Voriconazole and Sirolimus Coadministration after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT

“…15,39,40 The combination of voriconazole and sirolimus is contraindicated according to product information, 41 but sirolimus doses reduced by 70-90% have been used safely in combination with voriconazole. [42][43][44] In our study, no ADE was observed in a patient administered sirolimus (3 mg) as the initial dose, followed by 1 mg every 3 days in combination with voriconazole. Although we found no significant difference comparing the CYA blood concentrations in patients using antimycotics with those who do not, the mean CYA doses were significantly lower (3.1 vs 4.2 mg/kg/d; P ¼ 0.003), reflecting awareness of the potential risk for DDIs.…”

Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

“…All GVHD prophylaxis regimens were modeled as baseline exposures in the present study, which may have further attenuated the observed sirolimus-tacrolimus protective association for patients in whom sirolimus was subsequently discontinued due to adverse effects, 47 concern for drug interactions, 48 or withdrawal of immunosuppression to increase graft-versus-leukemia effect in cases of relapsed disease. Furthermore, whether the observed association is maintained beyond day ϩ100 was not studied, given the further investment needed for capturing sirolimus exposure later in the transplantation process when GVHD prophylaxis is systematically tapered.…”

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

“…However, compared with fluconazole, voriconazole may have greater toxicities [8][9][10] and drug interactions. 11,12 It is unknown if the benefit of voriconazole outweighs these risks.…”