Ciclosporin Azoles

Interactions Antacids ciclosporin colestipol druas metabolized bv cytochrome P450 3A4 fibrates oral-contraceptiyes warfarin niacin erythromycin diaoxin azole-antifunaals... 

The metabolism of ciclosporin is inhibited by diltiazem, verapamil, azole antifungal agents, erythromycin and clarithromycin with resultant potential for renal, hepatic and CNS toxicity. These interactions have been investigated as a cost saving device in organ transplant recipients, with the aim of using a lower dose of ciclosporin to achieve immunosuppression. 

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 To avoid severe myopathy, ciclosporin concentrations should be monitored frequently and statins should be withdrawn or the dosage should be reduced, as long as azoles need to be prescribed in transplant recipients.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... 

Continuous infusion of amphotericin has been assessed in an open study in six lung transplant recipients with invasive or semi-invasive bronchopulmonary azole-resistant candidal infections who were treated for 40 (17-73) days by 24-hour continuous infusions of amphotericin 1 mg/kg (113). They received at least 1000 ml/day of 0.9% saline intravenously. Apart from ciclosporin, five patients received aminoglycosides for at least 2 weeks, and four received ganciclovir. Calculated creatinine clearance fell from 57 (43-73) ml/minute to a nadir of 35 (28-39) and recovered to 52 (33-60) after the end of therapy. One patient needed temporary hemofiltration for 7 days. Besides three episodes of mild hypokalemia there were no adverse effects attributable to amphotericin. Asymptomatic colonization with Candida persisted for 10 months in one case, but the other five patients were cured. 

The concurrent use of ranolazine and moderate or potent inhibitors of CYP3A4, such as some azoles, diltiazem, grapefruit juice, macrolides, protease inhibitors, or verapamil will result in increased levels of ranolazine, and can predispose the patient to adverse effects including QT interval prolongation. Cimetidine and paroxetine do not interact to a clinically significant extent. Ranolazine may increase levels of ciclosporin, digoxin or simvastatin. 

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). 

Additional caution is required where ciclosporin and azoles are used in patients taking statins, and either ciclosporin dose reduction, replace-... 

In order to reduce the risk of myopathy the CSM in the UK have advised that statins should be used with care in patients who are at increased risk of this adverse effect. Among other risk factors, they mention concomitant use with fibrates, such as gemfibrozil , (p.llOO), and with inhibitors of CYP3A4 such as ciclosporin , (p.l097), macrolides ,(p.ll04), azoles , (p.l093), and protease inhibitors , (p.1108). They also recommend that patients should be made aware of the risks of myopathy and rhabdomyolysis, and asked to promptly report muscle pain, tenderness, or weakness, especially if accompanied by malaise, fever, or dark urine. A 2002 advisory on the use of statins gives some important safety recommendations, which are useful in the context of interactions ... 

Especially the inhibition or induction of cytochrome P450 subtype 3A4 (CYP 3A4) is clinically relevant, because a variety of active substances and food substances (e.g. grapefruit juice) are able to affect this enzyme. Substances inhibiting CYP 3A4 include ciclosporin, dihydropyridines, verapamil, midazolam, paclitaxel, simvastatin, lovastatin, atorvastatin, cimetidine, erythromycin, troleandomycin, ketoconazole (and other azoles). Substances inducing CYP 3A4 include steroids, rifampicin, phenobarbital and St John s wort. 

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