Voriconazole Sirolimus

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

Drugs affected by voriconazole include the following benzodiazepines, calcium channel blockers, cisapride, coumarin anticoagulants, cyclosporine, ergot alkaloids, HMG-CoA reductase inhibitors, NNRTIs, phenytoin, protease inhibitors, pimozide, proton pump inhibitors, quinidine, prednisolone, rifabutin, sirolimus, sulfonylureas, tacrolimus, vinca alkaloids. 

Sirolimus is metabolized by CYP2A4 and is a substrate of the P-glycoprotein drug efflux pump drugs like voriconazole, itraconazole, fluconazole and erythromycin increase its blood concentration. Conversely, the inducers of CYP3A4 will decrease blood levels of sirolimus. Cyclosporine increases the bioavailability of sirolimus, possibly due to P-GP inhibition and competition for CYP3A4. The bioavailability is more than 30-40% when the two drugs are administered 4 h apart and is more than... 

Prednisolone Progesterone Protease Inlaibitors Quinidine (1 )-Warfarin Rifampin Sertraline Sirolimus Simvastatin Tacrolimus Testosterone Trazadone Triazolam Voriconazole ... 

Clinically important, potentially hazardous interactions with abacavir, atorvastatin, bepridil, bupropion, carbamazepine, clarithromycin, cyclosporine, dexamethasone, digoxin, felodipine, fluticasone propionate, fosamprenavir, itraconazole, ketoconazole, lovastatin, methadone, midazolam, nicardipine, nifedipine, phenobarbital, phenytoin, rifabutin, simvastatin, sirolimus, St John s wort, systemic lidocaine, tacrolimus, tenofovir, trazodone, vinblastine, vincristine, voriconazole, warfarin, zidovudine... 

Sirolimus levels are markedly raised by ketoconazole, and itraconazole, posaconazole and voriconazole appear to interact similarly. Clotrimazole is are also predicted to interact with sirolimus. A case report suggests that fluconazole also raises sirolimus levels. In theory it is possible that miconazole oral gel may also interact with sirolimus. 

A case report describes a patient with a heart transplant who was given two doses of voriconazole 400 mg then 200 mg twice daily for 16 days. When sirolimus was started a dose of 1 mg gave a sirolimus trough level of 12.8 nanograms/mL, but after the voriconazole was stopped a dose of 3 mg only gave trough sirolimus levels of 7.4 nanograms/mL. Voriconazole has been seen to markedly raise sirolimus levels in a number of other patients. ... 

The concurrent use of sirolimus is contraindicated by the manufacturers of voriconazole. The rises in sirolimus levels caused by voriconazole are probably too large to be easily accommodated by reducing the dosage of the sirolimus. One study found that an initial empiric reduction in... 

The manufacturers of sirolimus say that concurrent use of strong inhibitors of CYP3A4, including ketoconazole, voriconazole and itraconazole... 

Mathis AS, Shah NK, Friedman GS. Combined use of sirolimus and voriconazole in renal transplantation a report of two cases. Transplant Proc (2004) 36,2708-9. 

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