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Immunosuppression increases the susceptibility to infection and the development of lymphoma and other malignancies, particularly of the skin (see Precautions and Adverse Reactions). Oversuppression of the immune system can also increase susceptibility to opportunistic infections, sepsis and fatal infections.
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of Rapamune (see Adverse Reactions).
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended.
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 recipients. 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 recipients, 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.
A clinical study in liver transplant patients randomized to conversion to a sirolimus-based regimen versus continuation of a CNI-based regimen 6-144 months post-liver transplantation demonstrated an increased number of deaths in the sirolimus conversion group compared to the CNI continuation group, although the difference was not statistically significant (see Pharmacology: Pharmacodynamics under Actions).
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.
Drug-Drug Interactions: Co-administration of Rapamune with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) is not recommended. Rapamune is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver. Inhibitors of CYP3A4 decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 increase the metabolism of sirolimus and decrease sirolimus levels (see Interactions).
There have been reports of increased blood levels of sirolimus during concomitant use with cannabidiol. Caution should be used when cannabidiol and Rapamune are co-administered, closely monitor sirolimus blood levels and for adverse events suggestive of sirolimus toxicity (see Sirolimus whole bloodtrough level monitoring under Dosage & Administration and Cannabidiol under Actions).
Wound Healing and Fluid Accumulation: There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence. 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 BMI greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature (see Adverse Reactions).
There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion and pericardial effusions (including hemodynamically significant effusions in children and adults), in patients receiving Rapamune.
Skin Malignancies: Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin. Therefore, patients taking Rapamune should limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protective factor (see Precautions and Adverse Reactions).
Hyperlipidemia: The use of Rapamune may lead to increased serum cholesterol and triglycerides that may require treatment. Patients must be monitored for hyperlipidemia.
Rhabdomyolysis: In clinical trials, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates was well tolerated. During Rapamune 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: Patients treated with cyclosporine and Rapamune had higher serum creatinine levels and lower glomerular filtration rates compared to patients treated with cyclosporine and placebo or azathioprine controls. The rate of decline in renal function was greater in patients receiving Rapamune and cyclosporine compared with control therapies (see Pharmacology: Pharmacodynamics under Actions). Therefore, renal function should be monitored during the co-administration of Rapamune with cyclosporine. Renal function should also be closely monitored during the co-administration of Rapamune with tacrolimus. Appropriate adjustments of the immunosuppressive regimen, including discontinuation of Rapamune and/or cyclosporine and/or tacrolimus, should be considered in patients with elevated serum creatinine levels.
Rapamune Following Cyclosporine Withdrawal: In a study that compared a regimen of Rapamune and cyclosporine to one in which cyclosporine was withdrawn 2-4 months post-transplantation, those in whom cyclosporine was not withdrawn had significantly higher serum creatinine levels and significantly lower glomerular filtration rates at 12 months through 60 months, and significantly lower graft survival at 48 months, the point at which it was decided by the sponsor to discontinue subjects from assigned therapy in the Rapamune and cyclosporine arm. When the protocol was amended all subjects had reached 48 months and some completed the 60 months of the study.
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 individual patients (see Precautions).
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 the 6 through 24 month after conversion to Rapamune compared with CNI continuation (23.6% versus 12.8%, respectively) [see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions]. Those patients in the highest quartile of urinary protein excretion prior to Rapamune conversion (urinary protein to creatinine ratio ≥0.27) were those whose protein excretion increased the most after conversion. New-onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study. 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.
Conversion to Rapamune in Patients with Glomerular Filtration Rate <40 mL/min: In a study evaluating conversion from calcineurin inhibitors (CNI) to Rapamune in maintenance renal transplant patients 6-120 months post-transplant (see Pharmacology: Pharmacodynamics under Actions), in a stratum of the Rapamune treatment arm with a calculated 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. The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.
De novo use without Calcineurin Inhibitor (CNI): The safety and efficacy of de novo use of Rapamune without a calcineurin inhibitor (CNI) is not established in renal transplant patients. In two multi-center clinical studies, de novo renal transplant patients treated with Rapamune, MMF, steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with a calcineurin inhibitor, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arms with de novo use of Rapamune without a CNI. It should be noted that an abbreviated schedule of administration of daclizumab was employed in one of the studies.
Calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA): The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA.
Angioedema: The concomitant administration of Rapamune and angiotensin-converting enzyme (ACE) inhibitors has resulted in angioneurotic edema-type reactions. Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema (see Inhibitors of Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) under Interactions). In some cases, the angioedema has resolved upon discontinuation or dose reduction of Rapamune.
Interstitial Lung Disease: Cases of interstitial lung disease (including pneumonitis, and infrequently bronchiolitis obliterans with 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 Rapamune level increases (see Interstitial Lung Disease under Adverse Reactions).
Latent Viral Infections: Patients treated with immunosuppressants, including Rapamune, are at increased risk for opportunistic infections, including activation of latent viral infections. Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal outcomes, including graft loss. Physicians should consider latent viral infections in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms (see Latent Viral Infections under Adverse Reactions).
Antimicrobial Prophylaxis: 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 infection.
Contraception: Effective contraception must be initiated before Rapamune therapy, and maintained during Rapamune therapy and for 12 weeks after Rapamune therapy has been stopped.
Use in High Risk Patients: The safety and efficacy of cyclosporine withdrawal in high-risk renal transplant patients have not been adequately studied and such use is therefore not recommended. This includes patients with Banff 93 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, renal re-transplants, multi-organ transplants, and patients with a high panel of reactive antibodies (see Indications/Uses and Pharmacology: Pharmacodynamics under Actions).
Abuse and Dependence: Rapamune has no potential for abuse. There is no evidence of dependence on Rapamune.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
