Rapamune Information
Rapamune (Sirolimus) Indications And Usage
Rapamune (Sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. Therapeutic drug monitoring is recommended for all patients receiving Rapamune (Sirolimus) [see ].
Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine > 4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [see ].
The safety and efficacy of in maintenance renal transplant patients have not been established [see ].
Rapamune (Sirolimus) Dosage And Administration
Rapamune (Sirolimus) is to be administered orally once daily, consistently with or without food [see ].
Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use.
The initial dose of Rapamune (Sirolimus) should be administered as soon as possible after transplantation. It is recommended that Rapamune (Sirolimus) be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see ].
Frequent Rapamune (Sirolimus) dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once Rapamune (Sirolimus) maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new Rapamune (Sirolimus) dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: Rapamune (Sirolimus) loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum Rapamune (Sirolimus) dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).
Two milligrams (2 mg) of Rapamune (Sirolimus) Oral Solution have been demonstrated to be clinically equivalent to 2 mg Rapamune (Sirolimus) Tablets; hence, are interchangeable on a mg-to-mg basis. However, it is not known if higher doses of Rapamune (Sirolimus) Oral Solution are clinically equivalent to higher doses of Rapamune (Sirolimus) Tablets on a mg‑to‑mg basis [see ].
Rapamune (Sirolimus) Contraindications
Rapamune (Sirolimus) is contraindicated in patients with a hypersensitivity to Rapamune (Sirolimus) [see ].
Rapamune (Sirolimus) Warnings And Precautions
The safety and efficacy of Rapamune (Sirolimus) as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of Rapamune (Sirolimus) has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and Hepatic Artery Thrombosis (HAT).
In a study in liver transplant patients, the use of Rapamune (Sirolimus) in combination with tacrolimus was associated with excess mortality and graft loss (22% in combination versus 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 liver transplant patients, the use of Rapamune (Sirolimus) in combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death.
In a clinical study in stable liver transplant patients 6-144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a Rapamune (Sirolimus) -based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [see ].
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in lung transplant patients when Rapamune (Sirolimus) has been used as part of an immunosuppressive regimen.
The safety and efficacy of Rapamune (Sirolimus) as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.
There have been reports of impaired or delayed wound healing in patients receiving Rapamune (Sirolimus) , including lymphocele and wound dehiscence [see ]. mTOR inhibitors such as sirolimus have been shown to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with Rapamune (Sirolimus) [see ]. Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m may be at increased risk of abnormal wound healing based on data from the medical literature.
There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving Rapamune (Sirolimus) .
Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with Rapamune (Sirolimus) compared with azathioprine or placebo controls in Studies 1 and 2 [see ]. There were increased incidences of hypercholesterolemia (43-46%) and/or hypertriglyceridemia (45-57%) in patients receiving Rapamune (Sirolimus) compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune (Sirolimus) .
Any patient who is administered Rapamune (Sirolimus) should be monitored for hyperlipidemia. If detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines.
In clinical trials concomitant administration of Rapamune (Sirolimus) and HMG-CoA reductase inhibitors .
During Rapamune (Sirolimus) therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents.
Renal function should be closely monitored during the co-administration of Rapamune (Sirolimus) with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and Rapamune (Sirolimus) were noted to have higher serum creatinine levels and lower glomerular filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1 and 2). The rate of decline in renal function in these studies was greater in patients receiving Rapamune (Sirolimus) and cyclosporine compared with control therapies.
Appropriate adjustment of the immunosuppressive regimen, including discontinuation of Rapamune (Sirolimus) and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. In patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients. Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function.
In patients with delayed graft function, Rapamune (Sirolimus) may delay recovery of renal function.
Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy, which has been observed in patients receiving immunosuppressants, including Rapamune (Sirolimus) . This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss [see ]. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with immunosuppressants, including Rapamune (Sirolimus) . PML commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.
Cases of pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for pneumonia should be administered for 1 year following transplantation.
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.
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Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies. Patient sample concentration values from different assays may not be interchangeable [see ].
Rapamune (Sirolimus) Adverse Reactions
The adverse reactions are discussed in greater detail in other sections of the label.
The most common (≥ 30%) adverse reactions observed with Rapamune (Sirolimus) in clinical studies are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.
The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical trials: creatinine increased, hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP).
Rapamune (Sirolimus) Drug Interactions
Sirolimus is known to be a substrate for both cytochrome P‑450 3A4 (CYP3A4) and p‑glycoprotein (P‑gp). Inducers of CYP3A4 and P‑gp may decrease sirolimus concentrations whereas inhibitors of CYP3A4 and P‑gp may increase sirolimus concentrations.
Rapamune (Sirolimus) Use In Specific Populations
The safety and efficacy of Rapamune (Sirolimus) in pediatric patients
The safety and efficacy of Rapamune (Sirolimus) Oral Solution and Rapamune (Sirolimus) Tablets have been established in children ≥ 13 years judged to be at low- to moderate-immunologic risk. Use of Rapamune (Sirolimus) Oral Solution and Rapamune (Sirolimus) Tablets in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of Rapamune (Sirolimus) Oral Solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [see ].
Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (
Rapamune (Sirolimus) Overdosage
Reports of overdose with Rapamune (Sirolimus) have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [see ].
General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD was greater than 800 mg/kg.
Rapamune (Sirolimus) Description
Rapamune (Sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by . The chemical name of sirolimus (also known as rapamycin) is (3,6,7,9,10,12,14,15,17,19,21,23,26,27,34a)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1)-2-[(1,3,4)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4,6,31)-pentone. Its molecular formula is CHNO and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows.
Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.
Rapamune (Sirolimus) is available for administration as an oral solution containing 1 mg/mL sirolimus. Rapamune (Sirolimus) is also available as a tan, triangular-shaped tablet containing 0.5 mg sirolimus, as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus.
The inactive ingredients in Rapamune (Sirolimus) Oral Solution are Phosal 50 PG (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Rapamune (Sirolimus) Oral Solution contains 1.5% - 2.5% ethanol.
The inactive ingredients in Rapamune (Sirolimus) Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, -alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide.
Rapamune (Sirolimus) Clinical Pharmacology
Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G to the S phase of the cell cycle.
Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific.
In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.
Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients.
The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with Rapamune (Sirolimus) 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in the following .
Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUC. Upon repeated, twice-daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2- to 3-fold over the initial 6 days of therapy, at which time steady-state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients [see ].
Rapamune (Sirolimus) Clinical Studies
The safety and efficacy of Rapamune (Sirolimus) as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation. Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe. Five hundred twenty-five (525) patients were enrolled. All patients in this study received the tablet formulation. This study compared patients who were administered Rapamune (Sirolimus) , cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal, the Rapamune (Sirolimus) dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values). At 3 months, 430 patients were equally randomized to either continue Rapamune (Sirolimus) with cyclosporine therapy or to receive Rapamune (Sirolimus) as a maintenance regimen following cyclosporine withdrawal.
Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤ 4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator). The primary efficacy endpoint was graft survival at 12 months after transplantation. Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).
The following summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups.
The following summarizes the results of first biopsy-proven acute rejection at 12 and 36 months. There was a significant difference in first biopsy-proven rejection rates between the two groups after randomization and through 12 months. Most of the post-randomization acute rejections occurred in the first 3 months following randomization.
Patients receiving renal allografts with ≥ 4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group, compared with patients who continued cyclosporine (15.3% vs. 3.0%). Patients receiving renal allografts with ≤ 3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% vs. 7.7%) following randomization.
The following summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).
The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving Rapamune (Sirolimus) as a maintenance regimen following cyclosporine withdrawal than for those in the Rapamune (Sirolimus) with cyclosporine therapy group. Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the Rapamune (Sirolimus) with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.
Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study. The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36. Fifty-two percent (112/215) of the patients in the Rapamune (Sirolimus) with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.
Rapamune (Sirolimus) was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level > 80%). Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice. The Rapamune (Sirolimus) dose was adjusted to achieve target whole blood trough sirolimus concentrations of 10-15 ng/mL (chromatographic method) throughout the 12-month study period. The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200-300 ng/mL through week 2, 150-200 ng/mL from week 2 to week 26, and 100-150 ng/mL from week 26 to week 52 [see ] for the observed trough concentrations ranges. Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients. The study was conducted at 35 centers in the United States. A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA. Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula. The below summarizes the result of these endpoints.
Patient survival at 12 months was 94.6%. The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity.
Conversion from calcineurin inhibitors (CNI) to Rapamune (Sirolimus) was assessed in maintenance renal transplant patients 6 months to 10 years post‑transplant (Study 5). This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to Rapamune (Sirolimus) . Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20-40 mL/min vs. greater than 40 mL/min). In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the Rapamune (Sirolimus) conversion arm. In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death [see ].
This study compared renal transplant patients (6-120 months after transplantation) who were converted from calcineurin inhibitors to Rapamune (Sirolimus) , with patients who continued to receive calcineurin inhibitors. Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids. Rapamune (Sirolimus) was initiated with a single loading dose of 12-20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8-20 ng/mL (chromatographic method). The efficacy endpoint was calculated GFR at 12 months post-randomization. Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death. Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (Rapamune (Sirolimus) conversion, n = 497; CNI continuation, n = 246) are summarized : There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline.
The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment-emergent adverse events occurred more frequently during the first 6 months after Rapamune (Sirolimus) conversion. The rates of pneumonia were significantly higher for the sirolimus conversion group.
While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the Rapamune (Sirolimus) conversion arm at 1 year and at 2 years, as shown in the below [see ]. In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios > 1 at 1 and 2 years after sirolimus conversion. This difference was seen in both patients who had a urinary protein to creatinine ratio ≤ 1 and those who had a protein to creatinine ratio > 1 at baseline. More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio > 3.5 (46/482 [9.5%] vs. 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded. The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio > 1 (13/29 vs. 1/14), excluding patients with baseline nephrotic range proteinuria.
The above information should be taken into account when considering conversion from calcineurin inhibitors to Rapamune (Sirolimus) in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to Rapamune (Sirolimus) . This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion.
Conversion from a CNI-based regimen to a Rapamune (Sirolimus) -based regimen was assessed in stable liver transplant patients 6-144 months post-transplant. The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to Rapamune (Sirolimus) without adversely impacting efficacy or safety. A total of 607 patients were enrolled.
The study failed to demonstrate superiority of conversion to a Rapamune (Sirolimus) -based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the Rapamune (Sirolimus) conversion group and 63 mL/min in the CNI continuation group). The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the Rapamune (Sirolimus) conversion group compared to the CNI continuation group (6.6% versus 5.6%). The number of deaths in the Rapamune (Sirolimus) conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant. The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the Rapamune (Sirolimus) conversion group compared to the CNI continuation group.
Rapamune (Sirolimus) How Supplied/storage And Handling
Since Rapamune (Sirolimus) is not absorbed through the skin, there are no special precautions. However, if direct contact of the oral solution occurs with the skin or eyes, wash skin thoroughly with soap and water; rinse eyes with plain water.
Do not use Rapamune (Sirolimus) after the expiration date that is located on the blister and carton. The expiration date refers to the last day of that month.
Rapamune (Sirolimus) Patient Counseling Information
Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of the document.
See FDA-Approved Medication Guide.
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