Rifabutin levels are increased by fluconazole,posaconazole, voriconazole, and possibly itraconazole. Patients taking this combination are at increased risk of rifabutin toxicity,specifically uveitis,and should be closely monitored. Rifabutin markedly reduces theplasma levels of itraconazole,posaconazole, and voriconazole.These azoles should be used cautiously with rifabutin,if at all. Rifabutin does not affect metabolism of fluconazole.
Twelve HIV positive patients were given zidovudine 500mg daily from day 1 to 44,fluconazole 200mg daily from days 3 to 30 and rifabutin 300mg daily from days 17 to 44. Rifabutin did not significantly affect pharmacokinetics of fluconazole,(See reference number 1) but fluconazole increased AUC of rifabutin by 82%, and AUC of rifabutin metabolite LM565 was increased by 216 % (See reference number 1). In another study in 10 patients with HIV infection, fluconazole 200mg daily increased AUC of rifabutin 300mg daily by 76 % and maximum level by 91%. When patients were also given clarithromycin 500mg daily, AUC of rifabutin was further increased to 152 % (See reference number 2). There is some evidence that fluconazole increases prophylactic efficacy of rifabutin against M. avium complex disease,although there was also an increase in incidence of leucopenia (See reference number 3). Uveitis developed in 6 HIV positive patients taking rifabutin 450 to 600mg daily and fluconazole,5 of whom were also taking clarithromycin,(See reference number 4)which is also known to increase rifabutin levels, see Macrolides + Rifamycins interaction. Uveitis has been attributed to concurrent use of rifabutin and fluconazole in other reports (See reference number 5,6). Rifabutin does not appear to significantly affect metabolism of fluconazole (See reference number 7,8).
Itraconazole serum levels reduced. In a three-period study,6 HIV positive patients were given itraconazole 200mg daily for 14 days, rifabutin 300mg daily for 10 days, and then both drugs for 14 days. It was found that rifabutin reduced peak plasma levels of itraconazole by 71 % and reduced its AUC by 74 % (See reference number 9).
Because of low plasma levels after 3 weeks itraconazole dose was increased to 900mg daily. A week later patient developed anterior uveitis. It was found that itraconazole trough serum levels were normal but rifabutin trough serum levels were raised to 153 nanograms/mL (expected to be less than 50 nanograms/mL after 24 hours). Rifabutin was stopped and uveitis was treated
In a study in healthy subjects concurrent use of posaconazole 200mg once daily and rifabutin 300mg once daily for 10 days increased AUC of rifabutin by 72 % and decreased AUC of posaconazole by 51 % when compared with either drug alone (See reference number 11)
Rifabutin 300mg daily decreased AUC and maximum plasma levels of voriconazole 200mg twice daily by 79 % and 67%, respectively. Increasing dose of voriconazole to 350mg twice daily in presence of ri-
Anthelmintics,Antifungals and Antiprotozoals 219
fabutin gave an AUC of 68 % of that achieved with voriconazole 200mg twice daily alone while maximum plasma levels were more or less same (See reference number 12,13). At a dose of 400mg twice daily, voriconazole increased maximum plasma level and AUC of rifabutin 300mg twice daily by about threefold and fourfold, respectively (See reference number 12,13).
Rifabutin increases metabolism of itraconazole, posaconazole and voriconazole, probably, at least in part, by inducing their metabolism by cytochrome P450 CYP3A subfamily. Fluconazole is largely excreted unchanged in urine and so it is not affected. The azoles apparently increase rifabutin levels by inhibiting its metabolism,probably by CYP3A4. Raised rifabutin levels can cause uveitis.
The interaction between rifabutin and fluconazole is established, general picture being that concurrent use can be advantageous. However, because of increased risk of uveitis, UK Committee on Safety of Medicines says that full consideration should be given to reducing dosage of rifabutin to 300mg daily. The rifabutin should be stopped if uveitis develops and patient referred to an ophthalmologist (See reference number 14). A later review suggests this 300mg dose is associated with a reduced risk of uveitis and maintains efficacy (See reference number 15). The combination should be well monitored. Note that effects of clarithromycin, , are additive with those of fluconazole.
Information on interaction between itraconazole and rifabutin is very limited, but monitor for reduced antifungal activity, raising itraconazole dosage as necessary, and watch for increased rifabutin levels and toxicity (in particular uveitis). More study is needed. Note that manufacturers recommend that combination should be avoided (See reference number 16,17).
The manufacturer of ketoconazole suggests that levels of both drugs may be affected if rifabutin is also taken. They suggest that rifabutin dose may need to be reduced (See reference number 18)
On basis of interaction between rifabutin and posaconazole, manufacturer suggests that combination be avoided unless benefit to patient outweighs risk (See reference number 19). If combination is used, monitor efficacy of posaconazole and toxicity of rifabutin, particularly full blood counts and uveitis.
The manufacturer in US contraindicates combination of voriconazole and rifabutin (See reference number 13). However, UK manufacturer permits concurrent use if benefits outweigh risks (See reference number 12). If used together, it is recommended that oral dose of voriconazole be increased from 200mg twice daily to 350mg twice daily (and from 100 to 200mg twice daily in patients under 40 kg). The intravenous dose should also be increased from 4 to 5 mg/kg twice daily. Importantly, manufacturer advises careful monitoring for rifabutin adverse effects (e.g. check full blood counts,monitor for uveitis) (See reference number 12).
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