Rifabutin
An amorphous red-violet powder. Very slightly soluble in water; sparingly soluble in alcohol; soluble in chloroform and in methyl alcohol. Store at a temperature not exceeding 40 degrees. Protect from light.
Adverse Effects and Precautions
As for Rifampicin. It produces a syndrome of polyarthralgia-arthritis at doses greater than 1 g daily. Uveitis has been reported, especially in patients also receiving clarithromycin or fluconazole. Asymptomatic corneal opacities have been reported after long-term use.
Rifabutin should be used with caution in patients with severe hepatic or renal impairment.
A polyarthralgia-arthritis syndrome has been reported in 9 of 10 patients receiving a daily dose of rifabutin greater than 1 g. The syndrome did not occur in patients receiving less than 1 g daily and disappeared on drug withdrawal. Two patients with polyarthralgia-arthritis symptoms developed uveitis and aphthous stomatitis at doses of about 1.8 g daily.
An orange-tan skin pigmentation has been reported to occur in most patients receiving rifabutin. Urine may be discoloured. A flu-like syndrome has been reported in 2 of 12 patients given 300 mg daily for Crohn's disease, in 1 of 16 HIV-infected patients on continuous rifabutin, and in 8 of 15 HIV-infected patients receiving increasing doses of rifabutin.
Other reported adverse effects include hepatitis, leucopenia (including neutropenia), epigastric pain, rash, erythema, and ageusia.
Rash, fever, and vomiting occurred in 1 of 2 children receiving 6.5 mg/kg daily.
Effects on the eyes.
Uveitis may occur a few weeks or months after starting rifabutin, and generally necessitates withdrawal of the drug and treatment with topical or systemic corticosteroids and cycloplegics. The UK CSM was aware of 48 reports of uveitis in patients taking rifabutin. Most patients were also receiving clarithromycin for treatment of AIDS-related Mycobacterium avium complex (MAC) infection and many were also receiving fluconazole. A dosage reduction to 300 mg rifabutin daily is now recommended in patients also receiving macrolides or triazole antifungals and is reported to produce a satisfactory response in MAC infections.
Interactions
As for Rifampicin, Rifabutin is reported to be a less potent inducer of microsomal enzymes than rifampicin, but similar interactions should nevertheless be anticipated.
Plasma concentrations of rifabutin are increased by clarithromycin (and possibly other macrolides) or fluconazole, resulting in increased rifabutin toxicity, in particular uveitis and neutropenia.
Antiretroviral drugs.
Rifabutin interacts with HIV-protease inhibitors, resulting in reductions in plasma concentrations of the HIV-protease inhibitor and increases in rifabutin plasma concentrations, with a possible risk of uveitis. Most clinical experience appears to have been gained with rifabutin in combination with indinavir. The Centers for Disease Control in the USA suggest that in patients with HIV infection who need treatment for tuberculosis, rifabutin could be used in those receiving amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir-ritonavir, nelfinavir, or ritonavir, or the NNRTIs efavirenz or nevirapine; however, dose modifications are required for rifabutin in some combinations and should be substantial (150 mg every other day or three times each week) when it is given with atazanavir, lopinavir-ritonavir, or ritonavir in particular. Rifabutin should not be given with delavirdine or saquinavir alone; however, saquinavir may be given with rifabutin if ritonavir is also given. Increases in doses of indinavir and nelfinavir are also required.
Although rifabutin is reported to reduce the plasma concentrations of zidovudine, studies have shown that the effect is not marked, and licensed product information for rifabutin suggests that the reduction may not be clinically relevant.
Azole antifungals.
As mentioned in Effects on the Eyes, many reports of rifabutin-associated uveitis have occurred in patients also receiving fluconazole. The area under the concentration-time curve for rifabutin and its active 25-deacetyl metabolite were increased by 82% and 216% respectively when fluconazole was given to 12 HIV-infected patients, and elevated plasma-rifabutin concentrations were reported in a patient who developed uveitis while also receiving itraconazole. The mechanism of the interaction remains uncertain but could involve microsomal cytochrome P450 isoenzyme CYP3A4 (see Metabolism under Pharmacokinetics.
Macrolides.
As discussed under Effects on the Eyes, most patients developing uveitis during rifabutin treatment are also receiving clarithromycin. In a study of the treatment of Mycobacterium avium complex infection in AIDS patients, uveitis or pseudojaundice or both were noted in those receiving rifabutin, ethambutol, and clarithromycin, but not in those receiving rifabutin, ethambutol, ciprofloxacin, and clofazimine. A retrospective study after an outbreak of uveitis in a similar patient population also found clarithromycin to be a risk factor, with a trend towards greater risk at higher rifabutin doses, although patient numbers were small. In 26 patients taking rifabutin with either clarithromycin or azithromycin, the incidence and severity of adverse effects in general was similar, although the 2 patients who developed uveitis were both receiving clarithromycin.
Pharmacokinetic studies have demonstrated increased rifabutin concentrations when clarithromycin is also used. A study in healthy subjects was terminated prematurely because of the high incidence of adverse effects, including neutropenia, fevers, and myalgia, particularly in subjects receiving rifabutin with azithromycin or clarithromycin. Mean serum concentrations of rifabutin and its 25-O-deacetyl metabolite in subjects also receiving clarithromycin were more than 4 times and 37 times those in subjects receiving rifabutin alone. Plasma concentrations were unaffected by azithromycin. Similar effects on rifabutin concentrations were found in HIV-infected subjects receiving clarithromycin and reductions in clarithromycin concentrations were also noted.
Antimicrobial Action
Rifabutin possesses a spectrum of antibacterial activity similar to that of rifampicin. However, most investigations have concentrated on its action against mycobacteria. Cross-resistance is common with rifampicin.
Antimycobacterial action.
Rifabutin possesses activity against most species of mycobacteria. It may be more active in vivo than in vitro studies suggest, as a result of its favourable pharmacokinetic profile and prolonged postantibiotic effect.
Rifabutin has been reported to be active in animal assays against Mycobacterium leprae, including a rifampicin-resistant strain. Synergistic activity against M. leprae has been reported in vitro for rifabutin with clinafloxacin and rifabutin with sparfloxacin.
Resistance.
Rifampicin-resistant strains of Mycobacterium tuberculosis have been identified in 2 patients receiving rifabutin alone as prophylaxis against M. avium complex. It is therefore important to exclude M. tuberculosis infection before beginning rifabutin prophylaxis.
Rifampicin-resistant M. kansasii has also been reported in a patient receiving rifabutin.
Acquired resistance has been reported in HIV-infected persons receiving highly intermittent regimens (once- or twice-weekly) of rifabutin for the treatment of active tuberculosis, and the CDC has advised that such patients receive daily treatment during the intensive phase of therapy and daily or 3 times-weekly treatment during the continuation phase.
Pharmacokinetics
Rifabutin is poorly absorbed from the gastrointestinal tract, but is widely distributed. About 70% is bound to plasma proteins. Both hepatic and renal clearance occurs. A mean terminal half-life of 45 hours has been reported.
HIV-infected patients.
The pharmacokinetics of rifabutin were studied in HIV-infected patients with normal renal and hepatic function. A two-compartment open pharmacokinetic model was proposed. Rifabutin was rapidly but incompletely absorbed from the gastrointestinal tract and bioavailability was poor, being 20% on day 1 of the study and 12% on day 28. Mean peak plasma concentrations occurred 2 to 3 hours after oral doses and were about 350, 500, and 900 nanograms/mL after doses of 300, 600, and 900 mg respectively. The peak and trough concentrations following 600 mg twice daily were about 900 and 200 nanograms/mL respectively. Rifabutin was about 70% bound to plasma proteins. The area under the curve showed a decrease on repeated dosage which might be explained by the induction of drug-metabolising liver enzymes. A large volume of distribution of 8 to 9 litres/kg, indicative of extensive tissue distribution, and a mean terminal half-life of 32 to 38 hours were reported.
This study also showed that the peak plasma concentration of the major metabolite, 25-deacetylrifabutin, was 10% of the parent compound. Only 4% of unchanged rifabutin was excreted in the urine after oral use and between 6 to 14% after intravenous use. Total urinary excretion of rifabutin and metabolite 72 hours after intravenous use was 44%; total faecal excretion was between 30 and 49%.
Peak and trough concentrations at steady state were reported as 900 and 200 nanograms/mL respectively in a patient with tuberculosis given rifabutin 450 mg daily. While these figures were the same as those previously reported with 600 mg twice daily, the earlier study showed that there was considerable interpatient variability.
CSF concentrations in 5 patients with AIDS on rifabutin 450 mg daily ranged from 36 to 70% of serum concentrations.
Metabolism.
Five metabolites of rifabutin were identified in an in-vitro study using human hepatic and enterocyte microsomes. Cytochrome P450 isoenzyme CYP3A4 was involved in the formation of all metabolites except 25-O-deacetylrifabutin. Deacetylation of rifabutin was apparently mediated by microsomal cholinesterase, although another study showed that further metabolism of 25-O-deacetylrifabutin is dependent on CYP3A4. The results also suggested that metabolism by intestinal CYP3A4 contributes significantly to presystemic metabolism of rifabutin (and consequently its low bioavailability) and to drug interactions with azole antifungals and with macrolides.
Uses and Administration
Rifabutin is a rifamycin antibacterial used for the prophylaxis of Mycobacterium avium complex (MAC) infection in immunocompromised patients. It is also used for the treatment of opportunistic non-tuberculous mycobacterial infections (including those due to MAC) and tuberculosis, including latent tuberculosis infection. When used for treatment rifabutin, like rifampicin, should be used with other antibacterials to prevent the emergence of resistant organisms.
Rifabutin is given by mouth as a single daily dose. The dose for the prophylaxis of MAC infection is 300 mg daily; although not licensed for children in the UK, the BNFC suggests those aged 1 to 12 years may be given 5 mg/kg (maximum of 300 mg) daily. For the treatment of opportunistic non-tuberculous mycobacterial infections the dose is 450 to 600 mg daily in a multidrug regimen for up to 6 months after negative cultures are obtained; the BNFC suggests giving 5 mg/kg daily in children aged 1 month to 12 years. For pulmonary tuberculosis the dose is 150 to 450 mg daily for at least 6 months as part of a multidrug regimen. Doses should be reduced to 300 mg daily in patients also receiving macrolides or azole antifungals. Dosage alterations may also be necessary in patients receiving HIV-protease inhibitors and in those with severe renal impairment.
Administration in renal impairment.
Dosage of rifabutin should be reduced by 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).
Cryptosporidiosis.
Rifabutin may have a potential prophylactic effect against cryptosporidiosis.
Mycobacterium avium complex infections.
Alterations in rifabutin dosage may be necessary in patients receiving antiretrovirals for the management of HIV infection.
Toxoplasmosis.
A beneficial response to rifabutin used with pyrimethamine was reported in a patient with AIDS-related Toxoplasma gondii encephalitis. The patient was allergic to sulfonamides and clindamycin, which are commonly used.
Tuberculosis and HIV infection.
The CDC in the USA recommends that rifabutin should be used in place of rifampicin in short-course therapy for tuberculosis in patients receiving antiretroviral drugs for HIV infection. However, dose modifications are often necessary;, additionally, some combinations, notably rifabutin with delavirdine or saquinavir alone, should not be used, although rifabutin may be given with saquinavir if ritonavir is also given.
In patients receiving atazanavir, lopinavir-ritonavir, or ritonavir, the dose of rifabutin should be substantially reduced from 300 mg daily or twice weekly to 150 mg every other day or three times each week. In those receiving amprenavir, fosamprenavir, indinavir, or nelfinavir the daily dose of rifabutin should be decreased from 300 mg to 150 mg, and the dose for intermittent therapy should be 300 mg three times weekly. The doses of indinavir and nelfinavir will need to be increased. In patients receiving efavirenz, the dose of rifabutin should be increased from 300 mg daily or twice weekly to 450 mg daily or 600 mg three times each week. In patients receiving nevirapine, the dose of rifabutin should be 300 mg daily or 300 mg three times each week. In patients with a CD4 count greater than 100 cells/microlitre, twice weekly administration of rifabutin may be considered with amprenavir, efavirenz, fosamprenavir, indinavir, nelfinavir, or nevirapine.