Ciclosporin serum levels are markedly reduced by rifampicin andtransplant rejection can rapidly develop. Rifamycin seems to interact similarly,but limited evidence suggests that rifabutin interacts to a lesser extent. Ethambutol and isoniazid do not generallyappear to interact with ciclosporin although case reports have described alterations in ciclosporin levels.
The clearance of ciclosporin in a patient with a kidney transplant doubled when isoniazid,ethambutol, pyridoxine and rifampicin 600mg daily were given. When these drugs were replaced by rifabutin 150mg and clofazimine 100mg daily ciclosporin clearance fell to about its former levels, but after about 3 weeks clearance was about 20 % greater than before antimycobacterial drugs were given (See reference number 1).
A study in 39 kidney transplant patients taking ciclosporin at a mean dose of 158mg daily found that ciclosporin dose needed to be increased by between 150 to 525mg daily (an average dose of 469mg daily) when rifampicin 450 to 600mg daily was taken as part of a regimen for tuberculosis
A heart transplant patient taking ciclosporin started taking rifampicin 600mg daily with amphotericin B for treatment of an Aspergillus fumigatus infection. The dosage of ciclosporin was increased stepwise and levels climbed to a plateau before suddenly falling again. The dosage had to be increased to more than 30 mg/kg daily to achieve serum levels in range 100 to 300 nanograms/mL (See reference number 3)
A considerable number of other reports about individual patients, both adult and paediatric, confirm that a very marked fall in serum ciclosporin levels occurs, often to undetectable levels, accompanied by transplantation rejection in many instances, if rifampicin is given either intravenously or orally without raising ciclosporin dosage (See reference number 1,4-28). Ciclosporin levels become toxic within 2 weeks of stopping rifampicin unless previously adjusted ciclosporin dosage is reduced (See reference number 4,6).
Three patients needed increases in dosage of ciclosporin when given rifampicin and erythromycin, although latter normally reduces ciclosporin requirements (See reference number 19,29,30). Another patient whose ciclosporin levels had been raised by clarithromycin,, had a fall in their levels when rifampicin was added (See reference number 31).
Rifamycin sodium used to irrigate a wound has been reported to reduce serum levels of ciclosporin in a kidney transplant patient (See reference number 32)
Isoniazid(See reference number 12,22,23) and ethambutol(See reference number 22,23) do not normally interact with ciclosporin. However, there is one case report describing a patient who had a gradual rise in serum ciclosporin levels when isoniazid and ethambutol were stopped,(See reference number 14) and another which attributed a marked rise in ciclosporin levels to use of isoniazid (See reference number 33). There have been several other case reports of successful treatment of tuberculosis in heart and kidney transplant patients using isoniazid,ethambutol, pyrazinamide with ofloxacin, or streptomycin (See reference number 34,35). Consider also pyrazinamide,, and quinolones, .
Rifampicin stimulates metabolism of ciclosporin by cytochrome P450 isoenzyme CYP3A(See reference number 36) resulting in a marked increase in ciclosporin clearance. In addition, rifampicin decreases ciclosporin absorption by inducing its metabolism by gut wall,(See reference number 37) thus producing a significant fall in ciclosporin levels. If rifampicin is given with erythromycin or clarithromycin, enzyme inhibitory effects of macrolides are swamped by more potent enzyme-inducing effects of rifampicin. Rifabutin has some enzyme-inducing properties but extent is quite small compared with rifampicin, and onset may be delayed (See reference number 38).
The interaction between ciclosporin and rifampicin is very well documented, well established and clinically important, as transplant rejection may occur unless ciclosporin dosage is markedly increased. In one study 27 % of patients taking rifampicin lost grafts due to rejection, and this was directly attributed to interaction (See reference number 22). The interaction develops within a few days (within a single day in one case(See reference number 20)). Monitor effects of concurrent use and increase ciclosporin dosage appropriately. Three- to fivefold dosage increases (sometimes frequency-increases from two to three times daily) have proved to be effective,with daily monitoring. Remember also to reduce ciclosporin dosage when rifampicin is stopped to reduce risk of ciclosporin toxicity.
They found that use of three antitubercular drugs (not including rifampicin) for at least 9 months reduced mortality. Other reports similarly found that regimens without rifampicin were suitable for treatment of tuberculosis in transplant patients (See reference number 23,34,35)
Another suggested alternative is to replace ciclosporin with another non-interacting immunosuppressant, such as azathioprine and low-dose prednisolone for immunosuppression, if rifampicin is needed (See reference number 13).
Other rifamycins may also be an option; limited evidence suggests that rifabutin interacts minimally. However, manufacturer(See reference number 39) and CSM in UK(See reference number 40)caution about possibility of an interaction, and close monitoring of ciclosporin levels would still be advisable. Topical rifamycin interacted like rifampicin in one patient when it was applied to a wound (See reference number 32).
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