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sirolimus 2 mg tablet generic rapamune

In stock Manufacturer GREENSTONE LLC. 59762100301
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Uses

Renal Allotransplantation

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immunologic risk, the manufacturer recommends that, at 2-4 months posttransplantation, cyclosporine be gradually withdrawn over a 4- to 8-week period and that the sirolimus dosage be adjusted to achieve recommended blood concentrations of the drug.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.

Hepatic Allotransplantation

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.)

Lung Allotransplantation

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.)

Dosage and Administration

Administration

Sirolimus is administered orally as tablets or oral solution. To minimize variability in systemic exposure to sirolimus, the drug should be given once daily, consistently with or without food. Grapefruit juice reduces cytochrome P-450 (CYP) 3A4 (CYP3A4)-mediated metabolism of sirolimus and should not be administered with or used for dilution of the drug.(See Drug Interactions: Grapefruit Juice.)

Sirolimus tablets should not be crushed, chewed, or split; the oral solution should be used in patients who are unable to take the tablets.

For dilution and administration of sirolimus oral solution, the prescribed amount of oral solution should be withdrawn from the bottle using the amber oral dose syringe supplied by the manufacturer and then the correct amount of the drug emptied into a glass or plastic container that holds at least 2 ounces (1/4 cup or 60 mL) of water or orange juice. Other liquids, including grapefruit juice, should not be used for dilution. The diluted oral solution should be stirred vigorously and drunk at once. The container should be refilled with an additional volume (minimum of 4 ounces [½ cup or 120 mL]) of water or orange juice, stirred vigorously, and then drunk at once.

Sirolimus therapy should be initiated as soon as possible following renal transplantation as part of an initial immunosuppressive regimen that includes both cyclosporine and corticosteroids. At 2-4 months following transplantation, gradual discontinuance of cyclosporine and adjustment of the sirolimus dosage to achieve recommended blood concentrations of the drug are recommended in patients at low to moderate immunologic risk. In patients at high immunologic risk (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%]), the manufacturer recommends that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following renal transplantation.

Dosage

Commercially available sirolimus tablets and oral solution are not bioequivalent. However, the manufacturer states that because 2-mg doses of sirolimus given as conventional tablets and as the oral solution have been shown to be therapeutically equivalent, such formulations may be interchangeable on a mg-per-mg basis at doses that do not exceed 2 mg. It is not known whether the commercially available sirolimus tablets and the oral solution are therapeutically equivalent at doses exceeding 2 mg.

Renal Allotransplantation

When sirolimus is used for the prevention of renal allograft rejection in patients who have undergone renal transplantation, the manufacturer cautions that frequent sirolimus dosage adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing since sirolimus has a long half-life. Once the maintenance dosage is adjusted, the renal transplant recipient should be maintained on the new sirolimus dosage for at least 7-14 days before subsequent dosage adjustment is made based on drug concentrations. If subsequent dosage adjustment is required, the manufacturer states that the new dosage can be estimated in most patients based on the following equation:

new sirolimus dosage = current sirolimus dosage x (target concentration / current concentration)

A loading dose may be necessary in addition to a new maintenance dosage if an increase in trough sirolimus concentrations is required and can be estimated based on the following equation:

sirolimus loading dose = 3 x (new maintenance dosage - current maintenance dosage)

The manufacturer states that no more than 40 mg of sirolimus should be given within any one-day period. If an estimated daily dose exceeds 40 mg because of the addition of a loading dose, the loading dose should be given in divided doses over a 2-day period. The manufacturer recommends that trough whole blood concentrations of sirolimus be monitored for at least 3-4 days after a loading dose is administered.

Therapeutic Drug Monitoring

Monitoring of trough whole blood sirolimus concentrations is recommended in all renal transplant patients receiving sirolimus for the prevention of renal allograft rejection, particularly in those patients likely to have altered drug metabolism, patients 13 years of age or older who weigh less than 40 kg, patients with hepatic impairment, when a change in sirolimus dosage form has been made, and during concurrent therapy with potent inhibitors or inducers of CYP3A4 (see Drug Interactions). However, therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy; careful attention to clinical signs and symptoms, tissue biopsy findings, and laboratory results is also necessary during therapy.

The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. In clinical practice, sirolimus whole blood concentrations currently are being measured by both chromatographic and immunoassay methodologies. However, the measured concentrations of sirolimus in whole blood depend on the type of assay used, and the concentrations obtained by these different methodologies are not interchangeable. Since results are assay and laboratory dependent and the results may change over time, any adjustments to the targeted therapeutic range must therefore be made with a detailed knowledge of the site-specific assay used to determine sirolimus trough concentrations. The manufacturer recommends that clinicians involved in the management of patients receiving sirolimus therapy determine the following: which assay is being used in their laboratories; whether there is any change to the assay used; and whether there is a change to the laboratory's reference range and/or a subsequent change to the institution's or referring center's recommended therapeutic range for sirolimus. With this information, target sirolimus levels can be appropriately adjusted to achieve optimal clinical results. It is essential that communication be maintained with the laboratory performing the sirolimus assays. Specialized references should be consulted for additional information on sirolimus therapeutic drug monitoring.

Patients at Low to Moderate Immunologic Risk

For the prevention of renal allograft rejection in renal transplant patients at low to moderate immunologic risk, sirolimus is administered orally once daily, with the initial dose administered as soon as possible after transplantation. The initial immunosuppressive regimen should include both cyclosporine and corticosteroids. De novo renal transplant recipients at low to moderate immunologic risk should receive a sirolimus loading dose equivalent to 3 times the maintenance dosage; for example, a 6-mg loading dose of sirolimus should be followed by a maintenance dosage of 2 mg daily. Although a regimen consisting of higher loading and maintenance doses (loading dose of 15 mg followed by a maintenance dosage of 5 mg daily) was used in clinical trials and found to be safe and effective, no efficacy advantage could be shown for the higher dosage in the overall patient population.(See Dosage and Administration: Special Populations.) In addition, sirolimus 2 mg daily demonstrated a superior safety profile compared with the 5-mg daily dosage. Therapeutic drug monitoring of sirolimus blood concentrations is recommended in all renal transplant patients to maintain drug concentrations within the recommended range.(See Therapeutic Drug Monitoring under Dosage: Renal Allotransplantation, in Dosage and Administration.)

Since concomitant administration of oral cyclosporine (modified) (e.g., Neoral) increases the rate and extent of sirolimus absorption (i.e., increased peak blood concentrations and AUC, respectively), the manufacturer recommends that sirolimus be taken 4 hours after administration of cyclosporine (modified) oral solution (e.g., Neoral oral solution, SangCya [no longer commercially available in the US] oral solution) or liquid-filled capsules (modified) (e.g., Neoral soft gelatin capsules).

In patients at low to moderate immunologic risk who have received concomitant sirolimus and cyclosporine therapy for 2-4 months following renal transplantation, gradual discontinuance of cyclosporine over a 4- to 8-week period is recommended by the manufacturer. Sirolimus dosage should be adjusted to maintain trough whole blood concentrations of the drug in the range of 16-24 ng/mL (based on chromatographic assay method) for the first year following transplantation; thereafter, trough concentrations of 12-20 ng/mL are recommended.(See Therapeutic Drug Monitoring under Dosage: Renal Allotransplantation, in Dosage and Administration.)

Patients at High Immunologic Risk

For the prevention of renal allograft rejection in renal transplant patients at high immunologic risk (defined as black ethnicity, repeat transplant following loss of a previous allograft for immunologic reasons, and/or recipient with a high level of panel-reactive antibodies [PRA; peak PRA level over 80%]), sirolimus is administered orally once daily, with the initial dose administered as soon as possible after transplantation. The initial immunosuppressive regimen should include both cyclosporine and corticosteroids. The manufacturer recommends that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following renal transplantation; however, safety and efficacy of this combined regimen have not been studied beyond 12 months following transplantation. Therefore, the manufacturer states that any adjustments to the immunosuppressive regimen after the first 12 months following transplantation should be considered based on the clinical status of the patient. Therapeutic drug monitoring of sirolimus blood concentrations is recommended in all renal transplant patients to maintain drug concentrations within the recommended range.(See Therapeutic Drug Monitoring under Dosage: Renal Allotransplantation, in Dosage and Administration.)

Since concomitant administration of oral cyclosporine (modified) (e.g., Neoral) increases the rate and extent of sirolimus absorption (i.e., increased peak blood concentrations and AUC, respectively), the manufacturer recommends that sirolimus be taken 4 hours after administration of cyclosporine (modified) oral solution (e.g., Neoral oral solution, SangCya [no longer commercially available in the US] oral solution) or liquid-filled capsules (modified) (e.g., Neoral soft gelatin capsules).

For renal transplant patients at high immunologic risk receiving combined sirolimus and cyclosporine therapy, the manufacturer states that sirolimus should be initiated with a loading dose of up to 15 mg on day 1 posttransplantation. Beginning on day 2, an initial maintenance dosage of 5 mg daily should be given. A trough level should be obtained between days 5 and 7, and the daily dosage of sirolimus should thereafter be adjusted. The initial dosage of cyclosporine should be up to 7 mg/kg daily given in divided doses and the dosage should subsequently be adjusted to achieve target whole blood trough concentrations. Prednisone should be administered at a dosage of at least 5 mg daily. Antibody induction therapy may be used.

Special Populations

The initial dosage of sirolimus for the prevention of renal allograft rejection in patients 13 years of age or older who weigh less than 40 kg should be 1 mg/m daily based on body surface area, with a loading dose of 3 mg/m.

Sirolimus is not extensively eliminated by the kidneys, and the manufacturer states that adjustment of sirolimus dosage is not necessary in renal transplant patients with impaired renal function receiving the drug.

Sirolimus is extensively metabolized by the liver, and the manufacturer recommends a reduction of approximately one-third in the maintenance dosage of sirolimus in renal transplant patients with mild or moderate hepatic impairment and a reduction of approximately one-half in renal transplant patients with severe hepatic impairment; the loading dose in these patients does not require modification.

The manufacturer states that routine dosage adjustment in geriatric patients receiving sirolimus for the prevention of renal allograft rejection is not necessary; however, dosage selection in geriatric patients should be cautious, usually starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic or cardiac function and of concomitant diseases or other drug therapy in this population.

Cautions

Contraindications

Known hypersensitivity to sirolimus or its derivatives or any ingredient in the sirolimus formulation.

Warnings/Precautions

Warnings

Sirolimus should be used only by clinicians experienced in immunosuppressive therapy and the management of renal transplant patients.Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources, and the clinician responsible for maintenance therapy should have complete information requisite for follow-up of the patient.

Increased Susceptibility to Infection and Possible Development of Lymphoma

Immunosuppression may result in increased susceptibility to infection (including opportunistic infections [e.g., tuberculosis], fatal infections, and sepsis) and possible development of lymphoma and other malignancies, particularly of the skin. Lymphoma/lymphoproliferative disease was reported in 0.7-3.2% of sirolimus-treated patients and 0.6-0.8% of patients receiving azathioprine and placebo in studies 1 and 2.(See Uses: Renal Allotransplantation.)

Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplant Patients

Use of sirolimus in combination with tacrolimus has been associated with excess mortality and graft loss in a study in de novo liver transplant patients (22% in combination compared with 9% on tacrolimus alone). Many of these patients had evidence of infection at or near the time of death. In this and another study in de novo liver transplant recipients, concurrent use of sirolimus with cyclosporine or tacrolimus was associated with an increased risk of hepatic artery thrombosis (HAT; 7% in combination compared with 2% in the control arm). Most cases of HAT occurred within 30 days posttransplantation and most resulted in graft loss or death. In a clinical study in stable liver transplant patients 6-144 months after transplantation and receiving a calcineurin inhibitor-based regimen, an increased number of deaths was observed in the group converted to a sirolimus-based regimen compared with those continued on a calcineurin-based regimen (3.8 and 1.4%, respectively; difference not statistically significant).(See Uses: Hepatic Allotransplantation and also see Drug Interactions: Cyclosporine and Other Immunosuppressants.) Because safety and efficacy of sirolimus as immunosuppressive therapy in liver transplant patients have not been established, such use is not recommended by the manufacturer.

Bronchial Anastomotic Dehiscence in Lung Transplant Patients

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. Because safety and efficacy of sirolimus as immunosuppressive therapy in lung transplant patients have not been established, such use is not recommended by the manufacturer.

Sensitivity Reactions

Hypersensitivity reactions, including anaphylactic or anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with sirolimus administration.

Sirolimus has been associated with angioedema. Concurrent use of other drugs known to cause angioedema (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents) may increase the risk of developing angioedema.

Other Warnings and Precautions

Fluid Accumulation and Abnormal Wound Healing

Impaired or delayed wound healing, including lymphocele and wound dehiscence, has been reported in sirolimus-treated patients. Lymphocele, a known surgical complication of renal transplantation, occurred more often in sirolimus-treated patients and appeared to be dose-related. In addition, abnormal wound healing following transplant surgery, including fascial dehiscence, incisional hernia, and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary), has been reported in patients receiving the drug. Clinicians should consider appropriate measures to minimize such complications (i.e., patient selection based on body mass index [BMI], reduced sirolimus dosage, use of closed suction drains, modifications of surgical technique). Patients with a BMI greater than 30 kg/m may be at increased risk of abnormal wound healing.

Fluid accumulation, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically important effusions and tamponade requiring intervention [e.g., pericardial drainage] in children and adults), also has been reported in patients receiving sirolimus.

Hyperlipidemia

Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in sirolimus-treated patients compared with those receiving azathioprine or placebo in studies 1 and 2.(See Uses: Renal Allotransplantation.) Increased incidences of hypercholesterolemia (43-46%) and/or hypertriglyceridemia (45-57%) were reported in patients receiving sirolimus compared with those receiving placebo (each 23%). Immunosuppressed renal transplant patients have a higher prevalence of clinically important hyperlipidemia than the general population, and the manufacturer states that the risks and benefits of sirolimus therapy in patients with preexisting hyperlipidemia should be carefully considered before initiating an immunosuppressive regimen containing sirolimus.

Patients receiving sirolimus should be monitored for hyperlipidemia. If hyperlipidemia is detected, interventions such as diet, exercise, and use of antilipemic agents should be initiated based on current clinical guidelines.

In clinical trials, concomitant use of sirolimus and HMG-CoA reductase inhibitors and/or fibric acid derivatives has generally been well tolerated. However, the manufacturer recommends that patients receiving sirolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative should be monitored for the possible development of rhabdomyolysis and other adverse effects (e.g., hepatic toxicity), which are described in the prescribing information for these antilipemic agents.(See Drug Interactions: Antilipemic Agents.)

Renal Function

Mean serum creatinine concentrations were increased and mean glomerular filtration rate (GFR) was decreased in patients receiving cyclosporine and sirolimus compared with those receiving cyclosporine with placebo or azathioprine. In addition, the rate of decline in renal function in these studies was greater in patients receiving sirolimus and cyclosporine compared with those receiving control therapies. Renal function should be closely monitored in patients receiving maintenance immunosuppression with regimens that include sirolimus and cyclosporine, since long-term combined use of these drugs has been associated with deterioration of renal function.

Appropriate adjustment of the immunosuppressive regimen, including discontinuance of sirolimus and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine concentrations. In patients at low to moderate immunologic risk, continuation of combination therapy with cyclosporine for longer than 4 months posttransplantation should be considered only in patients in whom the potential benefits outweigh the possible risks. Caution should be exercised when using other drugs (e.g., aminoglycosides, amphotericin B) that are known to have a deleterious effect on renal function in patients receiving sirolimus.

In patients with delayed graft function, sirolimus may delay recovery of renal function.

Proteinuria

The manufacturer recommends periodic quantitative monitoring of urinary protein excretion in patients receiving sirolimus. In a study evaluating conversion from calcineurin inhibitors to sirolimus for maintenance immunosuppression 6-120 months following renal transplantation, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to sirolimus compared with continuation of calcineurin inhibitors. Protein excretion increased the most following conversion in patients with the greatest amount of urinary protein excretion prior to sirolimus conversion. New-onset nephrosis (nephrotic syndrome) was reported in 2.2% of patients in the sirolimus conversion group compared with 0.4% of patients in the calcineurin inhibitor continuation group. Nephrotic-range proteinuria (defined as urinary protein to creatinine ratio higher than 3.5) was reported in 9.2% of patients in the sirolimus conversion group compared with 3.7% of patients in the calcineurin inhibitor continuation group. In some patients, reduction in the degree of urinary protein excretion was observed following sirolimus discontinuance. Early treatment of proteinuria may help prevent long-term adverse effects on graft survival.

The manufacturer states that safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established.(See Uses: Renal Allotransplantation.)

Latent Viral Infections

Immunosuppressed patients are at an increased risk for opportunistic infections, including reactivation of latent viral infections. These include BK virus-associated nephropathy (BKVN), which has been reported in patients receiving immunosuppressants, including sirolimus, cyclosporine, mycophenolate mofetil, and tacrolimus. Primary infection with polyoma BK virus typically occurs in childhood; following initial infection, the virus remains latent but reactivation may occur in immunocompromised patients. BKVN has principally been observed in renal transplant patients (usually within the first year posttransplantation) and may result in serious outcomes, including deterioration of kidney function and renal allograft loss. Risk of BK virus reactivation appears to be related to the degree of overall immunosuppression rather than use of any specific immunosuppressive agent; patients receiving a maintenance immunosuppressive regimen of 4 or more drugs appear to be at highest risk.

Patients should be monitored for possible signs of BKVN, including deterioration in renal function, during sirolimus therapy; screening assays for polyomavirus replication also have been recommended by some clinicians. Early intervention in patients who develop BKVN is critical; a reduction in immunosuppressive therapy should initially be considered in such patients. Although a variety of other treatment approaches have been used anecdotally in patients with BKVN, including antiviral therapy (e.g., cidofovir), leflunomide, IV immunoglobulins, and fluoroquinolone antibiotics, additional experience and well-controlled studies are necessary to more clearly establish the optimal treatment of such patients.

Cases of progressive multifocal leukoencephalopathy (PML; an opportunistic viral infection of the brain), sometimes fatal, have been reported in patients treated with immunosuppressive agents, including sirolimus. PML is caused by the polyomavirus JC (also called the JC virus) and risk factors include treatment with immunosuppressive therapies and impairment of immune function. PML commonly presents with hemiparesis, apathy, confusion, cognitive impairment, and ataxia, and the possible diagnosis of PML should be considered in immunocompromised patients receiving sirolimus who experience neurologic manifestations. Consultation with a neurologist is advised as clinically indicated. Decreasing total immunosuppression may improve the outcome of PML, but also may increase the risk of graft rejection in transplant recipients. Clinicians should consider the potential risks versus benefits of reduced immunosuppression in such cases. Although the optimal pharmacologic treatment of PML remains to be established, antiviral agents (e.g., cidofovir) have reportedly been successfully used in the treatment of PML in several transplant recipients to date. Early diagnosis of PML and rapid initiation of treatment appear to be essential for patient recovery from this progressive viral disease.

Interstitial Lung Disease

Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia, and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. Symptoms associated with interstitial pneumonitis have included dry cough, exertional dyspnea, and fatigue. The risk for such adverse effects may be increased with increased trough blood concentrations of sirolimus. In some cases, interstitial lung disease has resolved upon discontinuance or dosage reduction of sirolimus.

De Novo Use Without Cyclosporine

Safety and efficacy of de novo use of sirolimus without cyclosporine are not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil, corticosteroids, and an interleukin-2 (IL-2) receptor antagonist had substantially higher acute rejection rates and numerically higher death rates compared with those treated with cyclosporine, mycophenolate mofetil, corticosteroids, and an IL-2 receptor antagonist. A benefit in terms of better renal function was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine. These findings were also noted in a similar treatment group of another clinical trial.

Increased Risk of Calcineurin Inhibitor-induced Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy

Concurrent use of sirolimus and a calcineurin inhibitor (e.g., cyclosporine, tacrolimus) may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP)/thrombotic microangiopathy (TMA).

Antimicrobial Prophylaxis

Cases of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia have been reported in sirolimus-treated patients not receiving antimicrobial prophylaxis. Therefore, the manufacturer states that antimicrobial prophylaxis for P. jiroveci pneumonia should be administered for 1 year following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months following transplantation, particularly in patients at increased risk for CMV disease.

Assays for Sirolimus Therapeutic Drug Monitoring

The manufacturer states that the 24-hour trough concentration ranges for sirolimus recommended in the prescribing information for Rapamune are based on chromatographic methods. In current clinical practice, however, whole blood concentrations of sirolimus are being measured by both chromatographic and immunoassay methodologies. Because measured whole blood concentrations depend on the type of assay used, concentrations obtained by these different methodologies are not interchangeable.(See Therapeutic Drug Monitoring under Dosage: Renal Allotransplantation, in Dosage and Administration.)

Skin Cancer

Patients receiving immunosuppressive therapy are at increased risk for skin cancer. Patients should be advised to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a sunscreen with a high protection factor.(See Advice to Patients.)

Interaction with Potent Inhibitors and Inducers of Cytochrome P-450 Isoenzyme 3A4 and/or P-glycoprotein

Concurrent administration of sirolimus with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) and/or P-glycoprotein (including ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, and clarithromycin) or potent inducers of CYP3A4 and/or P-glycoprotein (including rifampin and rifabutin) is not recommended.(See Drug Interactions: Inhibitors or Inducers of Cytochrome P-450 Isoenzyme 3A4 and P-glycoprotein.)

Specific Populations

Pregnancy

Category C. Women of childbearing potential should use effective contraception before, during, and for 12 weeks after discontinuance of sirolimus therapy.

The National Transplantation Pregnancy Registry (NTPR) is a pregnancy registry for pregnant women receiving immunosuppressants following any solid organ transplantation; the NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant patients by telephone at 877-955-6877 or via their website: http://www.jefferson.edu/ntpr/index.cfm.

Lactation

Sirolimus is distributed into milk in trace amounts in rats; not known whether the drug is distributed into milk in humans. Discontinue nursing or the drug because of potential for serious adverse effects in infants.

Pediatric Use

Safety and efficacy of sirolimus have not been established in pediatric patients younger than 13 years of age.

Safety and efficacy of sirolimus have been established in pediatric and adolescent renal transplant patients 13 years of age and older judged to be at low to moderate immunologic risk. Use of sirolimus in this subpopulation of pediatric patients is supported by evidence from adequate and well-controlled trials of sirolimus in adults with additional pharmacokinetic data in pediatric renal transplant patients.(See Uses: Renal Allotransplantation and also see Dosage and Administration: Special Populations.)

Safety and efficacy data from a controlled, multicenter clinical trial of 36 months' duration in pediatric and adolescent renal transplant patients younger than 18 years of age judged to be at high immunologic risk (i.e., history of one or more acute rejection episodes and/or presence of chronic allograft nephropathy) did not support the chronic use of sirolimus in combination with calcineurin inhibitors and corticosteroids because of the higher incidence of lipid abnormalities and deterioration of renal function and the lack of a demonstrated therapeutic benefit compared with a calcineurin inhibitor-based regimen.

Geriatric Use

Clinical studies of sirolimus did not include a sufficient number of patients 65 years of age or older to determine whether they respond differently than younger patients. Differences in responses between geriatric patients and younger patients have not been identified. Following administration of sirolimus oral solution or tablets, sirolimus trough concentrations in renal transplant patients over 65 years of age were similar to those observed in adults 18-65 years of age. These data suggest that dosage adjustments based solely on age are not necessary in geriatric renal transplant patients. The manufacturer states that dosage selection in geriatric patients should generally be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic or cardiac function and of concomitant disease or other drug therapy.

Hepatic Impairment

In pharmacokinetic studies, patients with hepatic impairment had higher mean sirolimus area under the plasma concentration-time curve (AUC) values compared with individuals with normal hepatic function; as severity of hepatic impairment increased, steady increases in mean sirolimus elimination half-lives and decreases in mean sirolimus clearance normalized for body weight were observed. Therefore, maintenance dosage adjustment of sirolimus and therapeutic drug monitoring are recommended in all patients with hepatic impairment.(See Dosage and Administration: Special Populations.)

The safety and efficacy of sirolimus as immunosuppressive therapy in liver transplant patients have not been established, and therefore such use is not recommended.(See Dosage and Administration: Special Populations and also see Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplant Patients under Warnings/Precautions: Warnings, in Cautions.)

Common Adverse Effects

Adverse reactions occurring in 20% or more of patients receiving sirolimus in clinical trials include peripheral edema, hypercholesterolemia, hypertriglyceridemia, hypertension, increased serum creatinine concentrations, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, acne or acne-like eruption, rash, and thrombocytopenia. Adverse reactions that resulted in sirolimus discontinuance in more than 5% of patients in clinical trials were increased serum creatinine concentrations, hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP).

Drug Interactions

Inhibitors or Inducers of Cytochrome P-450 Isoenzyme 3A4 and P-glycoprotein

Sirolimus is a known substrate for both cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) and P-glycoprotein. Inducers of CYP3A4 and P-glycoprotein may decrease sirolimus blood concentrations while inhibitors of CYP3A4 and P-glycoprotein may increase sirolimus concentrations.

The manufacturer states that concomitant use of sirolimus with potent inducers (e.g., rifampin, rifabutin) and potent inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, erythromycin, telithromycin) of CYP3A4 and P-glycoprotein should be avoided. Alternative agents with lesser drug interaction potential should be considered.

Caution is advised when sirolimus is used with other drugs or other agents that are modulators of CYP3A4 and P-glycoprotein. The dosage of sirolimus and/or the concurrently administered drug(s) may require adjustment. The following drugs potentially may increase sirolimus blood concentrations: bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, dronedarone, fluconazole, HIV protease inhibitors (e.g., indinavir, ritonavir), metoclopramide, nicardipine, troleandomycin, and verapamil. The following drugs and other agents potentially may decrease sirolimus concentrations: carbamazepine, phenobarbital, phenytoin, rifapentine, and St. John's wort (Hypericum perforatum). When given concurrently with sirolimus, verapamil concentrations also may increase.(See Drug Interactions: Verapamil.)

Cyclosporine and Other Immunosuppressants

Cyclosporine, a substrate and inhibitor of CYP3A4 and P-glycoprotein, has been shown to increase sirolimus concentrations during concurrent administration. To minimize such potential increases, sirolimus should be taken 4 hours after administration of oral cyclosporine. If cyclosporine is withdrawn from combination therapy with sirolimus, a higher sirolimus dosage is necessary to maintain the recommended sirolimus trough concentration ranges.

Potential pharmacologic interaction when sirolimus is given with other immunosuppressants (increased risk of infectious complications and malignancies), particularly with more potent immunosuppressive regimens (see Cautions).

Potential pharmacologic interaction with cyclosporine or tacrolimus (increased risk of hepatic artery thrombosis) in de novo liver transplant recipients. Most cases of hepatic artery thrombosis occurred within 30 days posttransplantation and led to graft loss or death. In one study reporting excess mortality and graft loss in association with combined use of sirolimus and tacrolimus in de novo liver transplant recipients, many of the patients had evidence of infection at or near the time of death.

Possible decreased exposure to tacrolimus during concurrent administration of sirolimus. Potential pharmacologic interaction with concurrent sirolimus and tacrolimus administration (increased risk of wound healing complications, impaired renal function, and insulin-dependent posttransplant diabetes mellitus in heart transplant recipients). The manufacturer of tacrolimus recommends avoiding concomitant use of sirolimus and tacrolimus.

Concomitant use of sirolimus and a calcineurin inhibitor (e.g., cyclosporine, tacrolimus) may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.

Diltiazem

Pharmacokinetic interaction (increased bioavailability of sirolimus). Sirolimus concentration monitoring is recommended, with adjustment of sirolimus dosage if needed.

Dronedarone

Concomitant use of sirolimus and dronedarone potentially may increase plasma concentrations of sirolimus. In one case report, a more than threefold increase in trough sirolimus concentration compared with baseline was reported 3 days following initiation of dronedarone therapy in a renal transplant recipient. The manufacturer of dronedarone currently recommends monitoring plasma concentrations of sirolimus, with adjustment of sirolimus dosage, if needed, during concurrent administration. Some clinicians have suggested that combined dronedarone and sirolimus therapy be avoided, if possible. If concurrent use cannot be avoided, they recommend reducing the sirolimus dosage by 50-75% prior to initiating dronedarone therapy and close monitoring of sirolimus trough levels, particularly during the titration phase.

Ketoconazole

Pharmacokinetic interaction (increased bioavailability of sirolimus). Concomitant use should be avoided; alternative anti-infective therapy with less potential for enzyme induction should be considered.

Rifampin

Pharmacokinetic interaction (enzyme induction and decreased bioavailability of sirolimus). Concomitant use should be avoided; alternative anti-infective therapy with less potential for enzyme induction should be considered.

Verapamil

Pharmacokinetic interaction (increased bioavailability of sirolimus and verapamil). Caution is advised during concurrent administration; sirolimus concentration monitoring is recommended with adjustment of sirolimus dosage if needed. Adjustment of verapamil dosage is also recommended if needed.

Antilipemic Agents

Antilipemic agents are often used to treat hyperlipidemia in renal transplant recipients. In clinical trials, concurrent administration of sirolimus and antilipemic agents (i.e., HMG-CoA reductase inhibitors and/or fibric acid derivatives) appeared to be well tolerated. The manufacturer recommends monitoring for possible development of rhabdomyolysis and other adverse effects (e.g., hepatic toxicity) associated with HMG-CoA reductase inhibitors and/or fibric acid derivatives in patients receiving such concomitant therapy.(See Hyperlipidemia under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

A clinically important pharmacokinetic interaction between sirolimus and atorvastatin appears unlikely.

Nephrotoxic Drugs

The manufacturer recommends exercising caution when using drugs that may adversely affect renal function in patients receiving sirolimus (e.g., aminoglycosides, amphotericin B).(See Renal Function under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Vaccines

The possibility that immune response to vaccination may be diminished in patients receiving sirolimus should be considered. The manufacturer recommends that live vaccines (e.g., measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, typhoid vaccine live oral [containing the Ty21a strain of Salmonella typhi]) be avoided during therapy with the drug.

Grapefruit Juice

Grapefruit juice reduces CYP3A4-mediated metabolism of sirolimus and should not be administered with or used for dilution of the drug.

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