Class: Antituberculosis Agents
VA Class: AM500
Chemical Name: (S,12E,14S,15R,16S,17R,18R,19R,20S,21S,22E,24Z)-6,16,18,20-tetrahydroxy- 1′-isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethyl-spiro[9,4-( epoxypentadeca[1,11,13]trienimino)-2H-furo[2′,3′:7,8] naphth[1,2-dimidazole-2,4′-piperidine]-5,10,26-(3H,9H)-trione-16-acetate
CAS Number: 72559-06-9
Brands: Mycobutin
Introduction
Antimycobacterial agent; semisynthetic ansamycin antibiotic; spiropiperidyl derivative of rifamycin S.1 2 3 4 5 6 7 8 16
Uses for Rifabutin
Mycobacterium avium Complex (MAC) Infections
Primary prevention (primary prophylaxis) of disseminated MAC infection in adults, adolescents, and children† with advanced HIV infection;1 11 17 23 24 46 47 59 60 72 m designated an orphan drug by FDA for this use.17 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.72
Prevention of recurrence (secondary prophylaxis) of disseminated MAC infections† in HIV-infected adults, adolescents, and children†;72 f g designated an orphan drug by FDA for this use.17 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.72 f g
Treatment of pulmonary MAC infections† in conjunction with other antimycobacterials.60 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.60 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.60
Treatment of disseminated MAC infections† in conjunction with other antimycobacterials, including infections in HIV-infected adults, adolescents, and children†;60 f g designated an orphan drug by FDA for this use.17 ATS, CDC, NIH, and IDSA recommend a regimen of clarithromycin (or azithromycin) and ethambutol with or without rifabutin.60 f g
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).60 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.60 (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.60 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).67 73 82 (See Specific Drugs under Interactions.)
Other Mycobacterial Infections
Treatment of infections caused by M. xenopi† in conjunction with other antimycobacterials.60 Optimum regimens not established; in vivo response may not correlate with in vitro susceptibility.60 ATS and IDSA state that a regimen of clarithromycin, rifampin, and ethambutol has been used, although the rate of relapse is high.60 A regimen of isoniazid, rifampin (or rifabutin), ethambutol, and clarithromycin (with or without streptomycin during initial treatment) also has been suggested.60
Tuberculosis
Treatment of active (clinical) tuberculosis† (TB) in conjunction with other antituberculosis agents.65 66 67 82 f g m o
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.82
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).67 82 f g m Used in both the initial intensive treatment phase and continuation treatment phase.82
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).82 m Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,82 m 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.82 A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.82 m
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.82 f
Latent Tuberculosis Infection
Treatment of latent tuberculosis infection† (LTBI), including in HIV-infected adults and adolescents.67 72 73 o
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.67 73 m n o p LTBI is treated to decrease the risk of progression to active TB.67 73 o p
Regimen of choice for treatment of LTBI is isoniazid monotherapy, unless the patient has been in contact with an individual with drug-resistant TB.67 72 73 n o 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.67 72 73 n o 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).67 72 73 o
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.73 m n o
Prior to initiating treatment of LTBI, clinical (active) TB must be excluded using appropriate testing (e.g., radiographs).67 72 73 n o
Rifabutin Dosage and Administration
Administration
Oral Administration
Administer orally.1
May be administered without regard to meals,1 22 but administration with food may minimize adverse GI effects.1
In patients unable to swallow capsules, the drug may be mixed with food (e.g., applesauce).1 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.g
Dosage
May be used alone for primary prophylaxis of MAC infections in HIV-infected patients;1 72 must be used in conjunction with other antimycobacterials for treatment of pulmonary or disseminated MAC infections† in HIV-infected or immunocompetent patients60 f g or prevention of MAC recurrence† (secondary prophylaxis) in HIV-infected patients.72 f g
May be used alone for treatment of LTBI†;72 73 must be used in conjunction with other antimycobacterials for treatment of active TB†.65 66 67 82
If used for treatment of active TB†, can be used in daily or intermittent (2 or 3 times weekly) multiple-drug regimens.82 g
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/mm3.79 81 82 f g
If used in HIV-infected patients receiving certain PIs or NNRTIs, adjustment in the treatment regimen recommended.81 82 f (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.72
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.72
The safety of discontinuing primary MAC prophylaxis in HIV-infected infants and children receiving potent antiretroviral therapy has not been extensively studied.72
Primary Prevention of MAC in Adolescents with Advanced HIV Infection
Oral
300 mg once daily.72 Used alone or in conjunction with azithromycin.72
USPHS/IDSA recommends initiation of primary prophylaxis against MAC if CD4+ T-cell count is <50/mm3.72
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.72 Reinitiate prophylaxis if CD4+ T-cell count decreases to <50–100/mm3.72
Prevention of MAC Recurrence (Secondary Prophylaxis) in HIV-infected Children†
Oral
5 mg/kg (up to 300 mg) once daily.72 Used in conjunction with clarithromycin (or azithromycin) and ethambutol.72
Secondary prophylaxis to prevent MAC recurrence in HIV-infected children usually continued for life.72 The safety of discontinuing secondary MAC prophylaxis in children whose CD4+ T-cell count increases in response to antiretroviral therapy has not been studied.72
Prevention of MAC Recurrence (Secondary Prophylaxis) in HIV-infected Adolescents†
Oral
300 mg once daily.72 f Used in conjunction with clarithromycin (or azithromycin) and ethambutol.72 f
Secondary prophylaxis to prevent MAC recurrence usually continued for life in HIV-infected individuals.72 f
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.72 f Reinitiate prophylaxis if CD4+ T-cell count decreases to <100/mm3.72 f
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.g Used in conjunction with clarithromycin (or azithromycin) and ethambutol.g
Treatment of Disseminated MAC in HIV-infected Adolescents†
Oral
300 mg once daily.60 f Used in conjunction with clarithromycin (or azithromycin) and ethambutol.60 f
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.67 g
Adolescents ≥15 years of age: 5 mg/kg (up to 300 mg) once daily or 2 or 3 times weekly.65 66 67 82
Latent Tuberculosis Infection† (LTBI)
Oral
Adolescents: 300 mg once daily for 4 months.72
Adults
Mycobacterium avium Complex (MAC) Infections
Primary Prevention in Adults with Advanced HIV Infection
Oral
300 mg once daily.1 60 72 Alternatively, 150 mg twice daily with food may be used in patients experiencing nausea, vomiting, or other GI upset.1 Used alone1 60 72 or in conjunction with azithromycin.72
Primary prophylaxis against MAC should be initiated if CD4+ T-cell count is <50/mm3.72
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.72 Reinitiate prophylaxis if CD4+ T-cell count decreases to <50–100/mm3.72
Prevention of MAC Recurrence (Secondary Prophylaxis) in HIV-infected Adults†
Oral
300 mg once daily.72 f Used in conjunction with clarithromycin (or azithromycin) and ethambutol.72 f
Secondary prophylaxis to prevent MAC recurrence usually continued for life in HIV-infected individuals.72 f
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.72 f Reinitiate prophylaxis if CD4+ T-cell count decreases to <100/mm3.72 f
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.60 Continue until patient has been culture negative on treatment for 1 year.60 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.60
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.60 f Rifabutin dosages of 300–450 mg once daily have been used.60 Dosage may need to be adjusted in HIV-infected patients depending on the drugs included in the antiretroviral regimen.60 (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.65 66 67 82 f o
Latent Tuberculosis Infection† (LTBI)
Oral
5 mg/kg (up to 300 mg) once daily for 4 months.72 73
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.72
Treatment of Disseminated MAC in HIV-infected Infants and Children†
Oral
Maximum 300 mg once daily.g
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.65 66 67 82 g
Adults
Tuberculosis
Treatment of Active (Clinical) Tuberculosis†
Oral
Maximum 300 mg per dose in once-daily or 2- or 3-times weekly regimens.65 66 67 82 f
Special Populations
Hepatic Impairment
Dosage reductions may be needed in patients with severe hepatic impairment.82 (See Hepatic Impairment under Cautions.)
Renal Impairment
Clcr <30 mL/minute: Reduce dose by 50%.1 f To prevent inadequate dosage, some experts prefer to use usual dosage and monitor plasma rifabutin concentrations.f
Mild to moderate renal impairment: Dosage adjustment not required.1 82
Geriatric Patients
Select dosage with caution.1
Cautions for Rifabutin
Contraindications
Known hypersensitivity to rifabutin or other rifamycins (rifampin, rifapentine).1
Warnings/Precautions
Warnings
Precautions Related to Treatment of MAC Infections
Should not be used for prevention of MAC infection in patients with active TB.1 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.1
There is no evidence that rifabutin is effective for prevention of M. tuberculosis infections.1 Individuals requiring prophylaxis against M. tuberculosis (i.e., treatment of latent tuberculosis infection) and prophylaxis against MAC may receive isoniazid and rifabutin concomitantly.1
HIV-infected individuals frequently have TB and may present with atypical or extrapulmonary findings.1 The tuberculin skin test (TST) for diagnosis of TB may be nonreactive in such patients despite presence of active disease.1 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.1
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.1
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.82
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.82 The antituberculosis regimen should be modified as needed.82 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).82
Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.82 Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.82
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.73 82 f g m o
Sensitivity Reactions
Dermatologic Reactions.
Rash reported frequently.1 2 23
General Precautions
Discoloration of Body Tissues or Fluids
Orange or yellow skin discoloration may occur.1 27 30 Urine, feces, saliva, sputum, sweat, or tears may have a brown-orange coloration.1 23 Soft contact lenses may become permanently stained.1
Hematologic Effects
Neutropenia reported frequently; thrombocytopenia reported rarely.1
Consider monitoring hematologic status periodically during therapy.1
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 reported occasionally.1 27 30 31 32 33 34
Corneal deposits were reported in some HIV-infected children† who were receiving rifabutin as part of a multiple-drug regimen for MAC prophylaxis.1 These were tiny, almost transparent, asymptomatic peripheral and central corneal deposits that did not impair vision.1
If uveitis occurs, temporarily interrupt rifabutin therapy and obtain ophthalmic evaluation.1 33 In mild cases, rifabutin can be reinstituted; if signs and symptoms of uveitis recur, discontinue immediately.1 33 Permanent discontinuance may be necessary if uveitis is severe.27
Musculoskeletal Effects
Myalgia, arthralgia, myositis reported.1 23 26
Specific Populations
Pregnancy
Category B.1
ATS, CDC, and IDSA state that data are insufficient to recommend use of rifabutin in pregnant women.82
Lactation
Not known whether rifabutin is distributed into milk.1 Discontinue nursing or the drug.1
Pediatric Use
Safety and efficacy for prophylaxis of MAC infection in children have not been established.1 Has been used for primary or secondary prophylaxis of MAC infections in HIV-infected children†.72
Has been used in a limited number of children (concomitantly with other antimycobacterial agents) for the treatment of MAC infection†.1 g
Adverse effects reported in children (e.g., leukopenia, neutropenia, rash) are similar to those observed in adults.1 In addition, corneal deposits were reported in some children.1 (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.1
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.1
Hepatic Impairment
Use close clinical and laboratory monitoring when used in patients with hepatic impairment.82 Dosage reduction may be needed in severe impairment.82
Renal Impairment
Dosage adjustment recommended in patients with substantial renal impairment.1 (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.1 23
Interactions for Rifabutin
Metabolized by CYP3A.1
Induces CYP3A; induces hepatic enzymes to a lesser extent than rifampin.1 81
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.1
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
Antifungals, azoles | Fluconazole: Increased rifabutin concentrations and AUC; no change in fluconazole pharmacokinetics;1 increased incidence of uveitis if high rifabutin dosage used1 Itraconazole: Decreased itraconazole concentrations and AUC; possible loss of antifungal effects1 Posaconazole: Decreased posaconazole concentrations and AUC; increased rifabutin concentrations and AUC;j k possible increased risk of rifabutin-associated adverse effectsj | Fluconazole: Monitor patients receiving rifabutin concomitantly with fluconazole1 Posaconazole: Avoid concomitant use of rifabutin and posaconazole unless benefits outweigh risks;j k if concomitant use considered necessary, monitor frequently for adverse effects associated with rifabutin (e.g., uveitis, leukopenia)j k |
Atazanavir | Increased concentrations and AUC of rifabutin and rifabutin metabolite80 81 | Reduce rifabutin dosage up to 75% of usually recommended dosage (i.e., use 150 mg every other day or 3 times weekly)80 81 |
Co-trimoxazole | Decreased AUC of co-trimoxazole; no change in rifabutin pharmacokinetics1 | |
Dapsone | Decreased dapsone AUC1 | |
Darunavir | Increased rifabutin concentrations; decreased darunavir concentrationsi | Reduce rifabutin dosage to 150 mg once every other dayi 81 |
Delavirdine | Decreased delavirdine concentrations and AUC; increased rifabutin concentrations and AUC1 81 | Concomitant use not recommended1 81 |
Didanosine | Pharmacokinetic interaction unlikely1 | |
Efavirenz | Decreased rifabutin concentrations; no change in efavirenz AUC81 | Increase rifabutin dosage to 450–600 mg once daily or 600 mg 3 times weekly; efavirenz dosage adjustment not needed81 |
Erlotinib | Possible decreased erlotinib AUCh | Avoid concomitant use if possibleh |
Estrogens/Progestins | Hormonal contraceptives: Decreased concentrations of estrogen and/or progestin; decreased efficacy of the hormonal contraceptive1 | Use nonhormonal methods of contraception1 |
Ethambutol | Pharmacokinetic interaction unlikely1 | |
Fosamprenavir | Studies using amprenavir indicate slightly decreased amprenavir AUC and increased rifabutin concentrations and AUCd Rifabutin 150 mg every other day with ritonavir-boosted fosamprenavir: slightly increased amprenavir concentrationsd | If fosamprenavir used without ritonavir, reduce rifabutin dosage by at least 50% of usually recommended dosage (i.e., use 150 once daily or 300 mg 3 times weekly)81 d If ritonavir-boosted fosamprenavir used, reduce rifabutin dosage by at least 75% of the usual dosage of 300 mg daily (i.e., maximum dosage of 150 mg every other day or 3 times weekly)81 d Monitor for neutropenia by performing weekly CBC and as clinically indicatedd |
Indinavir | Increased rifabutin AUC; decreased indinavir AUC1 61 | Reduce rifabutin dosage by 50%;1 use rifabutin 150 mg once daily or 300 mg 3 times weekly and increase indinavir dosage to 1 g every 8 hours61 81 If ritonavir-boosted indinavir used, reduce rifabutin dosage to 150 mg once every other day or 3 times weekly and use usual boosted dosage of indinavir81 |
Isoniazid | Pharmacokinetic interaction unlikely1 | |
Lopinavir | Fixed combination of lopinavir and ritonavir: Increased concentrations of rifabutin and rifabutin metabolite48 81 | Reduce rifabutin dosage by at least 75% (maximum dosage of 150 mg every other day or 3 times weekly) and use usual dosage of fixed combination of lopinavir and ritonavir;48 81 further rifabutin dosage reductions may be necessary48 Monitor closely for adverse effects48 |
Macrolides | Clarithromycin: Increased rifabutin AUC; decreased clarithromycin AUC;1 increased incidence of uveitis if high rifabutin dosage used33 | Clarithromycin: Monitor patients receiving rifabutin and clarithromycin;1 decreased rifabutin dosage of 150 mg daily may be necessary 60 |
Maraviroc | Potential induction of maraviroc metabolism81 | Maraviroc dosage may need adjustment; monitor virologic response81 |
Methadone | Pharmacokinetic interaction unlikely1 | |
Nelfinavir | Increased rifabutin concentrations and AUC; decreased nelfinavir concentrations and AUC1 62 81 | Reduce rifabutin dosage by 50%;1 use nelfinavir 1.25 mg twice daily with rifabutin 150 mg once daily or 300 mg 3 times weekly62 81 |
Nevirapine | Increased rifabutin concentrations (high interindividual variability, some patients may experience large increases in rifabutin exposure);76 decreased nevirapine concentrations76 81 | Caution advised; monitor for rifabutin toxicity;76 dosage adjustment not needed if HIV PIs are not included in the regimen81 |
Raltegravir | Possible decreased raltegravir concentrations81 | If used with rifabutin, consider possibility of pharmacokinetic interaction if optimal virologic response is not achieved81 |
Ritonavir | Increased rifabutin concentrations and AUC;1 81 possible increased incidence of uveitis1 | Reduce rifabutin dosage to 150 mg once every other day or 3 times weekly and use usual ritonavir dosage; further rifabutin dosage reduction may be needed63 81 Manufacturer of rifabutin states concomitant use not recommended1 |
Saquinavir | Decreased saquinavir AUC1 81 | Rifabutin should not be used in patients receiving unboosted saquinavir;81 in patients receiving ritonavir-boosted saquinavir, a rifabutin dosage of 150 mg once every other day or 3 times weekly is recommended81 |
Theophylline | Pharmacokinetic interaction unlikely1 | |
Tipranavir | Increased rifabutin concentrations;81 l no change in tipranavir concentrationsl | Reduce rifabutin dosage by 75% (i.e., use 150 mg once every other day or 3 times weekly);81 l further rifabutin dosage reduction may be neededl Monitor closely for adverse effectsl |
Zidovudine | Slightly decreased concentrations and AUC of zidovudine; no change in rifabutin pharmacokinetics1 38 39 |
Rifabutin Pharmacokinetics
Absorption
Bioavailability
Readily absorbed from GI tract; peak plasma concentrations achieved within 2–4 hours.1 Absolute bioavailability in HIV-positive patients was 20%.1
Food
High-fat meal slows the rate but not the extent of absorption.1
Special Populations
Compared with patients who have Clcr 61–74 mL/minute, AUC is 71% higher in those with Clcr <30 mL/minute and 41% higher in those with Clcr 30–61 mL/minute.1 (See Renal Impairment under Dosage and Administration.)
Steady-state pharmacokinetics more variable in geriatric individuals >70 years of age than in younger adults.1
Distribution
Extent
Widely distributed.1 Intracellular concentrations higher than plasma concentrations; concentrations in lung tissue higher than plasma concentrations.1
Distributed into CNS when meninges are inflamed.82
Plasma Protein Binding
85%.1
Special Populations
Plasma protein binding not influenced by hepatic or renal impairment.1
Elimination
Metabolism
Metabolized by CYP3A.1 Metabolized to 5 metabolites; 1 metabolite has antimicrobial activity equal to that of rifabutin.1
Elimination Route
Excreted in urine (53%) principally as metabolites and excreted in feces (30%).1
Removal by hemodialysis unlikely.1
Half-life
45 hours (range: 16–69 hours).1
Stability
Storage
Oral
Capsules
25°C (may be exposed to 15–30°C); tight container.1
Actions and SpectrumActions
A spiropiperidyl rifamycin structurally and pharmacologically similar to other rifamycins (rifampin, rifapentine).2 3 4 5 6 7 8 16
Inhibits DNA-dependent RNA polymerases in susceptible Escherichia coli and Bacillus subtilis.1 Not known whether rifabutin inhibits DNA-dependent RNA polymerases in M. avium complex (MAC).1
Mycobacterium: Active in vitro and in clinical infections against M. avium complex (MAC) and M. tuberculosis.1 2 4 6 7 8 9 10 11 12 13 14 Active in vitro against M. gordonae,1 60 M. haemophilum,60 M. kansasii,1 60 and M. marinum.1 60 q Has some activity against M. leprae.1 15
Spectrum of activity against gram-positive and gram-negati
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