Sirolimus is used for the prevention of rejection of renal allografts in patients 13 years of age or older receiving renal transplants. The manufacturer recommends therapeutic drug monitoring in all patients receiving the drug.
Sirolimus is used initially in conjunction with both cyclosporine and corticosteroid therapy. The manufacturer cautions that safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients.
(See De Novo Use Without Cyclosporine under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
In clinical trials in renal transplant patients, a regimen consisting of sirolimus, cyclosporine, and corticosteroids was more effective than regimens consisting of either azathioprine or placebo in combination with cyclosporine and corticosteroids in preventing acute rejection, graft loss, or death at 6 months following transplantation. Concomitant therapy with sirolimus and cyclosporine appears to provide additive immunosuppressive effects while allowing reduced dosages of cyclosporine and/or a reduction in dosage or discontinuance of corticosteroids. However, long-term combined use of sirolimus and cyclosporine has been associated with deterioration of renal allograft function. Therefore, in patients with low to moderate immunologic risk, the manufacturer recommends that, at 2-4 months posttransplantation, cyclosporine be gradually withdrawn over a 4- to 8-week period and that the sirolimus dosage be adjusted to achieve recommended blood concentrations of the drug. In patients with high immunologic risk (e.g., black recipients, repeat renal transplant patients who lost a previous allograft for immunologic reason, and/or patients with a high level of panel-reactive antibodies [PRA; peak PRA level of more than 80%]), the manufacturer recommends that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation. However, safety and efficacy of sirolimus in combination with cyclosporine and corticosteroids have not been studied beyond one year in high immunologic risk patients; therefore, any adjustments to the immunosuppressive regimen in these patients should be considered based on the clinical status of the patient.
The current indication for sirolimus in the prevention of organ rejection is based on the results of several randomized, double-blind, multicenter controlled studies involving renal allograft recipients. In 2 studies, sirolimus was given in 2 different dosages (2 and 5 mg once daily) as the oral solution in immunosuppressive regimens that included both cyclosporine and corticosteroids (e.g., prednisone). Sirolimus was compared with azathioprine (2-3 mg/kg daily) in one study (study 1) and with placebo in the other (study 2). In both studies, the primary efficacy end point was the rate of treatment failure, defined as the first occurrence of an acute rejection episode (biopsy confirmed), graft loss, or death, in the first 6 months after transplantation. Sirolimus was more effective than azathioprine or placebo in reducing the incidence of treatment failure at 6 months following transplantation. In addition, antibody therapy (i.e., with muromonab-CD3 or antithymocyte globulin) for treatment of acute rejection was required less frequently in patients receiving sirolimus than in azathioprine or placebo recipients. The treatment failure rates at 6 months for sirolimus 2 mg, sirolimus 5 mg, and azathioprine 2-3 mg/kg daily in study 1 were 18.7, 16.8, and 32.3%, respectively; failure rates at 6 months for sirolimus 2 mg, sirolimus 5 mg, and placebo in study 2 were 30, 25.6, and 47.7%, respectively. Following 24 months of therapy, treatment failure rates for sirolimus 2 mg, sirolimus 5 mg, and azathioprine 2-3 mg/kg in study 1 were 32.8, 25.9, and 36%, respectively; failure rates at 36 months for sirolimus 2 mg, sirolimus 5 mg, and placebo in study 2 were 44.1, 41.6, and 54.6%, respectively. In both studies, long-term (24 or 36 months) follow-up indicated that graft survival rates were similar in patients receiving sirolimus and those receiving azathioprine or placebo, but renal function declined at a greater rate and glomerular filtration rates were lower in patients receiving sirolimus and cyclosporine than in those receiving azathioprine or placebo and cyclosporine. In study 1, which was prospectively stratified by race within treatment centers, treatment failure in black patients was lower with the 5-mg daily dosage of sirolimus compared with azathioprine but similar to azathioprine in those receiving sirolimus 2 mg daily. In study 2, which was not prospectively stratified by race, treatment failure was similar for both sirolimus dosages compared with placebo in black patients.
(See Dosage and Administration: Special Populations.)
In another multicenter clinical study (study 3), safety and efficacy of maintenance therapy with sirolimus following discontinuance of cyclosporine at 3-4 months following renal transplantation were evaluated in patients with low to moderate immunologic risk (i.e., patients without Banff grade III acute rejection or vascular rejection episodes in the 4-week period before randomization, patients with serum creatinine concentrations of 4.5 mg/dL or less, and patients with adequate renal function to support cyclosporine withdrawal [based on clinician judgment]). All patients received standard sirolimus therapy (sirolimus given as tablets, cyclosporine, and corticosteroids) for the first 3 months following transplantation and then were randomized to continue standard therapy or to receive sirolimus in dosages adjusted based on target sirolimus trough concentrations following gradual withdrawal of cyclosporine. Allograft survival rates at 12, 24, and 36 months following transplantation were similar in both treatment groups. Although the incidence of biopsy-proven acute rejection from randomization through 12 months was 4.2% in the group receiving standard therapy compared with 9.8% in the group receiving sirolimus following cyclosporine withdrawal, patients receiving sirolimus following cyclosporine withdrawal had higher mean glomerular filtration rates at 12, 24, and 36 months than did those who continued to receive standard therapy. In the subset of patients receiving renal allografts with 4 or more HLA mismatches, patients who received sirolimus following cyclosporine withdrawal had higher rates of acute rejection (15.3%) than did patients who continued to receive standard therapy (3%); however, among those receiving renal allografts with 3 or fewer HLA mismatches, rates of acute rejection were similar in both treatment groups. In a subsequent extension of this cyclosporine withdrawal study, the results for the cyclosporine withdrawal group at 48 and 60 months following transplantation were consistent with those observed at month 36; 52% of the patients in the sirolimus with cyclosporine withdrawal group remained on therapy through month 60 and demonstrated sustained glomerular filtration rates. The manufacturer states that cyclosporine withdrawal has not been studied in patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis dependent, those with serum creatinine concentrations greater than 4.5 mg/dL, black patients, multiorgan transplant recipients, secondary transplant recipients, or patients with a high level of panel-reactive antibodies.
Use of sirolimus in high immunologic risk renal transplant patients was studied in a multicenter clinical trial (study 4) of one year's duration in high risk patients (defined as black ethnicity, repeat transplant following loss of a previous allograft for immunologic reasons, and/or recipients with a high level of panel-reactive antibodies [PRA; peak PRA level over 80%]). Patients in the sirolimus plus cyclosporine arm of this study received an immunosuppressive regimen consisting of concentration-controlled sirolimus, concentration-controlled cyclosporine, and corticosteroids; antibody induction therapy was used in 88.4% of the patients. The sirolimus and cyclosporine immunosuppressive regimen was found to be effective in these high risk patients in the first year following renal transplantation, with an efficacy failure rate of 23.2%, a biopsy-proven acute rejection rate of 17.4%, and a graft survival rate of 90.2%.
Conversion from calcineurin inhibitors (e.g., cyclosporine, tacrolimus) to sirolimus has been evaluated in maintenance renal transplant recipients 6 months to 10 years following renal transplantation in a randomized, multicenter, and controlled study (study 5). The Sirolimus Renal Conversion Trial (CONVERT) was designed to determine whether renal function improved following conversion from a calcineurin inhibitor-based to a sirolimus-based immunosuppressive regimen. In this study, 830 patients 13 years of age or older who had been receiving maintenance therapy with either cyclosporine or tacrolimus along with corticosteroids and azathioprine or mycophenolate mofetil for at least 12 weeks were randomly assigned to continue the calcineurin inhibitor or to convert from the calcineurin inhibitor to sirolimus. The patients were stratified into 2 subsets according to their baseline glomerular filtration rate (GFR): 20-40 mL/minute or more than 40 mL/minute. In this trial, there was no benefit associated with conversion to sirolimus with regard to improvement in renal function, and a higher incidence of proteinuria was observed in the sirolimus conversion arm. In addition, enrollment of patients with a baseline GFR of 40 mL/minute or less was discontinued because of a higher incidence of serious adverse effects (including pneumonia, acute rejection, graft loss, and death). In the remaining group of patients with a baseline GFR greater than 40 mL/minute, sirolimus conversion at 2 years was associated with excellent patient and graft survival, no difference in acute rejection rate, increased urinary protein excretion, and a lower incidence of malignancy compared with calcineurin inhibitor continuation.
(See Proteinuria under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
The manufacturer states that safety and efficacy of conversion from calcineurin inhibitors (e.g., cyclosporine, tacrolimus) to sirolimus in maintenance renal transplant patients have not been established. In addition, the manufacturer recommends that the clinical results of the CONVERT trial be taken into account when considering a conversion from calcineurin inhibitors to sirolimus in stable renal transplant recipients because of the lack of evidence showing improved renal function following conversion and the increased urinary protein excretion and increased incidence of treatment-emergent nephrotic-range proteinuria following conversion, particularly in patients with preexisting abnormal urinary protein excretion prior to conversion.
Although sirolimus has been used for the prevention of rejection of liver allografts, the manufacturer states that safety and efficacy of the drug as immunosuppressive therapy have not been established in liver transplant patients and that such use is therefore not recommended. Sirolimus has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss, and hepatic artery thrombosis when used in combination with other immunosuppressants (e.g., cyclosporine, tacrolimus).
(See Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplant Patients under Warnings/Precautions: Warnings, in Cautions.)
Although sirolimus has been used for the prevention of rejection of lung allografts, the manufacturer states that safety and efficacy of the drug as immunosuppressive therapy have not been established in lung transplant patients and that such use is therefore not recommended. Cases of bronchial anastomotic dehiscence, most of which were fatal, have been reported in de novo lung transplant patients who received sirolimus in combination with other immunosuppressants.
(See Bronchial Anastomotic Dehiscence in Lung Transplant Patients under Warnings/Precautions: Warnings, in Cautions.)