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Black Box Warning
IMMUNOSUPPRESSION, EXCESS MORTALITY IN DE NOVO LIVER TRANSPLANTATION, AND BRONCHIAL ANASTOMOTIC DEHISCENCE
See full prescribing information for complete Boxed Warning.
INCREASED SUSCEPTIBILITY TO INFECTION AND THE POSSIBLE DEVELOPMENT OF LYMPHOMA AND OTHER MALIGNANCIES MAY RESULT FROM IMMUNOSUPPRESSION
Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Rapamune®.
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.
The use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. 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 in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen.
Overview
Sirolimus is a immunomodulatory drug that is FDA approved for the prophylaxis of organ rejection in renal transplantation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include lymphedema, pericardial effusion, hepatotoxicity, hypersensitivity, tuberculosis, interstitial lung disease, exfoliative dermatitis, nephrotic syndrome.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Prophylaxis of Organ Rejection in Renal Transplantation
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.
In patients at low- to moderate-immunologic risk, it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation.
In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation.
Limitations of Use
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.
In patients at high-immunologic risk, the safety and efficacy of Rapamune used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.
In pediatric patients, the safety and efficacy of Rapamune have not been established in patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-immunologic risk.
The safety and efficacy of de novo use of Rapamune without cyclosporine have not been established in renal transplant patients.
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.
Rapamune is to be administered orally once daily, consistently with or without food.
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 should be administered as soon as possible after transplantation. It is recommended that Rapamune be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED).
Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life.
Once Rapamune 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 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 loading dose = 3 x (new maintenance dose - current maintenance dose).
The maximum Rapamune 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 Oral Solution have been demonstrated to be clinically equivalent to 2 mg Rapamune Tablets; hence, are interchangeable on a mg-to-mg basis.
However, it is not known if higher doses of Rapamune Oral Solution are clinically equivalent to higher doses of Rapamune Tablets on a mg‑to‑mg basis.
Patients at Low- to Moderate-Immunologic Risk
Rapamune and Cyclosporine Combination Therapy
For de novo renal transplant patients, it is recommended that Rapamune Oral Solution and Tablets be used initially in a regimen with cyclosporine and corticosteroids.
A loading dose of Rapamune equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range.
Rapamune Following Cyclosporine Withdrawal
At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range.
Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the Rapamune dose is increased.
Patients at High-Immunologic Risk
In patients with high-immunologic risk, it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation. * The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.
For patients receiving Rapamune with cyclosporine, Rapamune therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of Rapamune should thereafter be adjusted.
The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations. Prednisone should be administered at a minimum of 5 mg/day.
Antibody induction therapy may be used.
Therapeutic Drug Monitoring
Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment,when a change in the Rapamune dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors.
Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters.
When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range.
Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL.
The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods (HPLC UV or LC/MS/MS) yield results that are approximately 20% lower than the immunoassay for whole blood concentration determinations.
Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable.
Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000.
Patients with Low Body Weight
The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2.
Patients with Hepatic Impairment
It is recommended that the maintenance dose of Rapamune be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the Rapamune loading dose.
Patients with Renal Impairment
Dosage adjustment is not needed in patients with impaired renal function.
Instructions for Dilution and Administration of Rapamune Oral Solution
The amber oral dose syringe should be used to withdraw the prescribed amount of Rapamune Oral Solution from the bottle. Empty the correct amount of Rapamune from the syringe into only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume [minimum of four (4) ounces (1/2 cup, 120 mL)] of water or orange juice, stir vigorously, and drink at once.
Rapamune Oral Solution contains polysorbate 80, which is known to increase the rate of di‑(2‑ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of Rapamune Oral Solution. It is important that these recommendations be followed closely.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sirolimus in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sirolimus in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sirolimus in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sirolimus in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sirolimus in pediatric patients.
Contraindications
Rapamune is contraindicated in patients with a hypersensitivity to Rapamune.
Warnings
IMMUNOSUPPRESSION, EXCESS MORTALITY IN DE NOVO LIVER TRANSPLANTATION, AND BRONCHIAL ANASTOMOTIC DEHISCENCE
See full prescribing information for complete Boxed Warning.
INCREASED SUSCEPTIBILITY TO INFECTION AND THE POSSIBLE DEVELOPMENT OF LYMPHOMA AND OTHER MALIGNANCIES MAY RESULT FROM IMMUNOSUPPRESSION
Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Rapamune®.
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.
The use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. 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 in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen.
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-treated patients) versus 0.6-0.8% (azathioprine and placebo control).
Oversuppression of the immune system can also increasesusceptibility 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. 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.
The use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients (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 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.
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen.
The safety and efficacy of Rapamune 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.
Angioedema
Rapamune has been associated with the development of angioedema. The concomitant use of Rapamune 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, including lymphocele and wound dehiscence.
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.
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 and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving Rapamune.
Hyperlipidemia
Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with Rapamune compared with azathioprine or placebo controls in Studies 1 and 2.
There were increased incidences of hypercholesterolemia (43-46%) and/or hypertriglyceridemia (45-57%) in patients receiving Rapamune 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.
Any patient who is administered Rapamune 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, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates appeared to be well-tolerated.
During Rapamune 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
Renal function should be closely monitored during the co-administration of Rapamune with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and Rapamune 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 and cyclosporine compared with control therapies.
Appropriate adjustment of the immunosuppressive regimen, including discontinuation of Rapamune 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 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 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.
Patients with the greatest amount of urinary protein excretion prior to Rapamune 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 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 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.
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.
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. 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.
De Novo Use Without Cyclosporine
The safety and efficacy of de novo use of Rapamune without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with Rapamune, 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 without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).
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
The label-recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. These concentration values are not interchangeable.
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 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
Adverse Reactions
Clinical Trials Experience
The following adverse reactions are discussed in greater detail in other sections of the label.
Increased susceptibility to infection, lymphoma, and malignancy
Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients.
Bronchial anastomotic dehiscence in lung transplant patients.
Hypersensitivity reactions
Exfoliative dermatitis
Angioedema
Fluid Accumulation and Wound Healing.
Hypertriglyceridemia, hypercholesterolemia
Decline in renal function in long-term combination of cyclosporine with Rapamune
The most common (≥ 30%) adverse reactions observed with Rapamune 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).
Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal Transplantation
The safety and efficacy of Rapamune Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. The safety profiles in the two studies were similar.
The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received Rapamune Oral Solution 2 mg/day, 208 received Rapamune Oral Solution 5 mg/day, and 124 received placebo is presented in the TABLE below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data (≥ 12 months post-transplant) presented in the following TABLE show the adverse reactions that occurred in at least one of the Rapamune treatment groups with an incidence of ≥ 20%.
The safety profile of the tablet did not differ from that of the oral solution formulation.
In general, adverse reactions related to the administration of Rapamune were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients.
Patients receiving 2 mg of Rapamune Oral Solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of Rapamune Oral Solution per day.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.
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The following adverse reactions were reported less frequently (≥ 3%, but < 20%)
Body as a Whole – Sepsis, lymphocele, herpes zoster, herpes simplex.
Cardiovascular – Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia.
Digestive System – Stomatitis.
Hematologic and Lymphatic System – Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia.
Metabolic/Nutritional – Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia.
Musculoskeletal System – Bone necrosis.
Respiratory System – Pneumonia, epistaxis.
Skin – Melanoma, squamous cell carcinoma, basal cell carcinoma.
Urogenital System – Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with Rapamune [see Warnings and Precautions (5.8)].
Less frequently (< 3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus.
Increased Serum Cholesterol and Triglycerides
The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.
In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol< 200 mg/dL or fasting, total serum triglycerides < 200 mg/dL, there was an increased incidence of hypercholesterolemia (fasting serum cholesterol > 240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides > 500 mg/dL), respectively, in patients receiving both Rapamune 2 mg and Rapamune 5 mg compared with azathioprine and placebo controls.
Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42‑52% of patients enrolled in the Rapamune arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm.
Abnormal Healing
Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).
Malignancies
The TABLE below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [see Clinical Studies (14.1)].
At 24 months (Study 1) and 36 months (Study 2), there were no significant differences among treatment groups.
6.2 Rapamune Following Cyclosporine Withdrawal
The incidence of adverse reactions was determined through 36 months in a randomized, multicenter, controlled trial (Study 3) in which 215 renal transplant patients received Rapamune as a maintenance regimen following cyclosporine withdrawal, and 215 patients received Rapamune with cyclosporine therapy [see Clinical Studies (14.2)]. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg Rapamune groups in Studies 1 and 2.
Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced higher incidences of the following adverse reactions: abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), hypokalemia, thrombocytopenia, and abnormal healing. Conversely, the incidence of the following adverse events was higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy: hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperkalemia, hyperuricemia, and gum hyperplasia. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal.
Malignancies
The incidence of malignancies in Study 3 [see Clinical Studies (14.2)] is presented in the TABLE following.
In Study 3, the incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy was higher in patients receiving Rapamune plus cyclosporine compared with patients who had cyclosporine withdrawn. Conclusions regarding these differences in the incidence of malignancy could not be made because Study 3 was not designed to consider malignancy risk factors or systematically screen subjects for malignancy. In addition, more patients in the Rapamune with cyclosporine group had a pretransplantation history of skin carcinoma.
6.3 High-Immunologic Risk Patients
Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [see Clinical Studies (14.3)]. Overall, the incidence and nature of adverse events was similar to those seen in previous combination studies with Rapamune. The incidence of malignancy was 1.3% at 12 months.
6.4 Conversion from Calcineurin Inhibitors to Rapamune in Maintenance Renal Transplant Population
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant population have not been established [see Clinical Studies (14.4)]. In an ongoing study evaluating the safety and efficacy of conversion from calcineurin inhibitors to Rapamune (initial target sirolimus concentrations of 12-20 ng/mL, and then 8-20 ng/mL, by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n = 87) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this stratum of the Rapamune treatment arm.
The subset of patients with a baseline glomerular filtration rate of less than 40 mL/min had 2 years of follow-up after randomization. In this population, the rate of pneumonia was 15/58 vs. 4/29, graft loss (excluding death with functioning graft loss) was 13/58 vs. 9/29, and death was 9/58 vs. 1/29 in the sirolimus conversion group and CNI continuation group, respectively.
In the subset of patients with a baseline glomerular filtration rate of greater than 40 mL/min, there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the Rapamune conversion arm.
Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus (11/551) and comparator (1/273) treatment groups was observed with 2:1 randomization scheme.
6.5 Pediatrics
Safety was assessed in a controlled clinical trial in pediatric (< 18 years of age) renal transplant patients considered at high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy [see Clinical Studies (14.5)]. The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with a higher incidence of deterioration of renal function (creatinine increased) compared to calcineurin inhibitor-based therapy, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Rapamune. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole – Lymphedema.
Cardiovascular – Pericardial effusion (including hemodynamically significant effusions and tamponade requiring intervention in children and adults).
Hematological/Lymphatic – The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA (see Warnings and Precautions (5.12)]; pancytopenia, neutropenia.
Hepatobiliary Disorders – Hepatotoxicity, including fatal hepatic necrosis, with elevated sirolimus trough concentrations.
Immune System – Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, and hypersensitivity vasculitis [see Warnings and Precautions (5.4)].
Infections – Tuberculosis.
Metabolic/Nutritional – Liver function test abnormal, AST/SGOT increased, ALT/SGPT increased, hypophosphatemia, hyperglycemia.
Respiratory – 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. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the sirolimus trough concentration increases [see Warnings and Precautions (5.10)]; pulmonary hemorrhage; pleural effusion; alveolar proteinosis
Skin – Exfoliative dermatitis [see Warnings and Precautions (5.4)].
Urogenital – Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis. Azoospermia has been reported with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases.
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.
7.1 Use with Cyclosporine
Cyclosporine, a substrate and inhibitor of CYP3A4 and P‑gp, was demonstrated to increase sirolimus concentrations when co‑administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that Rapamune be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is withdrawn from combination therapy with Rapamune, higher doses of Rapamune are needed to maintain the recommended sirolimus trough concentration ranges [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].
7.2 Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp
Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered [see Warnings and Precautions (5.16), Clinical Pharmacology (12.3)].
7.3 Grapefruit Juice
Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of Rapamune [see Dosage and Administration (2.7), Drug Interactions (7.3), Clinical Pharmacology (12.3)].
7.4 Inducers or Inhibitors of CYP3A4 and P-gp
Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of Rapamune and/or the co-administered drug may need to be adjusted [see Clinical Pharmacology (12.3)].
Drugs that could increase sirolimus blood concentrations:
Bromocriptione, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, HIV‑protease inhibitors (e.g., ritonavir, indinavir), metoclopramide, nicardipine, troleandomycin, verapamil
Drugs and other agents that could decrease sirolimus concentrations:
Carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort (Hypericum perforatum)
Drugs with concentrations that could increase when given with Rapamune:
Verapamil
7.5 Vaccination
Immunosuppressants may affect response to vaccination. Therefore, during treatment with Rapamune, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid.
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 therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped. Rapamune should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus.
