Itraconazole Ciclosporin

In two cases, rhabdomyolysis was caused by itraconazole in heart transplant recipients taking long-term ciclosporin and simvastatin (48,49). To avoid severe myopathy, ciclosporin concentrations should be monitored frequently and statins should be withdrawn or the dosage should be reduced, as long as azoles need to be prescribed in transplant recipients. Patients need to be educated about signs and symptoms that require immediate physician intervention. 

CICLOSPORIN AZOLES - ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE t plasma concentrations of ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity, excessive immunosuppression, with risk of infection and post-transplant lymphoproliferative disease Inhibition of CYP3A4-mediated metabolism of ciclosporin these inhibitors vary in potency. Ketoconazole and itraconazole are classified as potent inhibitors. Effect not clinically relevant with fluconazole Avoid co-administration with itraconazole or ketoconazole. Consider alternative azole but need to monitor plasma ciclosporin levels to prevent toxicity... 

Among the imidazole derivatives, numerous case reports or studies have shown that ketoconazole, fluconazole, and itraconazole can inhibit ciclosporin metabolism and increase blood ciclosporin concentrations (267). Ketoconazole, which is undoubtedly the most potent inhibitor, has been used to reduce the dose, and therefore the cost or adverse effects, of ciclosporin (268-270). There was also a beneficial effect on the rate of rejection or infection. In contrast, interactions with metronidazole and miconazole have only been described in isolated case histories (SEDA-19, 351) (5). 

The combination of itraconazole with ciclosporin leads to a marked increase in blood ciclosporin concentrations, and this can result in a rise in serum creatinine, clearly... 

In vitro studies have shown that the cytochrome P450 isoenzyme CYP3A4 is the principal enzyme involved in the metabolism of zonisamide. Based on in vitro data, it is predicted that ketoconazole, ciclosporin, miconazole and fluconazole may cause a modest to minor decrease in the clearance of zonisamide. Conversely, itraconazole and triazolam are not predicted to have an effect. In vitro predictions do not always mirror what happens in clinical use, therefore, further study is needed. 

The evidence suggests that all the azole antifungals can raise ciclosporin levels to a greater or lesser degree. Ketoconazole may cause five- to tenfold rises, while itraconazole, fluconazole and voriconazole may cause two- to threefold rises. A case report suggests that intravenous miconazole interacts similarly and in theory, miconazole oral gel may also interact. Posaconazole may also modestly raise ciclosporin levels. Rhabdomyolysis has been reported with the combination of ciclosporin and itraconazole, but four of these cases were complicated by the presence of statins. 

Rhabdomyolysis has been reported in 3 lung transplant patients and 2 heart transplant patients when itraconazole was used in combination with ciclosporin. However, in three of these cases the concurrent use of simvastatin and in one case concurrent simvastatin and gemfibrozil would also have been factors, " as both ciclosporin and itraconazole can increase simvastatin levels (see Statins -i- Ciclosporin , p.l097, and also Statins + Azoles , p.l093). 

Information about ciclosporin with fluconazole or itraconazole is less extensive, but concurrent use should be closely monitored, being alert for the need to reduce the ciclosporin dosage, in some cases by up to 50% or more, although some patients may demonstrate no significant changes at all. There is also some evidence that in the case of fluconazole, the interaction may possibly depend on its dosage, gender and ethnicity," and the route of ciclosporin administration. ... 

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