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) ].
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RAPAMUNE SUMMARY
Pharmacokinetics in Specific Populations
Rapamune® (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by
Streptomyces hygroscopicus.
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 In patients at low to moderate immunologic risk cyclosporine should be withdrawn 2 to 4 months after transplantation and Rapamune® dose should be increased to reach recommended blood concentrations (See DOSAGE AND ADMINISTRATION).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).
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NEWS HIGHLIGHTSMedia Articles Related to Rapamune (Sirolimus)
Physicians Must Treat Transplant Tourists
Source: MedPage Today Gastroenterology [2010.01.29]
Patients who travel to foreign countries to have organ transplants may come back with more problems than they left with (MedPage Today) -- and physicians here have a moral responsibility to treat them, researchers say.
Transplant Infectious Disease Experts Provide Pandemic Guidance
Source: Bird Flu / Avian Flu News From Medical News Today [2009.12.04]
Surgeons and other healthcare professionals specialising in solid organ transplants have been issued with expert advice to guide them through the complex clinical issues posed by the global H1N1 (swine flu) pandemic...
Published Studies Related to Rapamune (Sirolimus)
Safety and tolerability of sirolimus treatment in patients with autosomal dominant polycystic kidney disease. [2009.11]
CONCLUSION: Treatment of ADPKD patients with sirolimus with a dose of 1-2 mg/day is safe and does not cause proteinuria or impairment of GFR. Treatment adherence was excellent. (ClinicalTrials.gov number, NCT00346918.).
Long-Term outcome of drug-eluting stents compared with bare metal stents in ST-segment elevation myocardial infarction: results of the paclitaxel- or sirolimus-eluting stent versus bare metal stent in Primary Angioplasty (PASEO) Randomized Trial. [2009.09.15]
CONCLUSIONS: This study shows that among STEMI patients undergoing primary angioplasty, both SES and PES are associated with significant benefits in terms of target lesion revascularization at the long-term follow-up compared with BMS with no excess risk of thrombotic complications. Thus, until the results of further large randomized trials with long-term follow-up become available, drug-eluting stents may be considered among STEMI patients undergoing primary angioplasty.
Analysis of PTEN and HIF-1alpha and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-alpha. [2009.08.15]
BACKGROUND: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 alpha correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-alpha (IFN)... CONCLUSIONS: The baseline status of the molecular markers PTEN and HIF1 alpha did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 alpha status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma.
Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. [2009.08.10]
PURPOSE: Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease... CONCLUSION: Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.
Biolimus-eluting biodegradable polymer versus sirolimus-eluting permanent polymer stent performance in long lesions: results from the LEADERS multicentre trial substudy. [2009.08]
CONCLUSIONS: BES and SES appear similar with respect to MACE in long lesions in this "all-comer" patient population. However, long lesions tended to have a higher rate of binary in-segment restenosis and TLR following BES than SES treatment.
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.
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Page last updated: 2010-01-29
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