BOX WARNING: IMMUNOSUPPRESSION, EXCESS MORTALITY IN DE NOVO LIVER TRANSPLANTATION, AND BRONCHIAL ANASTOMOTIC DEHISCENCE
- 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 [see Warnings and Precautions ( 5.1 ) ].
- Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT)
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 [see Warnings and Precautions ( 5.2 ) ].
- Lung Transplantation– Bronchial Anastomotic Dehiscence
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 [see Warnings and Precautions (5.3)].
- The safety and efficacy of Rapamune (sirolimus) as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended [see Warnings and Precautions (5.2, 5.3) ].
Pharmacokinetics in Specific Populations
Rapamune® (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by
Rapamune® (sirolimus) is indicated for the prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunologic risk cyclosporine should be withdrawn 2 to 4 months after transplantation and Rapamune® dose should be increased to reach recommended blood concentrations (See DOSAGE AND ADMINISTRATION).
The safety and efficacy of cyclosporine withdrawal in high-risk patients have not been adequately studied and it is therefore not recommended. This includes patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, or with serum creatinine > 4.5 mg/dL, black patients, re-transplants, multi-organ transplants, patients with high panel of reactive antibodies (See CLINICAL STUDIES).
Media Articles Related to Rapamune (Sirolimus)
$257 million civil settlement with Wyeth over unlawful marketing of Rapamune
Source: Litigation / Medical Malpractice News From Medical News Today [2013.08.01]
Leading whistleblower law firm Grant & Eisenhofer P.A. represented two key whistleblowers behind a $257.
Published Studies Related to Rapamune (Sirolimus)
Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy. [2011.11]
BACKGROUND: There is a lack of new therapeutic strategies for IgA nephropathy. Low-dose sirolimus inhibits mesangial cell proliferation and renal fibrosis in animal models... CONCLUSION: The addition of low-dose sirolimus to enalapril and statin is safe, stabilizes renal function and reduces glomerular proliferative lesions in patients with poor prognosis IgA nephropathy.
Biodegradable polymer versus permanent polymer drug-eluting stents and everolimus- versus sirolimus-eluting stents in patients with coronary artery disease: 3-year outcomes from a randomized clinical trial. [2011.09.20]
OBJECTIVES: The aim of this study was to compare the 3-year efficacy and safety of biodegradable polymer with permanent polymer stents and of everolimus-eluting stents (EES) with sirolimus-eluting stents (SES). BACKGROUND: Biodegradable polymer drug-eluting stents (DES) offer potential for enhanced late outcomes in comparison with permanent polymer stents. In addition, there is increasing interest in the comparison of EES (Xience, Abbott Vascular, Abbott Park, Illinois) versus SES (Cypher, Cordis Corporation, Miami Lakes, Florida)... CONCLUSIONS: Biodegradable polymer and permanent polymer DES are associated with similar clinical outcomes at 3 years. In addition, EES are comparable to SES in terms of overall clinical efficacy and safety. (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting STents [ISAR-TEST 4]: Prospective, Randomized Trial of 3-limus Agent-eluting Stents With Different Polymer Coatings; NCT00598676). Copyright (c) 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Randomized comparison of everolimus-eluting stent versus sirolimus-eluting stent implantation for de novo coronary artery disease in patients with diabetes mellitus (ESSENCE-DIABETES): results from the ESSENCE-DIABETES trial. [2011.08.23]
CONCLUSION: Everolimus-eluting stents were noninferior to sirolimus-eluting stents in reducing in-segment late loss and reduced angiographic restenosis at 8 months in patients with diabetes mellitus and coronary artery disease.
Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. [2011.08.15]
BACKGROUND: Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI)-free regimen... CONCLUSION: In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI-based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance.
Randomized comparison of the nobori biolimus A9-eluting stent with the sirolimus-eluting stent in patients with stenosis in native coronary arteries. [2011.07.29]
Objectives: The aim of this randomized-controlled trial is to compare Biolimus A9-eluting stent (Nobori) to sirolimus eluting stent (Cypher). Background: The Nobori coronary stent is coated only abluminally with a biodegradable polymer, poly-lactic acid, and the antiproliferative agent Biolimus A9.Both stents showed excellent midterm results.
Clinical Trials Related to Rapamune (Sirolimus)
Pharmacokinetic Drug Interaction Between Ezetimibe and Sirolimus After Single Dose Administration in Healthy Subjects [Completed]
Study Evaluating Sirolimus in Kidney Transplant Recipients. [Completed]
Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM [Active, not recruiting]
The purpose of this study is to determine the safety and efficacy of the mTOR inhibitor
sirolimus as a treatment for renal angiomyolipomas in patients with tyberous sclerosis
complex or sporadic lymphangioleiomyomatosis.
Study Evaluating Sirolimus (Rapamune™) in Solid Organ Transplant Recipients [Active, not recruiting]
To evaluate the safety of long-term administration of sirolimus oral solution for up to 5
additional years, or until the tablet formulation is commercially available (whichever occurs
first) in solid organ transplant recipients who are currently receiving sirolimus and who
have completed clinical trials with sirolimus (with or without cyclosporine (CsA). To
evaluate the pharmacokinetics and safety of long-term administration of sirolimus tablets
administered for up to 5 years, or until the tablet formulation is commercially available in
solid organ transplant recipients who are currently receiving sirolimus and who have
completed clinical trials with sirolimus (with or without CsA) or who are currently enrolled
in protocol 0468E1-306-US.
Study of Combination of Sirolimus and Sutent in Patients With Advanced Solid Tumors Non-Curable With Standard Therapy [Active, not recruiting]
There are two drugs involved in this study. Sunitinib (Sutent(R)) is approved by the Food
and Drug Administration (FDA) for the treatment of advanced renal cell (kidney) cancer and
gastrointestinal stromal tumors. Sunitinib is thought to work by blocking the growth of
blood vessels into tumors; reducing the blood supply to tumors can slow their growth and
sometimes causes the tumors to shrink. Sirolimus has been approved by the FDA to prevent the
body from rejecting organ transplants. Sirolimus is being tested for its effects against
cancer because it can slow the growth of some tumors in animal models. Sirolimus is thought
to slow cancer growth in these animal models both by direct effects on the tumor cells, and
also by blocking production of growth factors that stimulate production of blood vessels. We
hope that the combined use of these two drugs will have better anti-cancer effects than
either agent alone. This study is designed to find out if different doses of Sirolimus
combined with a standard dose of Sutent are safe and well tolerated. Additionally, it is
hoped to gain knowledge about the way that Sutent(R) in combination with sirolimus affects
the blood vessels produced by cancer.
Reports of Suspected Rapamune (Sirolimus) Side Effects
Disease Progression (15),
Oedema Peripheral (15),
Drug Ineffective (11),
Interstitial Lung Disease (10),
Weight Decreased (9),
Graft Versus Host Disease (8), more >>
Page last updated: 2013-08-01