The following adverse reactions are discussed in greater detail in other sections of the label.

• Increased susceptibility to infection, lymphoma, and malignancy [see Boxed Warning, WARNINGS and PRECAUTIONS]
• Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients [see Boxed Warning, WARNINGS and PRECAUTIONS]
• Bronchial anastomotic dehiscence in lung transplant patients [see Boxed Warning, WARNINGS and PRECAUTIONS]
• Hypersensitivity reactions [see WARNINGS and PRECAUTIONS]
• Exfoliative dermatitis [see WARNINGS and PRECAUTIONS]
• Angioedema [see WARNINGS and PRECAUTIONS]
• Fluid Accumulation and Wound Healing [see WARNINGS and PRECAUTIONS]
• Hypertriglyceridemia, hypercholesterolemia [see WARNINGS and PRECAUTIONS]
• Decline in renal function in long-term combination of cyclosporine with Rapamune [see WARNINGS and PRECAUTIONS]
• Proteinuria [see WARNINGS and PRECAUTIONS]
• Interstitial lung disease [see WARNINGS and PRECAUTIONS]
• Increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [see WARNINGS and PRECAUTIONS]

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 [see Clinical Studies]. 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 [see Clinical Studies].

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.

ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥ 20% IN AT LEAST ONE OF THE RAPAMUNE TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥ 12 MONTHS POST-TRANSPLANTATION (STUDY 2)^a

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].

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].

At 24 months (Study 1) and 36 months (Study 2), there were no significant differences among treatment groups.

INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANT^a,b

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]. 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] 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.

INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANT^a,b

High Immunologic-Risk Patients

Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [see Clinical Studies]. 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.

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]. 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.

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]. 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]; 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].
• 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]; pulmonary hemorrhage; pleural effusion.
• Skin - Exfoliative dermatitis [see WARNINGS and PRECAUTIONS].
• Urogenital - Nephrotic syndrome, proteinuria. Azoospermia has been reported with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases.

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.

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, CLINICAL PHARMACOLOGY].

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, CLINICAL PHARMACOLOGY].

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, DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

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].

• 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

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.

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