Ciclosporin serum levels are normally unchanged by use ofciprofloxacin, but increased serum levels and nephrotoxicity mayoccur in a small number of patients. There is also some evidencethat immunosuppressant effects of ciclosporin are reduced byciprofloxacin. One study,and two case reports describe rises inciclosporin levels in patients given norfloxacin, but another studyfound no change. Similar results have been found with levofloxacin. No significant interaction appears to occur betweenciclosporin and enoxacin,ofloxacin, pefloxacin and trovafloxacin.
A single-dose study in 10 healthy subjects found that after taking ciprofloxacin 500mg twice daily for 7 days pharmacokinetics of oral ciclosporin 5 mg/kg were unchanged (See reference number 1). Five other studies confirm lack of a pharmacokinetic interaction in:
There were no changes in serum ciclosporin levels or evidence of nephrotoxicity. In contrast,a handful of cases of nephrotoxicity have been reported, with
three cases of increased ciclosporin levels (See reference number 7,8). A heart transplant patient developed acute renal failure within 4 days of being given ciprofloxacin 750mg every 8 hrs (See reference number 9). Another patient who had undergone a kidney transplant developed reversible nephrotoxicity (See reference number 10). Decreased renal function in a heart-lung transplant patient has been described in another report (See reference number 7). This patient and another also had increased ciclosporin blood levels when given ciprofloxacin 500mg three times daily (See reference number 7). Acute interstitial nephritis in a cardiac transplant patient has also been reported (See reference number 11-13). A patient taking ciclosporin for red cell aplasia had an increase in ciclosporin levels from 120 nanograms/mL to 297 nanograms/mL,requiring a dose reduction from 250mg to 200mg daily, when intravenous ciprofloxacin 200mg two or three times daily [exact dose unclear] was started. A ciclosporin dose increase back to 250mg daily was required when ciprofloxacin course was finished (See reference number 8).
A case-control study in 42 kidney transplant patients suggested that proportion of cases experiencing at least one episode of biopsy-proved rejection within 1 to 3 months of receiving a transplant were significantly greater in those who had taken ciprofloxacin (45%) than in those who had not (19%). There was also a marked increase in incidence of rejection associated with ciprofloxacin use (29%) compared with controls (2%) (See reference number 14)
A single-dose study in 12 healthy subjects found that levofloxacin 500mg had no effect on pharmacokinetics of ciclosporin oral solution (Sandimmune) (See reference number 16). A case report in a patient taking oral ciclosporin 250mg daily (as emulsion formulation) found no change in ciclosporin levels when he was given intravenous levofloxacin 500mg daily for 9 days (See reference number 8)
In contrast, in a study in 5 kidney transplant patients taking ciclosporin (microemulsion formulation) maximum ciclosporin blood concentration was increased by 23 % when levofloxacin 500mg twice daily for 5 days was taken for a urinary-tract infection. The authors concluded that this interaction may be clinically significant, and warned about extrapolating results from single-dose studies in healthy subjects (as above) to patients with transplants (See reference number 17).
Six renal transplant patients given norfloxacin 400mg twice daily for 3 to 23 days for urinary tract infections,(See reference number 18) and 4 heart transplant patients given norfloxacin 400mg for 7 to 140 days had no changes in their serum ciclosporin levels (See reference number 5). However,two reports describe rises, one marked, in serum ciclosporin levels in a heart transplant patient and a kidney transplant patient given norfloxacin (See reference number 19). A comparative study in 5 children (mean age,8 years) found that while receiving norfloxacin 5 to 10 mg/kg daily their daily dose of ciclosporin was 4.5 mg/kg daily compared with a control group of 6 children not taking norfloxacin who needed 7.4 mg/kg daily (See reference number 20).
A study in kidney transplant patients taking corticosteroids, azathioprine and ciclosporin found that pharmacokinetics of ciclosporin were not significantly changed by pefloxacin 400mg twice daily for 4 days (See reference number 22).
A placebo-controlled crossover study in 7 stable kidney transplant patients treated with ciclosporin (Sandimmune) found that pharmacokinetics of ciclosporin were not significantly altered by trovafloxacin 200mg daily for 7 days (See reference number 23)
The interaction between ciclosporin and norfloxacin probably occurs because norfloxacin inhibits cytochrome P450 isoenzyme CYP3A4, resulting in a reduction in ciclosporin metabolism (See reference number 20). The interaction between ciclosporin and ciprofloxacin may possibly be due to some antagonism by ciprofloxacin of ciclosporin-dependent inhibition of interleukin-2, which thereby opposes its immunosuppressant action (See reference number 14).
Information seems to be limited to these reports. They indicate that in children and adults dosage of ciclosporin will probably need to be reduced in presence of norfloxacin. Information with levofloxacin is currently limited,but a modest increase in ciclosporin levels may occur, and increased monitoring seems advisable.
There is also some evidence that immunosuppressant effects of ciclosporin may be reduced (See reference number 14)
There seem to be no reports of problems with enoxacin,ofloxacin, pefloxacin or trovafloxacin.
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