AHFS Class:

• Antituberculosis Agents 8:16.04

Generic Name(s):

• Rifabutin

Rifabutin, a semisynthetic spiropiperidyl derivative of rifamycin S, is an ansamycin antibiotic that is an antimycobacterial agent.1,2,3,4,5,6,7,8

Mycobacterium avium Complex (MAC) Infections

Primary Prevention of Disseminated MAC Infection

Rifabutin is used alone or in conjunction with azithromycin to prevent or delay the development of Mycobacterium avium complex (MAC) bacteremia and disseminated infections ( primary prophylaxis ) in patients with advanced human immunodeficiency virus (HIV) infection;1,11,23,24,35,46,47,59,60,72 rifabutin is designated an orphan drug by the US Food and Drug Administration (FDA) for this use.17 Prevention of disseminated MAC disease is an important goal in the management of patients with HIV infection and low helper/inducer (CD4⁺, T4⁺) T-cell counts because of the frequency with which the disease occurs in such patients and its associated morbidity.24,35 Current evidence indicates that MAC causes disseminated disease in a substantial proportion of HIV-infected patients and that prophylaxis with rifabutin, alone or combined with azithromycin, can reduce substantially the frequency of M. avium complex bacteremia and ameliorate clinical manifestations of the disease in patients with AIDS.1,18,19,23,24,35,42,43,44,59,60 Azithromycin or clarithromycin also is used alone to prevent disseminated MAC infection in HIV-infected patients. (See the sections on Primary Prevention of Disseminated MAC Infection, under Mycobacterium avium Complex (MAC) Infections, in Uses in Azithromycin 8:12.12.08 and Clarithromycin 8:12.12.08.) Prophylaxis with rifabutin or clarithromycin has been shown to improve survival in patients with advanced HIV infection.43,44,45 (See Primary Prevention of Disseminated MAC Infection, under Management of Other Mycobacterial Diseases: Mycobacterium avium Complex (MAC) Infections, in the Antituberculosis Agents General Statement 8:16.04.)

In controlled studies, patients with AIDS who received primary prophylaxis with rifabutin were one-half to one-third as likely to develop MAC bacteremia and its clinical manifestations as those receiving placebo.1,18,19,23,24,35 In 2 placebo-controlled studies in patients with AIDS20 whose CD4⁺ T-cell counts were 200/mm³ or less, MAC bacteremia occurred in 9-13% of patients receiving rifabutin prophylaxis compared with 22-28% of those receiving placebo.1,23,24,35 In addition, patients given the drug demonstrated fewer manifestations of disseminated MAC infection, including fever, night sweats, weight loss, fatigue, abdominal pain, anemia, and hepatic abnormalities.1,23 Most cases of therapeutic failure (e.g., development of MAC bacteremia despite rifabutin prophylaxis) occurred in patients whose CD4⁺ T-cell count was 100/mm³ or less on enrollment into the study.1,21,23,24 Although mortality rates in the individual studies were not significantly reduced with rifabutin prophylaxis, an analysis of the combined double-blind and open follow-up periods of these studies indicated that prophylaxis with the drug was associated with improved survival over a period of approximately 700 days of follow-up.45

Rifabutin also has been used in conjunction with azithromycin for the prevention of disseminated infection caused by MAC in patients with advanced HIV infection. In a randomized, comparative study in patients with advanced HIV infection (CD4⁺ T-cell counts less than 100/mm³), prophylaxis with rifabutin (300 mg daily), azithromycin (1.2 g once weekly), or both drugs concomitantly was associated with a cumulative incidence of MAC infection at 1 year of 15.3, 7.6, or 2.8%, respectively.46,49 The risk of MAC infection (after adjustment for baseline CD4⁺ counts) in patients receiving azithromycin prophylaxis was 47% lower than that with rifabutin prophylaxis, while prophylaxis with both drugs reduced the risk by 72% compared with rifabutin alone; survival among the 3 groups was similar.49 Although the overall incidence of adverse effects was similar among the 3 groups (i.e., 76, 86, or 90% of patients receiving rifabutin, azithromycin, or combined rifabutin-azithromycin prophylaxis, respectively),49 dose-limiting adverse effects (principally GI effects) occurred more frequently with combined azithromycin-rifabutin prophylaxis than with rifabutin or azithromycin alone.46,49 (See Primary Prevention of Disseminated Mycobacterium avium Complex (MAC) infection, in Uses in Azithromycin 8:12.12.08.)

Current evidence suggests that primary prophylaxis against disseminated MAC infection is superior to efforts aimed at early detection and treatment of the disease in terms of survival benefit.43,50 The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) currently recommends that primary prophylaxis against MAC disease be given to HIV-infected adults and adolescents (13 years of age or older) whose CD4⁺ counts are less than 50/mm³.72 Severely immunocompromised HIV-infected children younger than 13 years of age also should receive primary prophylaxis against MAC disease according to the following age-specific CD4⁺ T-cell counts: children 6-13 years of age, less than 50/mm³; children 2-6 years of age, less than 75/mm³; children 1-2 years of age, less than 500/mm³; and children younger than 1 year of age, less than 750/mm³.72 The USPHS/IDSA currently states that clarithromycin or azithromycin alone is the preferred regimen for primary prophylaxis; alternatively, if these drugs cannot be tolerated, rifabutin may be used alone.72 In selecting a prophylactic regimen, consideration should be given to the potential for clinically important interactions between rifabutin, macrolide antibiotics (e.g., azithromycin, clarithromycin), and other drugs commonly used in HIV-infected patients, including HIV protease inhibitors (e.g., amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) and nonnucleoside reverse transcriptase inhibitors (e.g., delavirdine, efavirenz, nevirapine).41,43,44,51,52,72 (See Drug Interactions: Antiretroviral Agents, and also see Patients Receiving Concurrent Antiretroviral Therapy, under Initial Treatment of Active Tuberculosis: Tuberculosis in HIV-infected Patients, in the Antituberculosis Agents General Statement 8:16.04.) Although the combination of azithromycin and rifabutin is more effective than azithromycin alone, the USPHS/IDSA currently does not recommend routine prophylaxis with the combination because of additional cost, increased incidence of adverse effects, potential for drug interactions, and absence of a difference in survival in patients receiving the combination compared with azithromycin alone.72 In addition, the USPHS/IDSA states that the combination of clarithromycin and rifabutin should not be used for primary MAC prophylaxis since such combined therapy is no more effective than clarithromycin alone and is associated with a higher incidence of adverse effects.72

Before MAC prophylaxis is initiated, patients should be assessed to ensure that they do not have active infection with MAC, M. tuberculosis , or other mycobacterial diseases.35,60,72 If such active disease is present, appropriate anti-infective treatment should be initiated.1,35 Preventive therapy with rifabutin should not be initiated in patients with active M. tuberculosis since administration of the drug as sole antimycobacterial therapy in such patients would likely lead to development of tuberculosis that is resistant to both rifabutin and rifampin.1,23,60 Patients who develop symptoms compatible with active tuberculosis while receiving rifabutin prophylaxis should be evaluated immediately and appropriate therapy instituted with an effective combination of antituberculosis agents.1,23

Current evidence indicates that primary MAC prophylaxis can be discontinued with minimal risk of developing disseminated MAC disease in HIV-infected adults and adolescents who have responded to highly active antiretroviral therapy (HAART) with an increase in CD4⁺ T-cell counts to greater than 100/mm³ that has been sustained for at least 3 months.72 The USPHS/IDSA states that discontinuance of primary prophylaxis is recommended in adults and adolescents meeting these criteria because prophylaxis appears to add little benefit in terms of disease prevention for MAC or bacterial infections, and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.72 However, the USPHS/IDSA states that primary MAC prophylaxis should be restarted in adults and adolescents if CD4⁺ T-cell counts decrease to less than 50-100/mm³.72 (See Primary Prevention of Disseminated MAC Infection, under Management of Other Mycobacterial Diseases: Mycobacterium avium Complex (MAC) Infections, in the Antituberculosis Agents General Statement 8:16.04.)

Treatment and Secondary Prevention of Disseminated MAC Infection

Rifabutin is designated an orphan drug by FDA for use in the treatment or prevention of recurrence of disseminated MAC infections†.17 For information on the use of rifabutin as a component of multiple-drug regimens for the treatment or secondary prevention of disseminated MAC infections, see Treatment or Secondary Prevention of Disseminated MAC Infection, under Management of Other Mycobacterial Diseases: Mycobacterium avium Complex (MAC) Infections, in the Antituberculosis Agents General Statement 8:16.04.

Tuberculosis

Active Tuberculosis

Rifabutin is used as an alternative to rifampin in multiple-drug regimens for the treatment of pulmonary tuberculosis†.65,66,67,82

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis.82 These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).82 Rifabutin is used as an alternative to rifampin and is considered a first-line antituberculosis agent for use in these regimens.82 The ATS, CDC, and IDSA state that use of rifabutin in the treatment of tuberculosis generally should be reserved for use in patients who cannot receive rifampin because of intolerance or because they are receiving other drugs (especially antiretroviral agents) that have a clinically important interaction with rifampin.82 For information on general principles used in the treatment of tuberculosis, see the Antituberculosis Agents General Statement 8:16.04.

Limited data in patients with previously untreated tuberculosis suggest that the efficacy of rifabutin in short-course (6-9-month) antituberculosis regimens compares favorably with that of rifampin in terms of bacteriologic conversion of sputum cultures and clinical improvement.65,66 Results of uncontrolled studies in a limited number of patients also suggest that rifabutin may provide some benefit in patients with multidrug-resistant pulmonary tuberculosis†, including those whose disease is resistant to rifampin and/or isoniazid.65,69,70,71 Additional well-controlled clinical trials are needed to confirm the efficacy of rifabutin for infections in patients with rifampin-resistant strains of M. tuberculosis .64,65

HIV-infected Individuals

Data from a limited number of studies in patients with HIV infection and pulmonary tuberculosis also suggest similar efficacy and safety of short-course (6-month) antituberculosis regimens containing either rifampin or rifabutin in conjunction with isoniazid, ethambutol, and pyrazinamide.65,67 However, there is evidence that use of antituberculosis regimens that include once- or twice-weekly administration of rifamycins (e.g., rifabutin, rifampin, rifapentine) in HIV-infected patients with CD4⁺ T-cell counts less than 100/mm³ is associated with an increased risk of acquired rifamycin resistance.79 Therefore, until additional data are available regarding this issue, the CDC recommends that HIV-infected individuals with CD4⁺ T-cell counts less than 100/mm³ not receive rifamycin regimens for the treatment of active tuberculosis that involve once- or twice-weekly administration.79,82 These individuals should receive daily therapy during the initial phase, and daily or 3-times weekly regimens during the second phase; directly observed therapy also is recommended for both the daily and 3-times weekly regimens.79

The fact that concomitant use of rifamycins and certain antiretroviral agents (e.g., HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors [NNRTIs]) can affect plasma concentrations of the antituberculosis agent and/or the antiretroviral agents must be considered when antituberculosis therapy is indicated for the treatment tuberculosis in HIV-infected patients.67,73 Because of the pharmacokinetic interactions between rifamycins and HIV protease inhibitors or NNRTIs and because rifabutin is a less potent inducer of cytochrome P-450 (CYP) isoenzymes than rifampin, the CDC and other experts previously stated that use of rifampin was contraindicated in patients receiving HIV protease inhibitors or NNRTIs and that use of rifabutin-containing regimens was the preferred alternative for the treatment of active tuberculosis in HIV-infected patients receiving these antiretroviral agents.67 However, the CDC and some experts now suggest that there are specific circumstances when HIV-infected patients with active tuberculosis can receive rifampin concomitantly with certain HIV protease inhibitors or certain NNRTIs.73 Rifampin can be used in patients receiving the following antiretroviral regimens (with appropriate dosage adjustments): efavirenz and 2 nucleoside reverse transcriptase inhibitors; ritonavir and 1 or 2 nucleoside reverse transcriptase inhibitors; or an antiretroviral regimen that includes both ritonavir and saquinavir.73 Rifabutin-containing regimens (with appropriate dosage adjustments) offer an alternative for HIV-infected patients receiving these and other antiretroviral regimens.73 Some advantages of rifabutin-containing antituberculosis regimens in HIV-infected patients include (1) less potential for drug interactions with drugs commonly prescribed in such patients (e.g., protease inhibitors, nonnucleoside reverse transcriptase inhibitors [NNRTIs], azole antifungal drugs, anticonvulsants, methadone), (2) potentially more reliable absorption in patients with advanced HIV disease, and (3) more tolerability in patients with rifampin-induced hepatotoxicity.67 (See Patients Receiving Concurrent Antiretroviral Therapy under Initial Treatment of Active Tuberculosis: Tuberculosis in HIV-Infected Patients, in the Antituberculosis Agents General Statement 8:16.04.)

Latent Tuberculosis Infection

Rifabutin (with appropriate dosage adjustments) is used alone in a 4-month regimen or in conjunction with pyrazinamide in a 2- to 3-month regimen to prevent the development of clinical tuberculosis† in HIV-infected adults and adolescents.67,72 Previously, “preventive therapy” or “chemoprophylaxis” was used to describe a simple drug regimen (e.g., isoniazid monotherapy) used to prevent the development of active tuberculosis disease in individuals known or likely to be infected with M. tuberculosis .73 However, since use of such a regimen rarely results in true primary prevention (i.e., prevention of infection in individuals exposed to infectious tuberculosis), the ATS and CDC currently state that “treatment of latent tuberculosis infection” rather than “preventive therapy” more accurately describes the intended intervention and potentially will result in greater understanding and more widespread implementation of this tuberculosis control strategy.73 (See Uses: Treatment of Latent Tuberculosis Infection, in Isoniazid 8:16.04.)

While therapy with rifabutin in tuberculin-positive patients with HIV infection has not been evaluated in clinical trials, the ATS and CDC state that the use of rifabutin in these short-course, multiple-drug regimens for treatment of latent tuberculosis infection is valid for the same scientific principles that support its use in the treatment of active tuberculosis.67,73 When use of rifabutin is being considered for the treatment of latent tuberculosis infection in HIV-infected patients, the possibility that drug regimens or dosages may have to be altered because of clinically important pharmacokinetic interactions between rifabutin and certain antiretroviral agents (e.g., HIV protease inhibitors, NNRTIs) should be considered.67 (See Drug Interactions: Antiretroviral Agents.)

Administration

Rifabutin is administered orally.1 Administration of rifabutin with a high-fat meal decreases the rate but not the extent of absorption.1,22 Therefore, the drug generally can be given orally without regard to meals.22

Dosage

Mycobacterium avium Complex (MAC) Infection

The usual dosage of rifabutin for primary prevention of M. avium complex (MAC) infection in adults and adolescents with advanced HIV infection is 300 mg once daily.1,35,72 Rifabutin in this dosage may be administered alone or concomitantly with the recommended dosage of azithromycin (1200 mg once weekly) for MAC prophylaxis.47,49,59,72 In patients who have a propensity to develop nausea, vomiting, or other GI upset, rifabutin may be administered with food and the dosage given as 150 mg twice daily.1

When indicated for the prevention of recurrence of disseminated MAC infection (secondary prophylaxis or maintenance therapy)†, the Prevention of Opportunistic Infections Working Group of the US Public health Service and the Infectious Diseases Society of America (USPHS/IDSA) states that HIV-infected adults and adolescents can receive rifabutin in a dosage of 300 mg once daily in conjunction with azithromycin (500 mg once daily) or clarithromycin (500 mg twice daily) and ethambutol (15 mg/kg once daily).72

Steady-state pharmacokinetics of rifabutin are more variable in geriatric patients older than 70 years of age and in symptomatic HIV-infected patients than in younger or healthy individuals.1 However, the manufacturer makes no specific recommendations for dosage adjustment in such patients.1 Steady-state pharmacokinetics of the drug during early stages of symptomatic HIV infection reportedly are similar to those in healthy individuals.1

The manufacturer states that safety and efficacy of rifabutin for MAC prophylaxis in children have not been established;1 however, rifabutin has been used in a limited number of children (concomitantly with other antimycobacterial agents) for the treatment of MAC infection without unusual adverse effect.1,35 Although rifabutin dosages averaging 18.5 mg/kg (up to 25 mg/kg) or 8.6 mg/kg (up to 18.6 mg/kg) daily have been used for active treatment in infants 1 year of age or children 2-10 years of age, respectively, the manufacturer states that there is no evidence that dosages exceeding 5 mg/kg daily are required for MAC infection.1 The USPHS/IDSA states that HIV-infected children 6 years of age or older may receive rifabutin in a dosage of 300 mg once daily for primary MAC prophylaxis† as an alternative to the regimen of choice (azithromycin or clarithromycin monotherapy).72 If rifabutin is used in conjunction with clarithromycin (or azithromycin) and ethambutol for secondary MAC prophylaxis† in children, the USPHS/IDSA recommends a rifabutin dosage of 5 mg/kg (maximum 300 mg) once daily in conjunction with azithromycin 5 mg/kg (maximum 250 mg) once daily and ethambutol 15 mg/kg (maximum 900 mg) once daily.72

Active Tuberculosis

In the treatment of clinical tuberculosis†, rifabutin should not be given alone.82 The drug is considered a first-line agent for use in multiple-drug regimens in patients with pulmonary tuberculosis who cannot receive rifampin because of intolerance or because they are receiving other drugs (especially antiretroviral agents) that have a clinically important interaction with rifampin.82 Therapy for tuberculosis should be continued long enough to prevent relapse. The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).82 However, completion of treatment is determined more accurately by the total number of doses and is not based solely on the duration of therapy.82 For information on general principles of antituberculosis therapy and recommendations regarding specific multiple-drug regimens and duration of therapy, see the Antituberculosis Agents General Statement 8:16.04.

Adult Dosage

When rifabutin is used in conjunction with other antituberculosis agents for the treatment of tuberculosis, the American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), Infectious Diseases Society of America (IDSA), and others recommend that adults and children 15 years of age or older receive a dosage of 5 mg/kg (up to 300 mg) given once daily or 5 mg/kg (up to 300 mg) given 2 or 3 times weekly.65,66,67,82

The fact that rifabutin dosage may need to be altered if the drug is used for the treatment of tuberculosis in HIV-infected individuals receiving certain antiretroviral agents (e.g., HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors) should be considered.82 (See Drug Interactions: Antiretroviral Agents.) In addition, because of concerns that there may be an increased risk of acquired rifamycin resistance in HIV-infected individuals with CD4⁺ T-cell counts less than 100/mm³ who receive intermittent rifamycin regimens, the ATS, CDC, and IDSA recommend that rifabutin be administered once daily or 3-times weekly and that rifabutin regimens that involve once- or twice-weekly administration be avoided in these HIV-infected individuals pending further accumulation of data.79,82 The CDC also recommends directly observed therapy (DOT) for both the daily and 3-times weekly regimens.79,82 (See Initial Treatment of Tuberculosis: Tuberculosis in HIV-Infected Patients, under General Principles in Antituberculosis Therapy in the Antituberculosis Agents General Statement 8:16.04.)

Pediatric Dosage

The ATS, CDC, and IDSA state that the appropriate dosage of rifabutin for use in conjunction with other antituberculosis agents for the treatment of tuberculosis in children has not been identified.82 However, the CDC has stated that a rifabutin dosage of 10-20 mg/kg (up to 300 mg) can be given daily or twice weekly in conjunction with other antituberculosis agents for the treatment of tuberculosis in children with HIV infection†.67

Latent Tuberculosis Infection

If rifabutin is used as monotherapy for the treatment of latent tuberculosis infection† in HIV-infected adults and adolescents, the recommended rifabutin dosage is 300 mg once daily for 4 months;72 some experts recommend that rifabutin monotherapy be continued for 4-6 months in HIV-infected individuals.67 When rifabutin is used in conjunction with pyrazinamide for the treatment of latent tuberculosis infection in HIV-infected adults and adolescents, the usual dosage of rifabutin is 300 mg once daily for 2-3 months.67,72

Dosage in Renal Impairment

Rifabutin concentrations reportedly are decreased in patients with impaired renal function as a result of decreased distribution and more rapid elimination of the drug.1 However, the clinical importance, if any, of this finding has not been determined, and the manufacturer currently makes no specific recommendations for modification of dosage in such patients.1

Rifabutin generally was well tolerated in controlled clinical trials.1,23 The most common adverse effects, including those that most frequently result in discontinuance of the drug, are rash, GI intolerance, and neutropenia.1,23 In controlled clinical trials in patients with severe HIV infection, adverse effects severe enough to require discontinuance occurred in 16% of patients receiving rifabutin and 8% of those receiving placebo.1,23 There is some evidence that adverse effects of rifabutin may be dose related.25,26,27 Because most HIV-infected patients receiving rifabutin to date have had serious underlying disease with multiple baseline symptomatology and clinical abnormalities and because many adverse effects that occurred in rifabutin-treated patients also occurred in patients receiving placebo, many reported effects may not be directly attributable to rifabutin.23,25 Adverse effects were reported in 51% of patients receiving rifabutin and 50% of those receiving placebo in controlled clinical trials.23

Hematologic Effects

The most common adverse effect of rifabutin is neutropenia (absolute neutrophil count [ANC] less than 750/mm³), which occurred in 25% of patients with severe HIV infection receiving the drug in controlled clinical trials.1 Neutropenia occurred substantially more frequently in patients receiving rifabutin than in those receiving placebo.1 Neutropenia resulted in discontinuance of rifabutin therapy in 2% of patients receiving the drug in controlled clinical trials.1,23 Leukopenia (white blood cell [WBC] count less than 1500/mm³) was reported in 17% of patients, anemia (hemoglobin concentration less than 8 g/dL) in 6%, and thrombocytopenia (platelet count less than 50,000/mm³) in 5% of patients receiving rifabutin in controlled clinical trials.1 Although the frequency of thrombocytopenia in rifabutin-treated patients was not substantially greater than in patients receiving placebo, rifabutin has been clearly associated with thrombocytopenia in rare cases.1 Eosinophilia occurred in 1% of patients receiving rifabutin in controlled clinical trials.1 Hemolysis was reported in less than 1% of patients.1 Thrombotic thrombocytopenic purpura, which was attributed to rifabutin, was reported in a patient receiving the drug in a controlled clinical trial.1

Dermatologic and Hypersensitivity Reactions

The most frequent adverse dermatologic effect of rifabutin is rash,1,2,23 which occurred in 11% of patients with severe HIV infection receiving the drug in controlled clinical trials.1 Rash resulted in discontinuance of the drug in 4% of patients in controlled clinical trials.1,23 Skin discoloration1,27 and a flu-like syndrome1 each occurred in less than 1% of patients receiving rifabutin in controlled clinical trials.1 Rifabutin-induced skin discoloration may be orange27 or yellow30 in appearance, similar to that occurring with jaundice (pseudojaundice),30 but buccal or scleral mucosa is not affected.27,30 The discoloration generally is not associated with pruritus27,30 or other symptoms30 and subsides slowly after discontinuance of the drug.27

GI Effects

Nausea1,2 occurred in 6%,1 nausea and vomiting in 3%,1 and vomiting1,2 in 1% of patients with severe HIV infection1 receiving rifabutin in controlled clinical trials.1 Abdominal pain occurred in 4% of patients1 and taste perversion,1,23 diarrhea,1,2 dyspepsia,1 and eructation1,23 each occurred in 3% of patients receiving the drug in controlled clinical trials.1 Ageusia, which subsided with discontinuance of therapy, has been reported rarely.28 Anorexia and flatulence each occurred in 2% of patients receiving rifabutin in controlled clinical trials.1 GI intolerance to rifabutin resulted in discontinuance of the drug in 3% of patients in controlled clinical trials.1,23 In patients who have a propensity to develop nausea, vomiting, or other GI upset, rifabutin may be administered with food and the total daily dosage may be given as two divided doses.1

Rifabutin-associated diarrhea and pseudomembranous colitis, caused by overgrowth of toxin-producing clostridia (e.g., C. difficile ), have been reported rarely.29 Aphthous stomatitis also has been reported rarely in patients receiving high dosages of the drug.27

Nervous System Effects

Headache occurred in 3% of patients with severe HIV infection receiving rifabutin in controlled clinical trials.1 Fever1,23 occurred in 2% of patients1 and asthenia, insomnia, and nonspecific complaints of pain each occurred in 1% of patients receiving the drug.1 Although a causal relationship to rifabutin has not been established,1 seizures,1,27 paresthesia,1 aphasia,1 and confusion1 have been reported in patients receiving the drug.

Musculoskeletal Effects

Myalgia1,23 occurred in 2% of patients with severe HIV infection receiving rifabutin in controlled clinical trials.1 Arthralgia and myositis each occurred in less than 1% of patients receiving the drug.1,23,26 The risk of rifabutin-induced arthralgia appears to be greatest in patients receiving a dosage of 1050 mg daily or higher.1,27 The arthralgia commonly involves the small joints of the hand and usually involves many joints; in some patients, periarticular swelling or joint tenderness may be present.27 The arthralgia was reversible following discontinuance of the drug.1,27

Ocular Effects

Uveitis, which may be unilateral or bilateral27,30,31,32 and is characterized by pain, redness, and possible temporary or permanent loss of vision,27,31,32,33 may occur occasionally in patients receiving rifabutin 300-900 mg daily in combination with other agents,1,27,30,31,32,33,34 particularly clarithromycin31,33 and/or fluconazole32,33 . (See Cautions: Precautions and Contraindications.) Uveitis also has occurred in association with arthralgia in a few patients receiving high dosages of the drug.27 In a patient receiving 2400 mg of rifabutin daily, severe uveitis manifested as unilateral panophthalmitis and reversible blindness responded slowly (over 6 weeks) to systemic corticosteroids and permanent discontinuance of rifabutin.27

Rifabutin-induced uveitis occurs rarely when the drug is used as sole antimycobacterial therapy at the usual prophylactic dosage (i.e., 300 mg daily) for the prevention of M. avium complex (MAC) infections in patients with advanced HIV infection, even in combination with macrolide antibiotics or fluconazole.33 The risk of uveitis appears to be greatest in patients receiving higher dosages of rifabutin in combination with macrolide antibiotics (e.g., clarithromycin) or fluconazole, probably in part because of inhibition of rifabutin metabolism by these drugs and resulting increased plasma rifabutin concentrations.31,32,33,53,54,55,56,57,58 (See Drug Interactions: Rifabutin and Rifampin, in Clarithromycin 8:12.12.08 and in Fluconazole 8:14.08.) Mild to severe symptoms associated with the uveitis usually have resolved following discontinuance of rifabutin and treatment with topical corticosteroids and/or mydriatics;27,30,31,32,33 in severe cases, resolution of manifestations may require more aggressive therapy and be delayed for several weeks.27,32,33 If uveitis occurs in patients receiving rifabutin, the drug should be discontinued temporarily and the patient should have an ophthalmologic evaluation.30,33 In most mild cases, rifabutin therapy subsequently may be reinstituted; however, if signs or symptoms recur, the drug should be discontinued immediately.1,33

Brown-orange discoloration of tears may occur during rifabutin therapy.1 In addition, permanent discoloration of soft contact lenses may occur.1

Hepatic Effects

Increased serum concentrations of ALT (SGPT) and AST (SGOT)1,27 (exceeding 150 U/L) occurred in 9 and 7% of patients with severe HIV infection, respectively, receiving rifabutin in controlled clinical trials.1 Increased serum alkaline phosphatase concentrations (exceeding 450 U/L) occurred in less than 1% of rifabutin-treated patients in controlled clinical trials.1 Hepatitis1,27 was reported in less than 1% of patients receiving the drug.1

Other Adverse Effects

Brown-orange discoloration of urine is common during rifabutin therapy.1,23 In controlled trials, such discoloration of urine was observed in 30% of patients,23 and should be anticipated.1,23 (See Cautions: Precautions and Contraindications.)

Chest pain occurred in 1% of patients with severe HIV infection receiving rifabutin in controlled clinical trials.1 Chest pressure or pain with dyspnea was reported in less than 1% of patients receiving the drug.1 Although a causal relationship to rifabutin has not been established, nonspecific T-wave changes on ECG have been reported in patients receiving the drug.1

Precautions and Contraindications

Because rifabutin may cause neutropenia or other adverse hematologic effects (e.g., thrombocytopenia), hematologic status should be monitored periodically during therapy with the drug.1

Patients receiving rifabutin should be advised regarding manifestations of MAC infection and those of tuberculosis and to contact a physician if either develops or worsens during therapy with the drug.1

The manufacturer states that preventive therapy with rifabutin should not be initiated in patients with active M. tuberculosis since administration of the drug as sole antimycobacterial therapy in such patients would likely lead to development of tuberculosis that is resistant to both rifabutin and rifampin.1 Patients who develop symptoms compatible with active tuberculosis while receiving rifabutin prophylaxis should be evaluated immediately and appropriate therapy instituted with an effective combination of antituberculosis agents.1

Because uveitis may occur in patients receiving rifabutin, patients should be instructed to report to their physician manifestations such as eye pain, redness, or loss of vision which may be indicative of the inflammatory ocular condition.1,33 If uveitis occurs in patients receiving rifabutin, the drug should be discontinued temporarily and the patient should have an ophthalmologic evaluation.30,33 Appropriate treatment should be initiated as necessary.27,30,31,32,33 In most mild cases, rifabutin therapy subsequently may be reinstituted; however, if signs or symptoms recur, the drug should be discontinued immediately.1,33 Permanent discontinuance of the drug may be necessary if uveitis is severe.27

A drug-induced lupus syndrome manifested principally by malaise, myalgias, arthritis, and peripheral edema has been reported in a few patients receiving rifabutin or rifampin concomitantly with ciprofloxacin and/or clarithromycin, known inhibitors of the hepatic P-450 enzyme system.68 (See Drug Interactions: Hepatic Microsomal Enzyme Induction, in Rifampin 8:16.04.)Careful surveillance for drug-induced lupus syndrome is advised when ciprofloxacin and/or clarithromycin are used concomitantly with a rifamycin.68 When rifabutin is administered to patients receiving oral contraceptives, consideration should be given to changing to a nonhormonal contraceptive method.1 Unlike rifampin, rifabutin does not appear to affect the acetylation of isoniazid.1

Pharmacokinetic interactions between rifamycin derivatives (e.g., rifabutin, rifampin) and HIV protease inhibitors (e.g., amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) or nonnucleoside reverse transcriptase inhibitors (e.g., delavirdine, efavirenz, nevirapine) have been reported or are expected to occur, which may complicate drug therapy for mycobacterial infections in HIV-infected patients.41,43,44,51,53 (See Drug Interactions: Antiretroviral Agents) and also see Treatment in Patients Receiving Concurrent Antiretroviral Therapy, under Initial Treatment of Active Tuberculosis: Tuberculosis in HIV-infected Patients, in the Antituberculosis Agents General Statement 8:16.04.)

Patients should be instructed to report to their physician manifestations such as joint stiffness, swelling, or tenderness or paresthesia which may be indicative of arthralgias or myositis.1

Patients receiving rifabutin should be advised that the drug and its metabolites may impart a brown-orange color to urine, feces, saliva, sputum, perspiration, tears, and skin and that soft contact lenses worn during such therapy may be stained permanently.1,23

Rifabutin is contraindicated in patients who have had clinically important hypersensitivity to the drug or to any other rifamycin (e.g., rifampin).1

Pediatric Precautions

The manufacturer states that safety and efficacy of rifabutin for prophylaxis against MAC infection in children have not been established.1 However, rifabutin reportedly has been used in a limited number of children (concomitantly with other antimycobacterial agents) for the treatment of MAC infection.1,35 Adverse effects reported were similar to those observed in adults and included leukopenia, neutropenia, and rash.1 In addition, rifabutin (5 mg/kg daily) was administered to a 3-month-old infant in combination with ethambutol as prophylaxis against MAC infection for 64 days without adverse effects.34

Geriatric Precautions

Although steady-state pharmacokinetics of rifabutin are more variable in geriatric individuals older than 70 years of age, the manufacturer makes no specific recommendations for dosage adjustment or monitoring precautions in such patients.1

Mutagenicity and Carcinogenicity

There was no evidence of mutagenicity when rifabutin was tested in vitro with the bacterial mutation assay (Ames test) using rifabutin-susceptible and -resistant strains.1 In addition, rifabutin was not mutagenic when tested in vitro using Schizosaccharomyces pombe P1 and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo.1

Long-term studies in mice using rifabutin dosages up to 180 mg/kg daily (36 times the recommended human daily dosage) and in rats using rifabutin dosages up to 60 mg/kg daily (12 times the recommended human daily dosage) have not revealed evidence of carcinogenicity.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using rifabutin dosages up to 200 mg/kg daily (40 times the recommended human daily dosage) did not reveal evidence of teratogenicity.1 In rats receiving 200 mg/kg daily, decreased fetal viability occurred.1 An increase in fetal skeletal variants was observed in rats receiving rifabutin dosages of 40 mg/kg daily (8 times the recommended human daily dosage).1 In rabbits receiving rifabutin dosages of 80 mg/kg daily (16 times the recommended human daily dosage), maternotoxicity and an increase in fetal skeletal anomalies occurred.1 There are no adequate and controlled studies to date using rifabutin in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1 The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that data are insufficient to date to recommend use of rifabutin in pregnant women.82

Fertility

Reproduction studies in male rats using rifabutin dosages of 160 mg/kg daily (32 times the recommended human daily dosage) revealed evidence of impaired fertility.1

Lactation

It is not known whether rifabutin is distributed into human milk.1 Because of the potential for serious adverse reactions to rifabutin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Rifabutin, like other rifamycins (e.g., rifampin) can induce hepatic microsomal enzymes which may result in drug interactions.1 Because of the structural similarity between rifampin and rifabutin and because rifampin is known to interact with numerous other drugs, rifabutin may be anticipated to have some effects on drugs known to be affected by rifampin (e.g., ketoconazole, cyclosporine, oral contraceptives).1,23 (See Drug Interactions in Rifampin 8:16.04.) In healthy individuals, rifabutin appears to induce hepatic microsomal enzymes to a lesser extent than rifampin, although the clinical relevance of this finding for drug interactions is not known.1,23

Antiretroviral Agents

Limited data suggest that rifamycin derivatives (e.g., rifabutin, rifampin) accelerate the metabolism of certain antiretroviral agents (i.e., HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors [NNRTIs]) by induction of hepatic cytochrome P-450 (CYP) oxidases, which may result in subtherapeutic plasma concentrations of some of these HIV protease inhibitors and NNRTIs.37,61,62,67,74,77,78,81 In addition, some HIV protease inhibitors and some NNRTIs (e.g., delavirdine) can reduce the metabolism of rifamycins, leading to increased plasma concentrations of rifamycins and an increased risk of toxicity37,48,61,62,63,67,74 and some other NNRTIs (e.g., efavirenz) can decrease plasma concentrations of rifabutin.75 The potential for alterations in the plasma concentrations of the antimycobacterial agents and/or HIV protease inhibitors or NNRTIs must be considered when antimycobacterial agents are indicated for the management of latent or active tuberculosis or the prophylaxis or treatment of Mycobacterium avium complex (MAC) infections in HIV-infected patients who are receiving or are being considered for antiretroviral therapy.36,67 Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.36,67

HIV Protease Inhibitors

Concomitant use of amprenavir and rifabutin can affect the pharmacokinetics of both drugs, resulting in a decrease in the area under the plasma concentration-time curve (AUC) of the protease inhibitor and a substantial increase in plasma concentrations and AUC of rifabutin.37,81 Because of this pharmacokinetic interaction, the manufacturer of amprenavir states that rifabutin dosage should be reduced to at least 50% of the usual dosage when concomitant use with amprenavir is necessary, and complete blood cell counts (CBCs) should be performed weekly and as clinically indicated to monitor for neutropenia.37 Although there is no published clinical experience, some experts state that usual dosage of amprenavir can be used concomitantly with a reduced dosage of rifabutin (150 mg once daily or 300 mg 2 or 3 times weekly) is a possibility.36,72,81

Concomitant use of atazanavir sulfate and rifabutin results in increased serum concentrations of rifabutin and its metabolite.80 The manufacturer of atazanavir recommends that the rifabutin dosage be reduced up to 75% (e.g., 150 mg every other day or 3 times weekly) in patients receiving atazanavir.80

Concomitant use of indinavir and rifabutin results in a decrease in the AUC of indinavir and a substantial increase in the AUC of rifabutin.61 Because of this pharmacokinetic interaction, the manufacturer of indinavir and some experts recommend that the dosage of indinavir be increased to 1000 mg every 8 hours and that the dosage of rifabutin be reduced by 50%61 (e.g., 150 mg once daily or 300 mg 2-3 times weekly) in patients receiving the drugs concomitantly.36 72,81 Some experts state that there is limited, but favorable, clinical experience with this dosage regimen.36

Concomitant use of lopinavir and rifabutin results in increased concentrations of rifabutin and its metabolite.48,81 The manufacturer of the fixed combination containing lopinavir and ritonavir and some clinicians recommend that the rifabutin dosage be reduced by at least 75%48 to a maximum of 150 mg every other day or 3 times weekly in patients receiving lopinavir and ritonavir.48,72,81 Increased monitoring for adverse effect is warranted in patients receiving the fixed combination and rifabutin concomitantly, and further reductions in rifabutin dosage may be necessary.48

Concomitant use of nelfinavir and rifabutin can result in alterations in the pharmacokinetics of both drugs.62,81 Because of the pharmacokinetic interaction between rifabutin and nelfinavir, the manufacturer of nelfinavir recommends that rifabutin dosage be decreased to 50% of the usual dosage in patients receiving nelfinavir and that a twice-daily regimen of nelfinavir (1250 mg twice daily) is the preferred regimen for patients receiving concomitant rifabutin.62 Some experts recommend increasing nelfinavir dosage to 1000 mg 3 times daily and decreasing rifabutin dosage to 150 mg once daily or 300 mg 3 times weekly.36,81 Others state that there is limited, but favorable, clinical experience with concomitant use of nelfinavir with a rifabutin dosage of 150 mg once daily or 300 mg 2 or 3 times weekly for the treatment of tuberculosis.36,72

If ritonavir is used concomitantly with rifabutin, the manufacturer of ritonavir and some experts recommend that rifabutin dosage be decreased by at least 75% (e.g., reduced to 150 mg every other day or 3 times weekly);63,81 further dosage reduction may be needed.63 For the treatment of tuberculosis, some experts state that the need to use substantially reduced rifabutin dosage (150 mg 2 or 3 times weekly) is certain in tuberculosis patients receiving ritonavir concomitantly with another HIV protease inhibitor (e.g., saquinavir).36

The manufacturer of saquinavir and some experts state that use of alternatives to rifabutin should be considered in patients receiving saquinavir hard gelatin capsules or liquid-filled (soft gelatin) capsules.77,78,81 Although pharmacokinetic data and clinical experience are limited, some experts state that concomitant use of saquinavir hard gelatin capsules and rifabutin is a possibility, provided the antiretroviral regimen also includes ritonavir and the rifabutin dosage is decreased to 150 mg 2 or 3 times weekly.36 Although pharmacokinetic data and clinical experience is limited, these experts state that saquinavir liquid-filled capsules probably may be given concomitantly with a rifabutin dosage of 300 mg daily or 300 mg 2 or 3 times weekly for the treatment of tuberculosis; however, rifabutin dosage should be decreased to 150 mg 2 or 3 times weekly if the antiretroviral regimen also contains ritonavir.36

For specific information on the pharmacokinetic interactions between HIV protease inhibitors and rifabutin, see Antimycobacterial Agents under Drug Interactions: Anti-infective Agents, in the individual monographs in 8:18.08.08.

Nonnucleoside Reverse Transcriptase Inhibitors

Concomitant use of rifabutin and delavirdine is not recommended.36,74,81

The manufacturer of efavirenz states that the daily dosage of rifabutin should be increased by 50% in patients receiving efavirenz and that consideration should be given to doubling the rifabutin dose used in 2- or 3-times weekly regimens if efavirenz is used concomitantly.75 Some experts state that concomitant use of efavirenz with a rifabutin dosage of 450-600 mg daily or 600 mg 2 or 3 times weekly is a possibility,36,72,81 provided that the antiretroviral regimen does not include an HIV protease inhibitor.81

The manufacturer of nevirapine states that concomitant use with rifabutin results in moderate increases in serum concentrations of the antimycobacterial agent and its metabolite; however, because of high interindividual variability, some patients may experience large increases in rifabutin concentrations and may be at higher risk of rifabutin toxicity.76 Therefore, caution is advised if nevirapine is used concomitantly with rifabutin.76 Although there is no published clinical experience regarding concomitant use of rifabutin and nevirapine, some experts suggest that, based on pharmacokinetic data, concomitant use of nevirapine with a rifabutin dosage of 300 mg daily or 2 or 3 times weekly is a possibility.36,72 Other experts state that no dosage adjustments are needed if nevirapine is used concomitantly with rifabutin, provided the antiretroviral regimen does not include an HIV protease inhibitor.81

For specific information on the pharmacokinetic interactions between nonnucleoside reverse transcriptase inhibitors and rifabutin, see Antimycobacterial Agents under Drug Interactions: Anti-infective Agents, in the individual monographs in 8:18.08.16.

Nucleoside Reverse Transcriptase Inhibitors

In HIV-infected patients receiving rifabutin (300 mg daily) and zidovudine (200 mg every 8 hours) concomitantly for 14 days, the mean elimination half-life of zidovudine decreased by 28% (from 1.5 to 1.1 hours); however, concomitant use of the drugs for 7 or 14 days did not substantially alter AUC, peak plasma drug concentration, or other pharmacokinetic parameters of zidovudine (i.e., less than 25% change in these parameters), and zidovudine dosage requirements are not expected to be altered by such concomitant therapy.38 In another study in HIV-infected patients designed to evaluate the effect of zidovudine on rifabutin pharmacokinetics, concomitant use of zidovudine (100 or 200 mg every 4 hours) and rifabutin (300 or 450 mg once daily) did not alter the pharmacokinetics of the antimycobacterial agent or its principal metabolite, and such use was not associated with any unusual adverse effects.39 In vitro studies indicate that rifabutin does not affect the inhibition of HIV by zidovudine.1

Following addition of rifabutin to therapy with didanosine (167-375 mg daily given in 2 divided doses) in HIV-infected patients, no clinically important changes in the pharmacokinetics of either drug were observed.1,40

Description

Rifabutin, a semisynthetic spiropiperidyl derivative of rifamycin S, is an ansamycin antibiotic.1,2,3,4,5,6,7,8 The drug is active in vitro1,2,4,6,7,8,9,10,11,12 and in vivo1,2,10,11,12,13,14 against Mycobacterium avium complex (MAC), including isolates obtained from patients with acquired immunodeficiency syndrome (AIDS). The MIC₉₀ of rifabutin for susceptible MAC isolates is approximately 1 mcg/mL.4,6,11 The drug also is active against most other mycobacteria, including M. leprae 15 and M. tuberculosis ; some rifampin-resistant strains of M. tuberculosis are susceptible to rifabutin.1,2,3,4,5,7,8,12,14,64 Rifabutin has a spectrum of in vitro activity similar to that of rifampin against gram-positive and gram-negative organisms.2,16

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Pharmacia & Upjohn. Mycobutin^® (rifabutin) capsules prescribing information. Kalamazoo, MI; 1996 Apr.

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52. The Indinavir (MK 639) Pharmacokinetic Study Group. Indinavir (MK 629) drug interaction studies. Presented at the XI International Conference on AIDS. Vancouver, BC, July 8, 1996.

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75. Bristol-Myers Squibb. Sustiva^® (efavirenz capsules) prescribing information. Princeton, NJ; 2003 Apr.

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78. Roche. Fortovase^® (saquinavir) soft gelatin capsules prescribing information. Nutley, NJ; 2002 Jul.

79. Centers for Disease Control and Prevention. Notice to readers: acquired rifamycin resistance in persons with advanced HIV disease treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR

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