Rapamune (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2- [(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6, 8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C₅₁H₇₉NO₁₃ and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows.

Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

Rapamune is available for administration as an oral solution containing 1 mg/mL sirolimus. Rapamune is also available as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus.

The inactive ingredients in Rapamune Oral Solution are Phosal 50 PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Rapamune Oral Solution contains 1.5% - 2.5% ethanol.

The inactive ingredients in Rapamune Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 2 mg dosage strength also contains iron oxide yellow 10 and iron oxide brown 70.

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 [see DOSAGE AND ADMINISTRATION, WARNINGS and PRECAUTIONS].

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recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [see DOSAGE AND ADMINISTRATION].

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 [see DOSAGE AND ADMINISTRATION, Clinical Studies].

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 [see Clinical Studies].

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 [see Clinical Studies].

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 [see ADVERSE REACTIONS, Clinical Studies]. The safety and efficacy of de novo use of Rapamune without cyclosporine have not been established in renal transplant patients [see WARNINGS and PRECAUTIONS].

The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established [see Clinical Studies].

Rapamune is to be administered orally once daily, consistently with or without food [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

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) [see DRUG INTERACTIONS].

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 [see CLINICAL PHARMACOLOGY].

Patients at Low- to Moderate-Immunologic

Risk Rapamune and Cyclosporine Combination Therapy

For denovo 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 [see DOSAGE AND ADMINISTRATION].

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 [SEE DOSAGE AND ADMINISTRATION (2.3)]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the Rapamune dose is increased [see CLINICAL PHARMACOLOGY].

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 [see Clinical Studies]. 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 [see DOSAGE AND ADMINISTRATION].

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 [see DOSAGE AND ADMINISTRATION]. 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, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see DRUG INTERACTIONS].

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 [see Clinical Studies, CLINICAL PHARMACOLOGY]. 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 [see WARNINGS and PRECAUTIONS, CLINICAL PHARMACOLOGY]. 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 [see References].

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 [see CLINICAL PHARMACOLOGY].

Patients with Renal Impairment

Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific Populations].

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 [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY]. 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.

Dosage Forms And Strengths

Rapamune Oral Solution

• 60 mg per 60 mL in amber glass bottle.

Rapamune Tablets

• 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” on one side.
• 2 mg, yellow-to-beige triangular-shaped tablets marked “RAPAMUNE 2 mg” on one side.

Storage And Handling

Since Rapamune is not absorbed through the skin, there are no special precautions. However, if direct contact with the skin or mucous membranes occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Rapamune Oral Solution

Each Rapamune Oral Solution carton, NDC 0008-1030-06, contains one 2 oz (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for fitting into the neck of the bottle, sufficient disposable amber oral syringes and caps for daily dosing, and a carrying case.

Rapamune® Oral Solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used within one month. If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles).

An amber syringe and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). The syringe should be discarded after one use. After dilution, the preparation should be used immediately.

Rapamune Oral Solution provided in bottles may develop a slight haze when refrigerated. If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears. The presence of this haze does not affect the quality of the product.

Rapamune Tablets

Rapamune Tablets are available as follows:

• NDC 0008-1041-05, 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” on one side; bottle containing 100 tablets.
• NDC 0008-1041-10, 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” on one side; in Redipak® cartons of 100 tablets (10 blister cards of 10 tablets each).
  
• NDC 0008-1042-05, 2 mg, yellow-to-beige triangular-shaped tablets marked “RAPAMUNE 2 mg” on one side; bottle containing 100 tablets.

Rapamune Tablets should be stored at 20° to 25°C (USP Controlled Room Temperature) (68° to 77°F). Use cartons to protect blister cards and strips from light. Dispense in a tight, light-resistant container as defined in the USP.

REFERENCES

Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see DOSAGE AND ADMINISTRATION].

For Rapamune Oral Tablets: Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101. For Rapamune Oral Solution: Manufactured for: Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. MADE IN CANADA. FDA revision date: 1/14/2008

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

	Rapamune Oral Solution
Adverse Reaction	2 mg/day (n = 218)	5 mg/day (n = 208)	Placebo (n = 124)
Peripheral edema	54	58	48
Hypertension	45	49	48
Hypercholesterolemia	43	46	23
Creatinine increased	39	40	38
Constipation	36	38	31
Abdominal pain	29	36	30
Diarrhea	25	35	27
Headache	34	34	31
Fever	23	34	35
Urinary tract infection	26	33	26
Anemia	23	33	21
Nausea	25	31	29
Arthralgia	25	31	18
Thrombocytopenia	14	30	9
Pain	33	29	25
Acne	22	22	19
Rash	10	20	6
Edema	20	18	15
a Patients received cyclosporine and corticosteroids.

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 Oral Solution 2 mg/day		Rapamune Oral Solution 5 mg/day		Azathioprine 2-3 mg/kg/day	Placebo
Malignancy	Study 1 (n = 284)	Study 2 (n = 227)	Study 1 (n = 274)	Study 2 (n = 219)	Study 1 (n = 161)	Study 2 (n = 130)
Lymphoma/ lymphoproliferative disease	0.7	1.8	1.1	3.2	0.6	0.8
Skin Carcinoma
Any Squamous Cellc	0.4	2.7	2.2	0.9	3.8	3.0
Any Basal Cellc	0.7	2.2	1.5	1.8	2.5	5.3
Melanoma	0.0	0.4	0.0	1.4	0.0	0.0
Miscellaneous/Not Specified	0.0	0.0	0.0	0.0	0.0	0.8
Total	1.1	4.4	3.3	4.1	4.3	7.7
Other Malignancy	1.1	2.2	1.5	1.4	0.6	2.3
a Patients received cyclosporine and corticosteroids. b Includes patients who prematurely discontinued treatment. c Patients may be counted in more than one category.

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

Malignancy	Nonrandomized (n = 95)	Rapamune with Cyclosporine Therapy (n = 215)	Rapamune Following Cyclosporine Withdrawal (n = 215)
Lymphoma/lymphoproliferative disease	1.1	1.4	0.5
Skin Carcinoma
Any Squamous Cellc	3.2	3.3	2.3
Any Basal Cellc	3.2	6.5	2.3
Melanoma	0.0	0.5	0.0
Miscellaneous/Not Specified	1.1	0.9	0.0
Total	4.2	7.9	3.7
Other Malignancy	3.2	3.3	1.9
a Patients received cyclosporine and corticosteroids. b Includes patients who prematurely discontinued treatment. c Patients may be counted in more than one category.

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.

Included as part of the PRECAUTIONS section.

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) [see ADVERSE REACTIONS]. Oversuppression of the immune system can also increase susceptibility 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.

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 (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.

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.

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 [see ADVERSE REACTIONS].

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 [see ADVERSE REACTIONS]. 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 [see ADVERSE REACTIONS]. 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 [see ADVERSE REACTIONS]. 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 [see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS]. 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 [see ADVERSE REACTIONS].

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, 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.

Increased Risk of 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 hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [see ADVERSE REACTIONS].

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 [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

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 [see DRUG INTERACTIONS].

Patient Counseling Information

See FDA-Approved Patient Labeling.

Dosage

Patients should be given complete dosage instructions [see Patient Counseling Information].

Skin Cancer Events

Patients should be told that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer [see WARNINGS and PRECAUTIONS].

Pregnancy Risks

Women of childbearing potential should be informed of the potential risks during pregnancy and told that they should use effective contraception prior to initiation of Rapamune therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped [see Use in Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

Fertility was diminished slightly in both male and female rats following oral administration of sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduction in sperm counts were observed. In female rats, reduced size of ovaries and uteri was observed. Reduction of sperm count in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at doses that were approximately equal to the clinical dose (adjusted for body surface area).

Use In Specific Populations

Pregnancy

Pregnancy Category C: 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.

Nursing Mothers

Sirolimus is excreted in trace amounts in milk of lactating rats. It is not known whether sirolimus is excreted in human milk. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from sirolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Rapamune in pediatric patients < 13 years have not been established.

The safety and efficacy of Rapamune Oral Solution and Rapamune Tablets have been established in children ≥ 13 years judged to be at low-to-moderate immunologic risk. Use of Rapamune Oral Solution and Rapamune® Tablets in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of Rapamune Oral Solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [see CLINICAL PHARMACOLOGY].

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent ( < 18 years of age) renal transplant patients judged to be at high immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of Rapamune Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [see Clinical Studies].

Geriatric Use

Clinical studies of Rapamune Oral Solution or Tablets did not include sufficient numbers of patients ≥ 65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, or cardiac function, and of concomitant disease or other drug therapy.

Patients with Hepatic Impairment

The maintenance dose of Rapamune should be reduced in patients with hepatic impairment [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Patients with Renal Impairment

Dosage adjustment is not required in patients with renal impairment [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Reports of overdose with Rapamune have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [see ADVERSE REACTIONS].

General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg.

Rapamune is contraindicated in patients with a hypersensitivity to Rapamune [see WARNINGS and PRECAUTIONS].

Mechanism Of Action

Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G₁ to the S phase of the cell cycle.

Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen specific.

In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

Pharmacokinetics

Sirolimus pharmacokinetic activity has been determined following oral administration in healthy subjects, pediatric patients, hepatically-impaired patients, and renal transplant patients.

Absorption

Following administration of Rapamune® Oral Solution, sirolimus is rapidly absorbed, with a mean time-to-peak concentration (tmax) of approximately 1 hour after a single dose in healthy subjects and approximately 2 hours after multiple oral doses in renal transplant recipients. The systemic availability of sirolimus was estimated to be approximately 14% after the administration of Rapamune Oral Solution. The mean bioavailability of sirolimus after administration of the tablet is about 27% higher relative to the oral solution. Sirolimus oral tablets are not bioequivalent to the oral solution; however, clinical equivalence has been demonstrated at the 2-mg dose level. (See DOSAGE AND ADMINISTRATION).

Distribution

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft recipients after administration of oral solution, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (V_ss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins. In man, the binding of sirolimus was shown mainly to be associated with serum albumin (97%), α₁-acid glycoprotein, and lipoproteins.

Metabolism

Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein (P-gp). Sirolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-gp drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Therefore, absorption and subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect these proteins. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations. (See WARNINGS and PRECAUTIONS: DRUG INTERACTIONS and Other drug interactions). Sirolimus is extensively metabolized by O-demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Glucuronide and sulfate conjugates are not present in any of the biologic matrices. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity.

Excretion

After a single dose of [¹⁴C]sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine.

Pharmacokinetics In Renal Transplant Patients

Rapamune Oral Solution: Pharmacokinetic parameters for sirolimus oral solution given daily in combination with cyclosporine and corticosteroids in renal transplant patients are summarized below based on data collected at months 1, 3, and 6 after transplantation (Studies 1 and 2; see Clinical Studies). There were no significant differences in any of these parameters with respect to treatment group or month.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN RENAL TRANSPLANT PATIENTS (MULTIPLE DOSE ORAL SOLUTION)^a,b

N	Dose	Cmax,ssc (ng/mL)	tmax,ss (h)	AUCτ ,ssc (ng•h/mL)	CL/F/WTd (mL/h/kg)
19	2 mg	12.2 ± 6.2	3.01 ± 2.40	158 ± 70	182 ± 72
23	5 mg	37.4 ± 21	1.84 ± 1.30	396 ± 193	221 ± 143
a: Sirolimus administered four hours after cyclosporine oral solution (MODIFIED) (e.g., Neoral® Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules). b: As measured by the Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS). c: These parameters were dose normalized prior to the statistical comparison. d: CL/F/WT = oral dose clearance.

Whole blood sirolimus trough concentrations (mean ± SD), expressed as chromatographic assay values, for the 2 mg/day and 5 mg/day dose groups were 6.9 ± 3.2 ng/mL (n = 226) and 13.8 ± 5.9 ng/mL (n = 219), respectively (see DOSAGE AND ADMINISTRATION). Whole blood trough sirolimus concentrations, as measured by LC/MS/MS, were significantly correlated (r² = 0.96) with AUCτ ,ss. Upon repeated twice daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2 to 3-fold over the initial 6 days of therapy at which time steady state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients. The mean ± SD terminal elimination half life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.

Rapamune Tablets: Pharmacokinetic parameters for sirolimus tablets administered daily in combination with cyclosporine and corticosteroids in renal transplant patients are summarized below based on data collected at months 1 and 3 after transplantation (Study 3; see Clinical Studies).

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN RENAL TRANSPLANT PATIENTS (MULTIPLE DOSE TABLETS)^a,b

n	Dose (2 mg/day)	Cmax,ssc (ng/mL)	tmax,ss (h)	AUCτ ,ssc (ng•h/mL)	CL/F/WTd (mL/h/kg)
17	Oral solution	14.4 ± 5.3	2.12 ± 0.84	194 ± 78	173 ± 50
13	Tablets	15.0 ± 4.9	3.46 ± 2.40	230 ± 67	139 ± 63
a: Sirolimus administered four hours after cyclosporine oral solution (MODIFIED) (e.g., Neoral® Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules). b: As measured by the Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS). c: These parameters were dose normalized prior to the statistical comparison. d: CL/F/WT = oral dose clearance.

Whole blood sirolimus trough concentrations (mean ± SD), expressed as chromatographic assay values, for 2 mg of oral solution and 2 mg of tablets over 6 months, were 7.1 ± 3.5 ng/mL (n = 172) and 7.6 ± 3.1 ng/mL (n = 179), respectively (see DOSAGE AND ADMINISTRATION). Whole blood trough sirolimus concentrations, as measured by LC/MS/MS, were significantly correlated (r² = 0.85) with AUC_{τ ,ss}. Mean whole blood sirolimus trough concentrations in patients receiving either Rapamune Oral Solution or Rapamune Tablets with a loading dose of three times the maintenance dose achieved steady-state concentrations within 24 hours after the start of dose administration.

Average Rapamune doses and sirolimus whole blood trough concentrations for tablets administered daily in combination with cyclosporine and following cyclosporine withdrawal, in combination with corticosteroids in renal transplant patients (Study 4; see Clinical Studies) are summarized in the table below.

AVERAGE RAPAMUNE DOSES AND SIROLIMUS TROUGH CONCENTRATIONS (MEAN ± SD) IN LOW- TO MODERATE- RISK RENAL TRANSPLANT PATIENTS AFTER MULTIPLE DOSE TABLET ADMINISTRATION

	Rapamune with Cyclosporine Therapya	Rapamune Following Cyclosporine Withdrawala
Rapamune Dose (mg/day)
Months 4 to 12	2.1 ± 0.7	8.2 ± 4.2
Months 12 to 24	2.0 ± 0.8	6.4 ± 3.0
Months 24 to 36	2.0 ± 0.8	5.3 ± 2.5
Sirolimus Cmin, (ng/mL)b
Months 4 to 12	8.6 ± 3.0	18.6 ± 4.0
Months 12 to 24	9.0 ± 3.3	18.0 ± 3.8
Months 24 to 36	9.1 ± 3.4	16.3 ± 4.3
a: 215 patients were randomized to each group. b: Expressed as chromatographic assay values and equivalence.

The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Larger Rapamune® doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target concentrations during concentration-controlled administration following cyclosporine withdrawal.

Average Rapamune doses and sirolimus whole blood trough concentrations for tablets administered daily in combination with cyclosporine and corticosteroids in high-risk renal transplant patients (Study 5; see Clinical Studies) are summarized in the table below.

AVERAGE RAPAMUNE DOSES AND SIROLIMUS TROUGH CONCENTRATIONS (MEAN ± SD) IN HIGH-RISK RENAL TRANSPLANT PATIENTS AFTER MULTIPLE-DOSE TABLET ADMINISTRATION

	Rapamune with Cyclosporine Therapy
Rapamune Dose (mg/day)
Months 3 to 6	5.1 ± 2.4
Months 6 to 9	5.1 ± 2.3
Months 9 to 12	5.0 ± 2.3
Sirolimus Cmin (ng/mL)a
Months 3 to 6b	11.8 ± 4.2
Months 6 to 9c	11.3 ± 5.2
Months 9 to 12d	11.2 ± 3.8
a: Expressed by chromatography b: n=109 c: n=113 d: n=127

Special Populations

Hepatic impairment: Sirolimus oral solution (15 mg) was administered as a single oral dose to 18 subjects with normal hepatic function and to 18 patients with Child-Pugh classification A or B hepatic impairment, in which hepatic impairment was primary and not related to an underlying systemic disease. Shown below are the mean ± SD pharmacokinetic parameters following the administration of sirolimus oral solution.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN 18 HEALTHY SUBJECTS AND 18 PATIENTS WITH HEPATIC IMPAIRMENT (15 MG SINGLE DOSE - ORAL SOLUTION)

Population	Cmax,ssa (ng/mL)	tmax (h)	AUC0-∞ (ng•h/mL)	CL/F/WT (mL/h/kg)
Healthy subjects	78.2 ± 18.3	0.82 ± 0.17	970 ± 272	215 ± 76
Hepatic impairment	77.9 ± 23.1	0.84 ± 0.17	1567 ± 616	144 ± 62
a: As measured by LC/MS/MS.

Compared with the values in the normal hepatic group, the hepatic impairment group had higher mean values for sirolimus AUC (61%) and t½ (43%) and had lower mean values for sirolimus CL/F/WT (33%). The mean t½ increased from 79 ± 12 hours in subjects with normal hepatic function to 113 ± 41 hours in patients with impaired hepatic function. The rate of absorption of sirolimus was not altered by hepatic disease, as evidenced by Cmax and tmax values. However, hepatic diseases with varying etiologies may show different effects and the pharmacokinetics of sirolimus in patients with severe hepatic dysfunction is unknown. Dosage adjustment is recommended for patients with mild to moderate hepatic impairment (see DOSAGE AND ADMINISTRATION).

Renal impairment: The effect of renal impairment on the pharmacokinetics of sirolimus is not known. However, there is minimal (2.2%) renal excretion of the drug or its metabolites.

Pediatric: Sirolimus pharmacokinetic data were collected in concentration-controlled trials of pediatric renal transplant patients who were also receiving cyclosporine and corticosteroids. The target ranges for trough concentrations were either 10-20 ng/mL for the 21 children receiving tablets, or 5-15 ng/mL for the one child receiving oral solution. The children aged 6-11 years (n = 8) received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m²). The children aged 12-18 years (n = 14) received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86 ± 0.61 mg/m²). At the time of sirolimus blood sampling for pharmacokinetic evaluation, the majority (80%) of these pediatric patients received the sirolimus dose at 16 hours after the once daily cyclosporine dose.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE DOSE CONCENTRATION CONTROL)^a,b

Age (y)	n	Body weight (kg)	Cmax,ss (ng/mL)	tmax,ss (h)	Cmin,ss (ng/mL)	AUCι ,ss (ng•h/mL)	CL/Fc (mL/h/kg)	CL/Fc (L/h/m²)
6-11	8	27 ± 10	22.1 ± 8.9	5.88 ± 4.05	10.6 ± 4.3	356 ± 127	214 ± 129	5.4 ± 2.8
12-18	14	52 ± 15	34.5 ± 12.2	2.7 ± 1.5	14.7 ± 8.6	466 ± 236	136 ± 57	4.7 ± 1.9
a: Sirolimus co-administered with cyclosporine oral solution (MODIFIED) (e.g., Neoral Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral Soft Gelatin Capsules). b: As measured by Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS). c: Oral-dose clearance adjusted by either body weight (kg) or body surface area (m²).

The table below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function.

SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC PATIENTS WITH STABLE CHRONIC RENAL FAILURE MAINTAINED ON HEMODIALYSIS OR PERITONEAL DIALYSIS (1, 3, 9, 15 MG/m² SINGLE DOSE)*

Age Group (y)	n	tmax (h)	t½ (h)	CL/F (mL/h/kg)
5-11	9	1.1 ± 0.5	71 ± 40	580 ± 450
12-18	11	0.79 ± 0.17	55 ± 18	450 ± 232
* All subjects received sirolimus oral solution

Geriatric: Clinical studies of Rapamune did not include a sufficient number of patients > 65 years of age to determine whether they will respond differently than younger patients. After the administration of Rapamune Oral Solution, sirolimus trough concentration data in 35 renal transplant patients > 65 years of age were similar to those in the adult population (n = 822) 18 to 65 years of age. Similar results were obtained after the administration of Rapamune Tablets to 12 renal transplant patients > 65 years of age compared with adults (n = 167) 18 to 65 years of age.

Gender: After the administration of Rapamune Oral Solution, sirolimus oral dose clearance in males was 12% lower than that in females; male subjects had a significantly longer t½ than did female subjects (72.3 hours versus 61.3 hours). A similar trend in the effect of gender on sirolimus oral dose clearance and t½ was observed after the administration of Rapamune Tablets. Dose adjustments based on gender are not recommended.

Race: In large phase 3 trials (Studies 1 and 2) using Rapamune Oral Solution and cyclosporine oral solution (MODIFIED) (e.g., Neoral® Oral Solution) and/or cyclosporine capsules (MODIFIED) (e.g., Neoral® Soft Gelatin Capsules), there were no significant differences in mean trough sirolimus concentrations over time between black (n = 139) and non-black (n = 724) patients during the first 6 months after transplantation at sirolimus doses of 2 mg/day and 5 mg/day. Similarly, after administration of Rapamune Tablets (2 mg/day) in a phase III trial, mean sirolimus trough concentrations over 6 months were not significantly different among black (n = 51) and non-black (n = 128) patients.

Clinical Studies

Rapamune® Oral Solution: 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. These studies compared two dose levels of Rapamune Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive Rapamune Oral Solution 2 mg/day, 274 were randomized to receive Rapamune Oral Solution 5 mg/day, and 161 to receive azathioprine 2-3 mg/kg/day. Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive Rapamune Oral Solution 2 mg/day, 219 were randomized to receive Rapamune Oral Solution 5 mg/day, and 130 to receive placebo. In both studies, the use of antilymphocyte antibody induction therapy was prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation. Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.

The tables below summarize the results of the primary efficacy analyses from these trials. Rapamune Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the < 0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo.

INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1^a,b

Parameter	Rapamune® Oral Solution 2 mg/day(n = 284)	Rapamune® Oral Solution 5 mg/day (n = 274)	Azathioprine 2-3 mg/kg/day (n = 161)
Efficacy failure at 6 monthsc	18.7	16.8	32.3
Components of efficacy failure
Biopsy-proven acute rejection	16.5	11.3	29.2
Graft loss	1.1	2.9	2.5
Death	0.7	1.8	0
Lost to follow-up	0.4	0.7	0.6
Efficacy failure at 24 months	32.8	25.9	36.0
Components of efficacy failure
Biopsy-proven acute rejection	23.6	17.5	32.3
Graft loss	3.9	4.7	3.1
Death	4.2	3.3	0
Lost to follow-up	1.1	0.4	0.6
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Primary endpoint.

INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2^a,b

Parameter	Rapamune® Oral Solution 2 mg/day (n = 227)	Rapamune® Oral Solution 5 mg/day (n = 219)	Placebo (n = 130)
Efficacy failure at 6 monthsc	30.0	25.6	47.7
Components of efficacy failure
Biopsy-proven acute rejection	24.7	19.2	41.5
Graft loss	3.1	3.7	3.9
Death	2.2	2.7	2.3
Lost to follow-up	0	0	0
Efficacy failure at 36 months	44.1	41.6	54.6
Components of efficacy failure
Biopsy-proven acute rejection	32.2	27.4	43.9
Graft loss	6.2	7.3	4.6
Death	5.7	5.9	5.4
Lost to follow-up	0	0.9	0.8
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Primary endpoint.

Patient and graft survival at 1 year were co-primary endpoints. The table below shows graft and patient survival at 1 and 2 years in Study 1 and 1 and 3 years in Study 2. The graft and patient survival rates were similar in patients treated with Rapamune and comparator-treated patients.

GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS)^a,b

Study 1

Parameter	Rapamune® Oral Solution 2 mg/day	Rapamune® Oral Solution 5 mg/day	Azathioprine 2-3 mg/kg/day	Placebo
(n = 284)	(n = 274)	(n = 161)
Graft survival
Month 12	94.7	92.7	93.8
Month 24	85.2	89.1	90.1
Patient survival
Month 12	97.2	96.0	98.1
Month 24	92.6	94.9	96.3
Study 2	(n = 227)	(n = 219)		(n = 130)
Graft survival
Month 12	89.9	90.9		87.7
Month 36	81.1	79.9		80.8
Patient survival
Month 12	96.5	95.0		94.6
Month 36	90.3	89.5		90.8
a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment.

The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with Rapamune compared with the control groups included a reduction in all grades of rejection.

In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for Rapamune Oral Solution 2 mg/day and lower for Rapamune Oral Solution 5 mg/day compared with azathioprine in black patients. In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both Rapamune Oral Solution doses compared with placebo in black patients. The decision to use the higher dose of Rapamune Oral Solution in black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the Rapamune Oral Solution 5-mg dose (see ADVERSE REACTIONS).

PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS^a,b

<

Parameter	Rapamune® Oral Solution 2 mg/day	Rapamune® Oral Solution 5 mg/day	Azathioprine 2-3 mg/kg/day	Placebo
Study 1
Black (n = 166)	34.9 (n = 63)	18.0 (n = 61)	33.3 (n = 42)
Non-black (n = 553)	14.0 (n = 221)