Rifabutin, a semisynthetic spiropiperidyl derivative of rifamycin S, is an ansamycin antibiotic. The drug is active in vitro and in vivo 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. The drug also is active against most other mycobacteria, including M. leprae and M. tuberculosis; some rifampin-resistant strains of M. tuberculosis are susceptible to rifabutin. Rifabutin has a spectrum of in vitro activity similar to that of rifampin against gram-positive and gram-negative organisms.
SumMon®. For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity.
Cautions
Rifabutin generally was well tolerated in controlled clinical trials. The most common adverse effects, including those that most frequently result in discontinuance of the drug, are rash, GI intolerance, and neutropenia. 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.
There is some evidence that adverse effects of rifabutin may be dose related. 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. Adverse effects were reported in 51% of patients receiving rifabutin and 50% of those receiving placebo in controlled clinical trials.
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. Neutropenia occurred substantially more frequently in patients receiving rifabutin than in those receiving placebo. Neutropenia resulted in discontinuance of rifabutin therapy in 2% of patients receiving the drug in controlled clinical trials. 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. 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. Eosinophilia occurred in 1% of patients receiving rifabutin in controlled clinical trials. Hemolysis was reported in less than 1% of patients. Thrombotic thrombocytopenic purpura, which was attributed to rifabutin, was reported in a patient receiving the drug in a controlled clinical trial.
Dermatologic and Hypersensitivity Reactions
The most frequent adverse dermatologic effect of rifabutin is rash, which occurred in 11% of patients with severe HIV infection receiving the drug in controlled clinical trials. Rash resulted in discontinuance of the drug in 4% of patients in controlled clinical trials. Skin discoloration and a flu-like syndrome each occurred in less than 1% of patients receiving rifabutin in controlled clinical trials. Rifabutin-induced skin discoloration may be orange or yellow in appearance, similar to that occurring with jaundice (pseudojaundice), but buccal or scleral mucosa is not affected. The discoloration generally is not associated with pruritus or other symptoms and subsides slowly after discontinuance of the drug.
GI Effects
Nausea occurred in 6%, nausea and vomiting in 3%, and vomiting in 1% of patients with severe HIV infection receiving rifabutin in controlled clinical trials. Abdominal pain occurred in 4% of patients and taste perversion, diarrhea, dyspepsia, and eructation each occurred in 3% of patients receiving the drug in controlled clinical trials. Ageusia, which subsided with discontinuance of therapy, has been reported rarely. Anorexia and flatulence each occurred in 2% of patients receiving rifabutin in controlled clinical trials. GI intolerance to rifabutin resulted in discontinuance of the drug in 3% of patients in controlled clinical trials. 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.
Rifabutin-associated diarrhea and pseudomembranous colitis, caused by overgrowth of toxin-producing clostridia (e.g., C. difficile), have been reported rarely. Aphthous stomatitis also has been reported rarely in patients receiving high dosages of the drug.
Nervous System Effects
Headache occurred in 3% of patients with severe HIV infection receiving rifabutin in controlled clinical trials. Fever occurred in 2% of patients and asthenia, insomnia, and nonspecific complaints of pain each occurred in 1% of patients receiving the drug. Although a causal relationship to rifabutin has not been established, seizures, paresthesia, aphasia, and confusion have been reported in patients receiving the drug.
Musculoskeletal Effects
Myalgia occurred in 2% of patients with severe HIV infection receiving rifabutin in controlled clinical trials. Arthralgia and myositis each occurred in less than 1% of patients receiving the drug. The risk of rifabutin-induced arthralgia appears to be greatest in patients receiving a dosage of 1050 mg daily or higher. 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. The arthralgia was reversible following discontinuance of the drug.
Ocular Effects
Uveitis, which may be unilateral or bilateral and is characterized by pain, redness, and possible temporary or permanent loss of vision, may occur occasionally in patients receiving rifabutin 300-900 mg daily in combination with other agents, particularly clarithromycin and/or fluconazole. (See Cautions: Precautions and Contraindications.) Uveitis also has occurred in association with arthralgia in a few patients receiving high dosages of the drug. 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.
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. 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. Mild to severe symptoms associated with the uveitis usually have resolved following discontinuance of rifabutin and treatment with topical corticosteroids and/or mydriatics; in severe cases, resolution of manifestations may require more aggressive therapy and be delayed for several weeks. If uveitis occurs in patients receiving rifabutin, the drug should be discontinued temporarily and the patient should have an ophthalmologic evaluation. In most mild cases, rifabutin therapy subsequently may be reinstituted; however, if signs or symptoms recur, the drug should be discontinued immediately.
Brown-orange discoloration of tears may occur during rifabutin therapy. In addition, permanent discoloration of soft contact lenses may occur.
Hepatic Effects
Increased serum concentrations of ALT (SGPT) and AST (SGOT) (exceeding 150 U/L) occurred in 9 and 7% of patients with severe HIV infection, respectively, receiving rifabutin in controlled clinical trials. Increased serum alkaline phosphatase concentrations (exceeding 450 U/L) occurred in less than 1% of rifabutin-treated patients in controlled clinical trials. Hepatitis was reported in less than 1% of patients receiving the drug.
Other Adverse Effects
Brown-orange discoloration of urine is common during rifabutin therapy. In controlled trials, such discoloration of urine was observed in 30% of patients, and should be anticipated.
Chest pain occurred in 1% of patients with severe HIV infection receiving rifabutin in controlled clinical trials. Chest pressure or pain with dyspnea was reported in less than 1% of patients receiving the drug. Although a causal relationship to rifabutin has not been established, nonspecific T-wave changes on ECG have been reported in patients receiving the drug.
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.
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.
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. 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.
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. If uveitis occurs in patients receiving rifabutin, the drug should be discontinued temporarily and the patient should have an ophthalmologic evaluation. Appropriate treatment should be initiated as necessary. In most mild cases, rifabutin therapy subsequently may be reinstituted; however, if signs or symptoms recur, the drug should be discontinued immediately. Permanent discontinuance of the drug may be necessary if uveitis is severe.
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. (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. When rifabutin is administered to patients receiving oral contraceptives, consideration should be given to changing to a nonhormonal contraceptive method. Unlike rifampin, rifabutin does not appear to affect the acetylation of isoniazid.
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.
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.
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.
Rifabutin is contraindicated in patients who have had clinically important hypersensitivity to the drug or to any other rifamycin (e.g., rifampin).
Pediatric Precautions
The manufacturer states that safety and efficacy of rifabutin for prophylaxis against MAC infection in children have not been established. However, rifabutin reportedly has been used in a limited number of children (concomitantly with other antimycobacterial agents) for the treatment of MAC infection. Adverse effects reported were similar to those observed in adults and included leukopenia, neutropenia, and rash. 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.
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.
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. 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.
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.
Pregnancy, Fertitlity 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. In rats receiving 200 mg/kg daily, decreased fetal viability occurred. 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). 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. 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. 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.
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.
Lactation
It is not known whether rifabutin is distributed into human milk. 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.
Drug Interactions
Rifabutin, like other rifamycins (e.g., rifampin) can induce hepatic microsomal enzymes which may result in drug interactions. 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).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.
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. 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 toxicity and some other NNRTIs (e.g., efavirenz) can decrease plasma concentrations of rifabutin. 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. 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.
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. 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. 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.
Concomitant use of atazanavir sulfate and rifabutin results in increased serum concentrations of rifabutin and its metabolite. 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.
Concomitant use of indinavir and rifabutin results in a decrease in the AUC of indinavir and a substantial increase in the AUC of rifabutin. 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% (e.g., 150 mg once daily or 300 mg 2-3 times weekly) in patients receiving the drugs concomitantly.Some experts state that there is limited, but favorable, clinical experience with this dosage regimen.
Concomitant use of lopinavir and rifabutin results in increased concentrations of rifabutin and its metabolite. 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. 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.
Concomitant use of nelfinavir and rifabutin can result in alterations in the pharmacokinetics of both drugs. 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. 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. 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.
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); further dosage reduction may be needed. 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).
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. 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. 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.
Nonnucleoside Reverse Transcriptase Inhibitors
Concomitant use of rifabutin and delavirdine is not recommended.
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. 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, provided that the antiretroviral regimen does not include an HIV protease inhibitor.
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. Therefore, caution is advised if nevirapine is used concomitantly with rifabutin. 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. 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.
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. 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. In vitro studies indicate that rifabutin does not affect the inhibition of HIV by zidovudine.
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.
Preparations
Rifabutin Oral Capsules 150 mg Mycobutin®, Pfizer