oral

300 mg once daily. Used alone or in conjunction with azithromycin.

USPHS/IDSA recommends initiation of primary prophylaxis against MAC if CD4⁺ T-cell count is <50/mm³.

Primary MAC prophylaxis may be discontinued if there is immune recovery in response to antiretroviral therapy with an increase in CD4⁺ T-cell count to >100/mm³ sustained for ≥3 months. Reinitiate prophylaxis if CD4⁺ T-cell count decreases to <50–100/mm³.

Prevention of MAC Recurrence (Secondary Prophylaxis) in HIV-infected Children†

Oral

5 mg/kg (up to 300 mg) once daily. Used in conjunction with clarithromycin (or azithromycin) and ethambutol.

Secondary prophylaxis to prevent MAC recurrence in HIV-infected children usually continued for life. The safety of discontinuing secondary MAC prophylaxis in children whose CD4⁺ T-cell count increases in response to antiretroviral therapy has not been studied.

Prevention of MAC Recurrence (Secondary Prophylaxis) in HIV-infected Adolescents†

Oral

300 mg once daily. Used in conjunction with clarithromycin (or azithromycin) and ethambutol.

Secondary prophylaxis to prevent MAC recurrence usually continued for life in HIV-infected individuals.

Consideration can be given to discontinuing secondary MAC prophylaxis after ≥12 months in those who remain asymptomatic with respect to MAC and have an increase in CD4⁺ T-cell count to >100/mm³ that has been sustained for ≥6 months. Reinitiate prophylaxis if CD4⁺ T-cell count decreases to <100/mm³.

Treatment of Disseminated MAC in HIV-infected Infants and Children†

Oral

10–20 mg/kg (up to 300 mg) once daily recommended by CDC and others. Used in conjunction with clarithromycin (or azithromycin) and ethambutol.

Treatment of Disseminated MAC in HIV-infected Adolescents†

Oral

300 mg once daily. Used in conjunction with clarithromycin (or azithromycin) and ethambutol.

Tuberculosis†

Treatment of Active (Clinical) Tuberculosis†

Oral

Children <15 years of age or weighing ≤40 kg^†: 10–20 mg/kg (up to 300 mg) once daily or 2 or 3 times weekly.

Adolescents ≥15 years of age: 5 mg/kg (up to 300 mg) once daily or 2 or 3 times weekly.

Latent Tuberculosis Infection† (LTBI)

Oral

Adolescents: 300 mg once daily for 4 months.

Adults

Mycobacterium avium Complex (MAC) Infections

Primary Prevention in Adults with Advanced HIV Infection

Oral

300 mg once daily. Alternatively, 150 mg twice daily with food may be used in patients experiencing nausea, vomiting, or other GI upset. Used alone or in conjunction with azithromycin.

Primary prophylaxis against MAC should be initiated if CD4⁺ T-cell count is <50/mm³.

Primary MAC prophylaxis may be discontinued if there is immune recovery in response to antiretroviral therapy and an increase in CD4⁺ T-cell count to >100/mm³ has been sustained for ≥3 months. Reinitiate prophylaxis if CD4⁺ T-cell count decreases to <50–100/mm³.

Prevention of MAC Recurrence (Secondary Prophylaxis) in HIV-infected Adults†

Oral

300 mg once daily. Used in conjunction with clarithromycin (or azithromycin) and ethambutol.

Secondary prophylaxis to prevent MAC recurrence usually continued for life in HIV-infected individuals.

Consideration can be given to discontinuing secondary MAC prophylaxis after ≥12 months in those who remain asymptomatic with respect to MAC and have an increase in CD4⁺ T-cell count to >100/mm³ that has been sustained for ≥6 months. Reinitiate prophylaxis if CD4⁺ T-cell count decreases to <100/mm³.

Initial Treatment of Pulmonary MAC Infections (Fibrocavitary or Severe Nodular/bronchiectatic Disease) Caused by Macrolide-susceptible Strains†

Oral

150–300 mg once daily in conjunction with ethambutol (15 mg/kg once daily) and either clarithromycin (0.5–1 g daily) or azithromycin (250 mg once daily) recommended by ATS and IDSA. Continue until patient has been culture negative on treatment for 1 year. Consideration can be given to including amikacin or streptomycin 3 times weekly during the first 2–3 months of treatment for extensive, especially fibrocavitary, disease or when previous therapy has failed.

Treatment of Disseminated MAC in HIV-infected and Other Adults†

Oral

300 mg once daily in conjunction with ethambutol (15 mg/kg once daily) in conjunction with either clarithromycin (500 mg twice daily) or azithromycin (500 mg once daily) recommended by ATS, CDC, and IDSA. Rifabutin dosages of 300–450 mg once daily have been used. Dosage may need to be adjusted in HIV-infected patients depending on the drugs included in the antiretroviral regimen. (See Specific Drugs under Interactions.)

Tuberculosis†

Treatment of Active (Clinical) Tuberculosis†

Oral

5 mg/kg (up to 300 mg) once daily or 2 or 3 times weekly.

Latent Tuberculosis Infection† (LTBI)

Oral

5 mg/kg (up to 300 mg) once daily for 4 months.

Prescribing Limits

Pediatric Patients

Mycobacterium avium Complex (MAC) Infections

Prevention of MAC Recurrence (Secondary Prophylaxis) in HIV-infected Children†

Oral

Maximum 300 mg once daily.

Treatment of Disseminated MAC in HIV-infected Infants and Children†

Oral

Maximum 300 mg once daily.

Tuberculosis†

Treatment of Active (Clinical) Tuberculosis in Children or Adolescents†

Oral

Maximum 300 mg per dose in once-daily or 2- or 3-times weekly regimens.

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis†

Oral

Maximum 300 mg per dose in once-daily or 2- or 3-times weekly regimens.

Special Populations

Hepatic Impairment

Dosage reductions may be needed in patients with severe hepatic impairment. (See Hepatic Impairment under Cautions.)

Renal Impairment

Cl_cr <30 mL/minute: Reduce dose by 50%. To prevent inadequate dosage, some experts prefer to use usual dosage and monitor plasma rifabutin concentrations.

Mild to moderate renal impairment: Dosage adjustment not required.

Geriatric Patients

Select dosage with caution.

Cautions for Rifabutin

Contraindications

• Known hypersensitivity to rifabutin or other rifamycins (rifampin, rifapentine).

Warnings/Precautions

Warnings

Precautions Related to Treatment of MAC Infections

Should not be used for prevention of MAC infection in patients with active TB. If rifabutin monotherapy is used for prevention of MAC infection in patients with active TB, M. tuberculosis resistant to both rifabutin and rifampin may emerge.

There is no evidence that rifabutin is effective for prevention of M. tuberculosis infections. Individuals requiring prophylaxis against M. tuberculosis (i.e., treatment of latent tuberculosis infection) and prophylaxis against MAC may receive isoniazid and rifabutin concomitantly.

HIV-infected individuals frequently have TB and may present with atypical or extrapulmonary findings. The tuberculin skin test (TST) for diagnosis of TB may be nonreactive in such patients despite presence of active disease. In addition to chest radiographs and sputum cultures, blood culture, urine culture, or biopsy of suspicious lymph nodes may be useful in the diagnosis of TB in HIV-infected individuals.

Any patient developing symptoms consistent with active TB while receiving rifabutin for MAC prophylaxis should be evaluated immediately so that those with active disease can be given an effective multiple-drug regimen for treatment of TB.

Precautions Related to Treatment of Tuberculosis

Should not be used alone for the treatment of active TB; must be used in conjunction with other antituberculosis agents.

Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response. The antituberculosis regimen should be modified as needed. Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical. Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.

To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active (clinical) TB and for treatment of LTBI whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.

Sensitivity Reactions

Dermatologic Reactions.

Rash reported frequently.

General Precautions

Discoloration of Body Tissues or Fluids

Orange or yellow skin discoloration may occur. Urine, feces, saliva, sputum, sweat, or tears may have a brown-orange coloration. Soft contact lenses may become permanently stained.

Hematologic Effects

Neutropenia reported frequently; thrombocytopenia reported rarely.

Consider monitoring hematologic status periodically during therapy.

Ocular Effects

Uveitis, which may be unilateral or bilateral and is characterized by pain, redness, and possible temporary or permanent loss of vision, reported occasionally.

Corneal deposits were reported in some HIV-infected children^† who were receiving rifabutin as part of a multiple-drug regimen for MAC prophylaxis. These were tiny, almost transparent, asymptomatic peripheral and central corneal deposits that did not impair vision.

If uveitis occurs, temporarily interrupt rifabutin therapy and obtain ophthalmic evaluation. In mild cases, rifabutin can be reinstituted; if signs and symptoms of uveitis recur, discontinue immediately. Permanent discontinuance may be necessary if uveitis is severe.

Musculoskeletal Effects

Myalgia, arthralgia, myositis reported.

Specific Populations

Pregnancy

Category B.

ATS, CDC, and IDSA state that data are insufficient to recommend use of rifabutin in pregnant women.

Lactation

Not known whether rifabutin is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy for prophylaxis of MAC infection in children have not been established. Has been used for primary or secondary prophylaxis of MAC infections in HIV-infected children^†.

Has been used in a limited number of children (concomitantly with other antimycobacterial agents) for the treatment of MAC infection^†.

Adverse effects reported in children (e.g., leukopenia, neutropenia, rash) are similar to those observed in adults. In addition, corneal deposits were reported in some children. (See Ocular Effects under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Select dosage with caution, starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Use close clinical and laboratory monitoring when used in patients with hepatic impairment. Dosage reduction may be needed in severe impairment.

Renal Impairment

Dosage adjustment recommended in patients with substantial renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Rash, GI effects (abdominal pain, nausea, vomiting, diarrhea, dyspepsia, eructation, taste perversion), neutropenia, headache, discolored urine.

Drug Interactions

Metabolized by CYP3A.

Induces CYP3A; induces hepatic enzymes to a lesser extent than rifampin.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A with possible alteration of the metabolism of rifabutin and/or other drug.

Specific Drugs

Rifabutin Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from GI tract; peak plasma concentrations achieved within 2–4 hours. Absolute bioavailability in HIV-positive patients was 20%.

Food

High-fat meal slows the rate but not the extent of absorption.

Special Populations

Compared with patients who have Cl_cr 61–74 mL/minute, AUC is 71% higher in those with Cl_cr <30 mL/minute and 41% higher in those with Cl_cr 30–61 mL/minute. (See Renal Impairment under Dosage and Administration.)

Steady-state pharmacokinetics more variable in geriatric individuals >70 years of age than in younger adults.

Distribution

Extent

Widely distributed. Intracellular concentrations higher than plasma concentrations; concentrations in lung tissue higher than plasma concentrations.

Distributed into CNS when meninges are inflamed.

Plasma Protein Binding

85%.

Special Populations

Plasma protein binding not influenced by hepatic or renal impairment.

Elimination

Metabolism

Metabolized by CYP3A. Metabolized to 5 metabolites; 1 metabolite has antimicrobial activity equal to that of rifabutin.

Elimination Route

Excreted in urine (53%) principally as metabolites and excreted in feces (30%).

Removal by hemodialysis unlikely.

Half-life

45 hours (range: 16–69 hours).

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C); tight container.

Actions and Spectrum

• A spiropiperidyl rifamycin structurally and pharmacologically similar to other rifamycins (rifampin, rifapentine).

• Inhibits DNA-dependent RNA polymerases in susceptible Escherichia coli and Bacillus subtilis. Not known whether rifabutin inhibits DNA-dependent RNA polymerases in M. avium complex (MAC).

• Mycobacterium: Active in vitro and in clinical infections against M. avium complex (MAC) and M. tuberculosis. Active in vitro against M. gordonae, M. haemophilum, M. kansasii, and M. marinum. Has some activity against M. leprae.

• Spectrum of activity against gram-positive and gram-negative bacteria similar to that of rifampin.

• Cross-resistance occurs between rifabutin and other rifamycins (rifampin, rifapentine). M. tuberculosis resistant to rifampin usually are resistant to both rifabutin and rifapentine; only rarely are rifampin-resistant strains susceptible to rifabutin.

Advice to Patients

• Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.

• Importance of completing full course of therapy; importance of not missing any doses.

• Advise patient of the signs and symptoms of MAC infections and TB; importance of consulting clinician if new symptoms consistent with either disease occur.

• Possibility of uveitis; importance of consulting clinician if signs or symptoms of an inflammatory ocular condition occur (e.g., eye pain, redness, loss of vision).

• Possibility of arthralgias or myositis; importance of consulting clinician if signs or symptoms of these disorders occur (e.g., joint stiffness, swelling, tenderness, paresthesia).

• Advise patient that rifabutin may impart a brown-orange color to urine, feces, saliva, sputum, sweat, tears, and skin. Soft contact lenses may become permanently stained.

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

• Advise that reliability of systemic hormonal contraceptives may be affected; alternative contraceptives should be considered.

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

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

Preparations

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

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

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