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Included as part of the PRECAUTIONS section.

Increased Susceptibility to Infection and the Possible Development of Lymphoma

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7-3.2% (for Rapamune (sirolimus) -treated patients) versus 0.6-0.8% (azathioprine and placebo control) [see ADVERSE REACTIONS]. Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Rapamune (sirolimus) . Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT)

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 de novo 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 de novo 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 Clinical Studies].

Lung Transplantation – Bronchial Anastomotic Dehiscence

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo 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.

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of Rapamune [see ADVERSE REACTIONS].

Angioedema

Rapamune (sirolimus) has been associated with the development of angioedema. The concomitant use of Rapamune (sirolimus) with other drugs known to cause angioedema, such as ACE-inhibitors, may increase the risk of developing angioedema.

Fluid Accumulation and Wound Healing

There have been reports of impaired or delayed wound healing in patients receiving Rapamune (sirolimus) , including lymphocele and wound dehiscence [see ADVERSE REACTIONS]. mTOR inhibitors such as sirolimus have been shown in vitro 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 [see ADVERSE REACTIONS]. Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m² 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) .

Hyperlipidemia

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 ADVERSE REACTIONS]. 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 of patients receiving Rapamune (sirolimus) plus cyclosporine or Rapamune (sirolimus) after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels > 240 mg/dL and triglycerides above recommended target levels. The concomitant administration of Rapamune (sirolimus) and HMG-CoA reductase inhibitors resulted in adverse events such as CPK elevations (3%), myalgia (6.7%) and rhabdomyolysis ( < 1%). In these trials, the number of patients was too small and duration of follow-up too short to evaluate the long-term impact of Rapamune (sirolimus) on cardiovascular mortality.

During Rapamune (sirolimus) therapy with or without cyclosporine, patients should be monitored for elevated lipids, and 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

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.

Proteinuria

Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to Rapamune (sirolimus) in maintenance renal transplant patients 6-120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to Rapamune compared with CNI continuation [see Clinical Studies, ADVERSE REACTIONS]. Patients with the greatest amount of urinary protein excretion prior to Rapamune (sirolimus) conversion were those whose protein excretion increased the most after conversion. New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse event in 2.2% of the Rapamune (sirolimus) conversion group patients in comparison to 0.4% in the CNI continuation group of patients. Nephrotic range proteinuria (defined as urinary protein to creatinine ratio > 3.5) was also reported in 9.2% in the Rapamune (sirolimus) conversion group of patients in comparison to 3.7% in the CNI continuation group of patients. In some patients, reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of Rapamune (sirolimus) . The safety and efficacy of conversion from calcineurin inhibitors to Rapamune (sirolimus) in maintenance renal transplant patients have not been established.

Latent Viral Infections

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 ADVERSE REACTIONS]. 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.

Interstitial Lung Disease

Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune (sirolimus) . In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the trough sirolimus concentration increases [see ADVERSE REACTIONS].

De Novo Use Without Cyclosporine

The safety and efficacy of de novo use of Rapamune (sirolimus) without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with Rapamune (sirolimus) , mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of Rapamune (sirolimus) without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy (HUS/TTP/TMA)

The concomitant use of Rapamune (sirolimus) with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [see ADVERSE REACTIONS].

Antimicrobial Prophylaxis

Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii 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.

Assay for Sirolimus Therapeutic Drug Monitoring

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 DOSAGE AND ADMINISTRATION].

Skin Cancer Events

Patients on immunosuppressive therapy are at increased risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Interaction with Strong Inhibitors and Inducers of CYP3A4 and/or P-gp

Co-administration of Rapamune (sirolimus) with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) is not recommended [see DRUG INTERACTIONS].

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.

Dosage

Patients should be given complete dosage instructions [see FDA-Approved Medication Guide].

Skin Cancer Events

Patients should be told that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer [see WARNINGS AND PRECAUTIONS].

Pregnancy Risks

Women of childbearing potential should be informed of the potential risks during pregnancy and told that they should use effective contraception prior to initiation of Rapamune (sirolimus) therapy, during Rapamune (sirolimus) therapy, and for 12 weeks after Rapamune (sirolimus) therapy has been stopped [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

Fertility was diminished slightly in both male and female rats following oral administration of sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduction in sperm counts were observed. In female rats, reduced size of ovaries and uteri was observed. Reduction of sperm count in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at doses that were approximately equal to the clinical dose (adjusted for body surface area).

Use In Specific Populations

Pregnancy

Pregnancy Category C

Sirolimus was embryo/fetotoxic in rats when given in doses approximately 0.2 to 0.5 the human doses (adjusted for body surface area). Embryo/fetotoxicity was manifested as mortality and reduced fetal weights (with associated delays in skeletal ossification). However, no teratogenesis was evident. In combination with cyclosporine, rats had increased embryo/feto mortality compared with sirolimus alone. There were no effects on rabbit development at a maternally toxic dosage approximately 0.3 to 0.8 times the human doses (adjusted for body surface area). There are no adequate and well-controlled studies in pregnant women. Effective contraception must be initiated before Rapamune (sirolimus) therapy, during Rapamune (sirolimus) therapy, and for 12 weeks after Rapamune (sirolimus) therapy has been stopped. Rapamune (sirolimus) should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus.

Nursing Mothers

Sirolimus is excreted in trace amounts in milk of lactating rats. It is not known whether sirolimus is excreted in human milk. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from sirolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Rapamune (sirolimus) in pediatric patients < 13 years have not been established.

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 CLINICAL PHARMACOLOGY].

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent ( < 18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of Rapamune (sirolimus) Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [see Clinical Studies].

Geriatric Use

Clinical studies of Rapamune (sirolimus) Oral Solution or Tablets did not include sufficient numbers of patients ≥ 65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, or cardiac function, and of concomitant disease or other drug therapy.

Patients with Hepatic Impairment

The maintenance dose of Rapamune (sirolimus) should be reduced in patients with hepatic impairment [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Patients with Renal Impairment

Dosage adjustment is not required in patients with renal impairment [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 1/10/2011
This monograph has been modified to include the generic and brand name in many instances.