Sirolimus

Sirolimus oral solution is an mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in patients aged ≥13 years receiving renal transplants: Patients at low- to moderate-immunologic risk: Use initially with cyclosporine (CsA) and corticosteroids. CsA withdrawal is recommended 2 to 4 months after transplantation ( 1.1 ). Patients at high-immunologic risk: Use in combination with CsA and corticosteroids for the first 12 months following transplantation ( 1.1 ). Safety and efficacy of CsA withdrawal has not been established in high risk patients ( 1.1 , 1.2 , 14.3 ). Sirolimus oral solution is an mTOR inhibitor indicated for the treatment of patients with lymphangioleiomyomatosis ( 1.3 ).

1.1 Prophylaxis of Organ Rejection in Renal Transplantation Sirolimus oral solution is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk , it is recommended that sirolimus oral solution be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [ see Dosage and Administration (2.2) ]. 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 sirolimus oral solution be used in combination with cyclosporine and corticosteroids for the first year following transplantation [ see Dosage and Administration (2.3) and Clinical Studies (14.3) ].

1.2 Limitations of Use in Renal Transplantation 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 (14.2) ]. In patients at high-immunologic risk , the safety and efficacy of sirolimus oral solution 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 (14.3) ]. In pediatric patients , the safety and efficacy of sirolimus oral solution 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 (6.5) and Clinical Studies (14.6) ]. The safety and efficacy of de novo use of sirolimus oral solution without cyclosporine have not been established in renal transplant patients [ see Warnings and Precautions (5.12) ]. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus oral solution in maintenance renal transplant patients have not been established [ see Clinical Studies (14.4) ].

1.3 Treatment of Patients with Lymphangioleiomyomatosis Sirolimus oral solution is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

1.1 Prophylaxis of Organ Rejection in Renal Transplantation Sirolimus oral solution is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk , it is recommended that sirolimus oral solution be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [ see Dosage and Administration (2.2) ]. 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 sirolimus oral solution be used in combination with cyclosporine and corticosteroids for the first year following transplantation [ see Dosage and Administration (2.3) and Clinical Studies (14.3) ].

1.2 Limitations of Use in Renal Transplantation 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 (14.2) ]. In patients at high-immunologic risk , the safety and efficacy of sirolimus oral solution 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 (14.3) ]. In pediatric patients , the safety and efficacy of sirolimus oral solution 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 (6.5) and Clinical Studies (14.6) ]. The safety and efficacy of de novo use of sirolimus oral solution without cyclosporine have not been established in renal transplant patients [ see Warnings and Precautions (5.12) ]. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus oral solution in maintenance renal transplant patients have not been established [ see Clinical Studies (14.4) ].

Sirolimus oral solution is to be administered orally once daily, consistently with or without food [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Renal Transplant Patients: Administer once daily by mouth, consistently with or without food (2) . Administer the initial dose as soon as possible after transplantation and 4 hours after CsA (2.1 , 7.1) . Adjust the sirolimus oral solution maintenance dose to achieve sirolimus trough concentrations within the target-range (2.5) . Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment (2.7 , 8.6 , 12.3 ). In renal transplant patients at low-to moderate-immunologic risk : Sirolimus Oral Solution and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg (2.2) . Sirolimus Oral Solution Following CsA Withdrawal: 2 to 4 months post-transplantation, withdraw CsA over 4 to 8 weeks (2.2) . In renal transplant patients at high-immunologic risk: Sirolimus Oral Solution and CsA Combination Therapy (for the first 12 months post-transplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg (2.3) . Lymphangioleiomyomatosis Patients: Administer once daily by mouth, consistently with or without food ( 2 ). Recommended initial sirolimus oral solution dose is 2 mg/day ( 2.4 ). Adjust the sirolimus oral solution dose to achieve sirolimus trough concentrations between 5 to 15 ng/mL ( 2.4 ). Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment ( 2.7 , 8.6 , 12.3 ). Therapeutic drug monitoring is recommended for all patients ( 2.5 , 5.17 ).

2.1 General Dosing Guidance for Renal Transplant Patients The initial dose of sirolimus oral solution should be administered as soon as possible after transplantation. It is recommended that sirolimus oral solution be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED) [ see Drug Interactions (7.2) ]. Frequent sirolimus oral solution dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus oral solution 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 sirolimus oral solution 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: sirolimus oral solution loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum sirolimus oral solution 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 sirolimus oral solution have been demonstrated to be clinically equivalent to 2 mg sirolimus tablets; hence, at this dose these two formulations are interchangeable. However, it is not known if higher doses of sirolimus oral solution are clinically equivalent to higher doses of sirolimus tablets on a mg-to-mg basis [ see Clinical Pharmacology (12.3) ].

2.2 Renal Transplant Patients at Low- to Moderate-Immunologic Risk Sirolimus Oral Solution and Cyclosporine Combination Therapy For de novo renal transplant patients, it is recommended that sirolimus oral solution be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus oral solution 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 (2.5) ]. Sirolimus Oral Solution Following Cyclosporine Withdrawal At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus oral solution dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [ see Dosage and Administration (2.5) ]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus oral solution dose is increased [ see Clinical Pharmacology (12.3) ].

2.3 Renal Transplant Patients at High-Immunologic Risk In patients with high-immunologic risk, it is recommended that sirolimus oral solution be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [ see Clinical Studies (14.3) ]. 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 sirolimus oral solution with cyclosporine, sirolimus oral solution 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 sirolimus oral solution should thereafter be adjusted [ see Dosage and Administration (2.5) ]. 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 (2.5) ]. Prednisone should be administered at a minimum of 5 mg/day. Antibody induction therapy may be used.

2.4 Dosing in Patients with Lymphangioleiomyomatosis For patients with lymphangioleiomyomatosis, the initial sirolimus oral solution dose should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain concentrations between 5 ng/mL to 15 ng/mL [see Dosage and Administration (2.5) ] . In most patients, dose adjustments can be based on simple proportion: new sirolimus oral solution dose = current dose x (target concentration/current concentration). Frequent sirolimus oral solution dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life. Once sirolimus oral solution 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. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every three months.

2.5 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, when a change in the sirolimus oral solution dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see Warnings and Precautions (5.20, 5.21) and Drug Interactions (7) ] . Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus oral solution 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 (14) and Clinical Pharmacology (12.3) ] . Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 ng/mL to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 ng/mL to 20 ng/mL. The above 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. 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 (5.17) and Clinical Pharmacology (12.3) ] . Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [ see References (15) ].

2.6 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/m 2 /day. The loading dose should be 3 mg/m 2 .

2.7 Patients with Hepatic Impairment It is recommended that the maintenance dose of sirolimus oral solution 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. It is not necessary to modify the sirolimus oral solution loading dose [ see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

2.8 Patients with Renal Impairment Dosage adjustment is not needed in patients with impaired renal function [ see Use in Specific Populations (8.7) ].

2.9 Instructions for Dilution and Administration of Sirolimus Oral Solution The amber oral dose syringe should be used to withdraw the prescribed amount of sirolimus oral solution from the bottle. Empty the correct amount of sirolimus oral solution 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 (7.3) and Clinical Pharmacology (12.3) ] . 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. Sirolimus 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 sirolimus oral solution. It is important that these recommendations be followed closely.

2.1 General Dosing Guidance for Renal Transplant Patients The initial dose of sirolimus oral solution should be administered as soon as possible after transplantation. It is recommended that sirolimus oral solution be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED) [ see Drug Interactions (7.2) ]. Frequent sirolimus oral solution dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus oral solution 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 sirolimus oral solution 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: sirolimus oral solution loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum sirolimus oral solution 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 sirolimus oral solution have been demonstrated to be clinically equivalent to 2 mg sirolimus tablets; hence, at this dose these two formulations are interchangeable. However, it is not known if higher doses of sirolimus oral solution are clinically equivalent to higher doses of sirolimus tablets on a mg-to-mg basis [ see Clinical Pharmacology (12.3) ].

2.2 Renal Transplant Patients at Low- to Moderate-Immunologic Risk Sirolimus Oral Solution and Cyclosporine Combination Therapy For de novo renal transplant patients, it is recommended that sirolimus oral solution be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus oral solution 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 (2.5) ]. Sirolimus Oral Solution Following Cyclosporine Withdrawal At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus oral solution dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [ see Dosage and Administration (2.5) ]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus oral solution dose is increased [ see Clinical Pharmacology (12.3) ].

2.3 Renal Transplant Patients at High-Immunologic Risk In patients with high-immunologic risk, it is recommended that sirolimus oral solution be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [ see Clinical Studies (14.3) ]. 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 sirolimus oral solution with cyclosporine, sirolimus oral solution 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 sirolimus oral solution should thereafter be adjusted [ see Dosage and Administration (2.5) ]. 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 (2.5) ]. Prednisone should be administered at a minimum of 5 mg/day. Antibody induction therapy may be used.

2.5 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, when a change in the sirolimus oral solution dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see Warnings and Precautions (5.20, 5.21) and Drug Interactions (7) ] . Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus oral solution 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 (14) and Clinical Pharmacology (12.3) ] . Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 ng/mL to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 ng/mL to 20 ng/mL. The above 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. 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 (5.17) and Clinical Pharmacology (12.3) ] . Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [ see References (15) ].

2.6 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/m 2 /day. The loading dose should be 3 mg/m 2 .

2.7 Patients with Hepatic Impairment It is recommended that the maintenance dose of sirolimus oral solution 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. It is not necessary to modify the sirolimus oral solution loading dose [ see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

2.8 Patients with Renal Impairment Dosage adjustment is not needed in patients with impaired renal function [ see Use in Specific Populations (8.7) ].

2.9 Instructions for Dilution and Administration of Sirolimus Oral Solution The amber oral dose syringe should be used to withdraw the prescribed amount of sirolimus oral solution from the bottle. Empty the correct amount of sirolimus oral solution 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 (7.3) and Clinical Pharmacology (12.3) ] . 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. Sirolimus 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 sirolimus oral solution. It is important that these recommendations be followed closely.

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions (5.4) Angioedema (5.5) Fluid Accumulation and Impairment of Wound Healing (5.6) Hyperlipidemia (5.7) Decline in Renal Function (5.8) Proteinuria (5.9) Latent Viral Infections (5.10) Interstitial Lung Disease/Non-Infectious Pneumonitis (5.11) De Novo Use Without Cyclosporine (5.12) Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/ Thrombotic Thrombocytopenic Purpura/ Thrombotic Microangiopathy (5.13) Embryo-Fetal Toxicity: Can cause fetal harm. Use of highly effective contraception is recommended for females of reproductive potential during treatment and for 12 weeks after final dose of sirolimus ( 5.15 , 8.1 ) Male Infertility: Azoospermia or oligospermia may occur ( 5.16 , 13.1 ) Immunizations: Avoid live vaccines ( 5.19 )

5.1 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% to 3.2% (for sirolimus-treated patients) versus 0.6% to 0.8% (azathioprine and placebo control) [see Adverse Reactions (6.1) , (6.2) ] . 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 sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. 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.

5.2 Liver Transplantation – Excess Mortality, Graft Loss and Hepatic Artery Thrombosis The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of sirolimus has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT). In a study in de novo liver transplant patients, the use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss (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 sirolimus 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. In a clinical study in stable liver transplant patients 6 to 144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a sirolimus-based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [see Clinical Studies (14.5) ] .

5.3 Lung Transplantation – Bronchial Anastomotic Dehiscence Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.

5.4 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of sirolimus [ see Adverse Reactions (6.7) ].

5.5 Angioedema Sirolimus has been associated with the development of angioedema. The concomitant use of sirolimus with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema [see Drug Interactions (7.2) ] . In some cases, the angioedema has resolved upon discontinuation or dose reduction of sirolimus.

5.6 Fluid Accumulation and Impairment of Wound Healing There have been reports of impaired or delayed wound healing in patients receiving sirolimus, including lymphocele and wound dehiscence [see Adverse Reactions (6.1) ] . Mammalian target of rapamycin (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 sirolimus [see Adverse Reactions (6.1) ] . Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m 2 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, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving sirolimus.

5.7 Hyperlipidemia Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with sirolimus compared with azathioprine or placebo controls in Studies 1 and 2 [see Adverse Reactions (6.1) ] . There were increased incidences of hypercholesterolemia (43% to 46%) and/or hypertriglyceridemia (45% to 57%) in patients receiving sirolimus compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus. Any patient who is administered sirolimus 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 of patients receiving sirolimus plus cyclosporine or sirolimus after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels. The concomitant administration of sirolimus and HMG-CoA reductase inhibitors resulted in adverse reactions such as CPK elevations (3%), myalgia (6.7%) and rhabdomyolysis (<1%). In these trials, the number of patients was too small and duration of follow-up too short to evaluate the long-term impact of sirolimus on cardiovascular mortality. During sirolimus 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.

5.8 Decline in Renal Function Renal function should be closely monitored during the co-administration of sirolimus with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and sirolimus 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 sirolimus and cyclosporine compared with control therapies. Appropriate adjustment of the immunosuppressive regimen, including discontinuation of sirolimus 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, sirolimus may delay recovery of renal function.

5.9 Proteinuria Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to sirolimus in maintenance renal transplant patients 6 to 120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to sirolimus compared with CNI continuation [see Clinical Studies (14.4) and Adverse Reactions (6.4) ] . Patients with the greatest amount of urinary protein excretion prior to sirolimus conversion were those whose protein excretion increased the most after conversion. New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse reaction in 2.2% of the sirolimus 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 sirolimus 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 sirolimus. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established.

5.10 Latent Viral Infections Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy, which has been observed in renal transplant patients receiving immunosuppressants, including sirolimus. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions (6.7) ] . Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with immunosuppressants, including sirolimus. PML commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.

5.11 Interstitial Lung Disease/Non-Infectious Pneumonitis Cases of interstitial lung disease [ILD] (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 sirolimus. In some cases, the ILD was reported with pulmonary hypertension (including pulmonary arterial hypertension [PAH]) as a secondary event. In some cases, the ILD has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the trough sirolimus concentration increases [see Adverse Reactions (6.7) ] .

5.12 De Novo Use Without Cyclosporine The safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (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 sirolimus without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

5.13 Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/ Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy The concomitant use of sirolimus 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 (6.7) ] .

5.14 Antimicrobial Prophylaxis Cases of Pneumocystis carinii pneumonia have been reported in transplant 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.

5.15 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , sirolimus can cause fetal harm when administered to a pregnant woman. In animal studies, sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using sirolimus and for 12 weeks after ending treatment [see Use in Specific Populations (8.1) ].

5.16 Male Infertility Azoospermia or oligospermia may be observed [see Adverse Reactions (6.7) and Nonclinical Toxicology (13.1) ]. Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

5.17 Different Sirolimus Trough Concentrations Reported between Chromatographic and Immunoassay Methodologies Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies. Patient sample concentration values from different assays may not be interchangeable [see Dosage and Administration (2.5) ] .

5.18 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 broad spectrum sunscreen with a high protection factor [see Adverse Reactions ( 6.1 , 6.2 , 6.7 )] .

5.19 Immunizations The use of live vaccines should be avoided during treatment with sirolimus; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective.

5.20 Interaction with Strong Inhibitors and Inducers of CYP3A4 and/or P-gp Avoid concomitant use of sirolimus 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) [ see Drug Interactions (7.2) ].

5.21 Cannabidiol Drug Interactions When cannabidiol and sirolimus are co-administered, closely monitor for an increase in sirolimus blood levels and for adverse reactions suggestive of sirolimus toxicity. A dose reduction of sirolimus should be considered as needed when sirolimus is co-administered with cannabidiol [see Dosage and Administration (2.5) and Drug Interactions (7.5) ] .

5.1 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% to 3.2% (for sirolimus-treated patients) versus 0.6% to 0.8% (azathioprine and placebo control) [see Adverse Reactions (6.1) , (6.2) ] . 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 sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. 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.

5.2 Liver Transplantation – Excess Mortality, Graft Loss and Hepatic Artery Thrombosis The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of sirolimus has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT). In a study in de novo liver transplant patients, the use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss (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 sirolimus 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. In a clinical study in stable liver transplant patients 6 to 144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a sirolimus-based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [see Clinical Studies (14.5) ] .

5.3 Lung Transplantation – Bronchial Anastomotic Dehiscence Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.

5.4 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of sirolimus [ see Adverse Reactions (6.7) ].

5.5 Angioedema Sirolimus has been associated with the development of angioedema. The concomitant use of sirolimus with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema [see Drug Interactions (7.2) ] . In some cases, the angioedema has resolved upon discontinuation or dose reduction of sirolimus.

5.6 Fluid Accumulation and Impairment of Wound Healing There have been reports of impaired or delayed wound healing in patients receiving sirolimus, including lymphocele and wound dehiscence [see Adverse Reactions (6.1) ] . Mammalian target of rapamycin (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 sirolimus [see Adverse Reactions (6.1) ] . Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m 2 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, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving sirolimus.

5.7 Hyperlipidemia Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with sirolimus compared with azathioprine or placebo controls in Studies 1 and 2 [see Adverse Reactions (6.1) ] . There were increased incidences of hypercholesterolemia (43% to 46%) and/or hypertriglyceridemia (45% to 57%) in patients receiving sirolimus compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus. Any patient who is administered sirolimus 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 of patients receiving sirolimus plus cyclosporine or sirolimus after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels. The concomitant administration of sirolimus and HMG-CoA reductase inhibitors resulted in adverse reactions such as CPK elevations (3%), myalgia (6.7%) and rhabdomyolysis (<1%). In these trials, the number of patients was too small and duration of follow-up too short to evaluate the long-term impact of sirolimus on cardiovascular mortality. During sirolimus 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.

5.8 Decline in Renal Function Renal function should be closely monitored during the co-administration of sirolimus with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and sirolimus 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 sirolimus and cyclosporine compared with control therapies. Appropriate adjustment of the immunosuppressive regimen, including discontinuation of sirolimus 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, sirolimus may delay recovery of renal function.

5.9 Proteinuria Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to sirolimus in maintenance renal transplant patients 6 to 120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to sirolimus compared with CNI continuation [see Clinical Studies (14.4) and Adverse Reactions (6.4) ] . Patients with the greatest amount of urinary protein excretion prior to sirolimus conversion were those whose protein excretion increased the most after conversion. New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse reaction in 2.2% of the sirolimus 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 sirolimus 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 sirolimus. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established.

5.10 Latent Viral Infections Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy, which has been observed in renal transplant patients receiving immunosuppressants, including sirolimus. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions (6.7) ] . Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with immunosuppressants, including sirolimus. PML commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.

5.11 Interstitial Lung Disease/Non-Infectious Pneumonitis Cases of interstitial lung disease [ILD] (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 sirolimus. In some cases, the ILD was reported with pulmonary hypertension (including pulmonary arterial hypertension [PAH]) as a secondary event. In some cases, the ILD has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the trough sirolimus concentration increases [see Adverse Reactions (6.7) ] .

5.12 De Novo Use Without Cyclosporine The safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (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 sirolimus without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

5.13 Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/ Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy The concomitant use of sirolimus 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 (6.7) ] .

5.14 Antimicrobial Prophylaxis Cases of Pneumocystis carinii pneumonia have been reported in transplant 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.

5.15 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , sirolimus can cause fetal harm when administered to a pregnant woman. In animal studies, sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using sirolimus and for 12 weeks after ending treatment [see Use in Specific Populations (8.1) ].

5.17 Different Sirolimus Trough Concentrations Reported between Chromatographic and Immunoassay Methodologies Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies. Patient sample concentration values from different assays may not be interchangeable [see Dosage and Administration (2.5) ] .

5.18 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 broad spectrum sunscreen with a high protection factor [see Adverse Reactions ( 6.1 , 6.2 , 6.7 )] .

5.20 Interaction with Strong Inhibitors and Inducers of CYP3A4 and/or P-gp Avoid concomitant use of sirolimus 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) [ see Drug Interactions (7.2) ].

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. Avoid concomitant use with strong CYP3A4/P-gp inducers or strong CYP3A4/P-gp inhibitors that decrease or increase sirolimus concentrations (7.4 , 12.3) . Therapeutic drug monitoring and dose reduction for sirolimus oral solution should be considered when sirolimus oral solution is co-administered with cannabidiol ( 5.21 , 7.5 ). See full prescribing information for complete list of clinically significant drug interactions (12.3) .

7.1 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 sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges [ see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ].

7.2 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 (5.20) and Clinical Pharmacology (12.3) ].

7.3 Grapefruit Juice Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of sirolimus [ see Dosage and Administration (2.9) , Drug Interactions (7.3) and Clinical Pharmacology (12.3) ].

7.4 Weak and Moderate 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 sirolimus and/or the co-administered drug may need to be adjusted [ see Clinical Pharmacology (12.3) ]. Drugs that could increase sirolimus blood concentrations: Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors (e.g., HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir), 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 sirolimus: Verapamil 7.5 Cannabidiol The blood levels of sirolimus may increase upon concomitant use with cannabidiol. When cannabidiol and sirolimus are co-administered, closely monitor for an increase in sirolimus blood levels and for adverse reactions suggestive of sirolimus toxicity. A dose reduction of sirolimus should be considered as needed when sirolimus is co-administered with cannabidiol [see Dosage and Administration (2.5) and Warnings and Precautions (5.21) ] .

7.1 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 sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges [ see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ].

7.2 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 (5.20) and Clinical Pharmacology (12.3) ].

7.3 Grapefruit Juice Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of sirolimus [ see Dosage and Administration (2.9) , Drug Interactions (7.3) and Clinical Pharmacology (12.3) ].

7.4 Weak and Moderate 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 sirolimus and/or the co-administered drug may need to be adjusted [ see Clinical Pharmacology (12.3) ]. Drugs that could increase sirolimus blood concentrations: Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors (e.g., HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir), 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 sirolimus: Verapamil

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 and Warnings and Precautions (5.1) ] Excess mortality, graft loss and hepatic artery thrombosis in liver transplant patients [ see Boxed Warning and Warnings and Precautions (5.2) ] Bronchial anastomotic dehiscence in lung transplant patients [ see Boxed Warning and Warnings and Precautions (5.3) ] Hypersensitivity reactions [ see Warnings and Precautions (5.4) ] Exfoliative dermatitis [ see Warnings and Precautions (5.4) ] Angioedema [ see Warnings and Precautions (5.5) ] Fluid accumulation and impairment of wound healing [ see Warnings and Precautions (5.6) ] Hypertriglyceridemia, hypercholesterolemia [ see Warnings and Precautions (5.7) ] Decline in renal function in long-term combination of cyclosporine with sirolimus [ see Warnings and Precautions (5.8) ] Proteinuria [ see Warnings and Precautions (5.9) ] Interstitial lung disease [ see Warnings and Precautions (5.11) ] Increased risk of calcineurin inhibitor-induced HUS/TTP/TMA [ see Warnings and Precautions (5.13) ] Embryo-fetal toxicity [ see Warnings and Precautions (5.15) ] Male infertility [ see Warnings and Precautions (5.16) ] The most common (≥ 30%) adverse reactions observed with sirolimus in clinical studies for organ rejection prophylaxis in recipients of renal transplantation are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. The most common (≥20%) adverse reactions observed with sirolimus in the clinical study for the treatment of LAM are: stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia. The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical trials for renal transplant rejection prophylaxis: creatinine increased, hypertriglyceridemia, and TTP. In patients with LAM, 11% of subjects discontinued due to adverse reactions, with no single adverse reaction leading to discontinuation in more than one patient being treated with sirolimus. Prophylaxis of organ rejection in patients receiving renal transplants: Most common adverse reactions (incidence ≥ 30%) are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia (6) . Lymphangioleiomyomatosis: Most common adverse reactions (incidence ≥20%) are stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia ( 6.6 ). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal Transplantation The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [ see Clinical Studies (14.1) ]. 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 sirolimus oral solution 2 mg/day, 208 received sirolimus oral solution 5 mg/day, and 124 received placebo is presented in Table 1 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 sirolimus 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 (14.1) ]. In general, adverse reactions related to the administration of sirolimus 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 sirolimus oral solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of sirolimus 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. TABLE 1: ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥ 20% IN AT LEAST ONE OF THE SIROLIMUS TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥ 12 MONTHS POST-TRANSPLANTATION (STUDY 2) a –––Sirolimus Oral Solution––– 2 mg/day 5 mg/day Placebo Adverse Reaction (n = 218) (n = 208) (n = 124) Peripheral edema 54 58 48 Hypertriglyceridemia 45 57 23 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, diabetes mellitus. 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 sirolimus [ see Warnings and Precautions (5.8) ], ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia). 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 sirolimus 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 sirolimus 2 mg and sirolimus 5 mg compared with azathioprine and placebo controls. Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42% to 52% of patients enrolled in the sirolimus arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other sirolimus renal transplant studies, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels [ see Warnings and Precautions (5.7) ]. Abnormal Healing Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary). Malignancies Table 2 below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [ see Clinical Studies (14.1) ]. At 24 months (Study 1) and 36 months (Study 2) post-transplant, there were no significant differences among treatment groups. TABLE 2: INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANT a,b Sirolimus Oral Solution 2 mg/day Sirolimus Oral Solution 5 mg/day Azathioprine 2 to 3 mg/kg/day Placebo Study 1 Study 2 Study 1 Study 2 Study 1 Study 2 Malignancy (n = 284) (n = 227) (n = 274) (n = 219) (n = 161) (n = 130) Lymphoma/lymphoproliferative disease 0.7 1.8 1.1 3.2 0.6 0.8 Skin Carcinoma Any Squamous Cell c 0.4 2.7 2.2 0.9 3.8 3 Any Basal Cell c 0.7 2.2 1.5 1.8 2.5 5.3 Melanoma 0 0.4 0 1.4 0 0 Miscellaneous/Not Specified 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.

6.2 Sirolimus 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 sirolimus as a maintenance regimen following cyclosporine withdrawal, and 215 patients received sirolimus with cyclosporine therapy [ see Clinical Studies (14.2) ]. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg sirolimus 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 (14.2) ] is presented in Table 3. 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 sirolimus 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 sirolimus with cyclosporine group had a pre-transplantation history of skin carcinoma. TABLE 3: INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANT a,b Malignancy Nonrandomized Sirolimus with Cyclosporine Therapy Sirolimus Following Cyclosporine Withdrawal (n = 95) (n = 215) (n = 215) Lymphoma/lymphoproliferative disease 1.1 1.4 0.5 Skin Carcinoma Any Squamous Cell c 3.2 3.3 2.3 Any Basal Cell c 3.2 6.5 2.3 Melanoma 0 0.5 0 Miscellaneous/Not Specified 1.1 0.9 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.

6.3 High-Immunologic Risk Renal Transplant Patients Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [ see Clinical Studies (14.3) ]. Overall, the incidence and nature of adverse reactions was similar to those seen in previous combination studies with sirolimus. The incidence of malignancy was 1.3% at 12 months.

6.4 Conversion from Calcineurin Inhibitors to Sirolimus in Maintenance Renal Transplant Population The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population have not been established [ see Clinical Studies (14.4) ]. In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (initial target sirolimus concentrations of 12 ng/mL to 20 ng/mL, and then 8 ng/mL to 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 sirolimus 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 25.9% (15/58) versus 13.8% (4/29), graft loss (excluding death with functioning graft loss) was 22.4% (13/58) versus 31.0% (9/29), and death was 15.5% (9/58) versus 3.4% (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 sirolimus conversion arm. Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus 2.0% (11/551) and comparator 0.4% (1/273) treatment groups was observed with 2:1 randomization scheme. In a second study evaluating the safety and efficacy of conversion from tacrolimus to sirolimus 3 to 5 months post-kidney transplant, a higher rate of adverse events, discontinuations due to adverse events, acute rejection, and new onset diabetes mellitus was observed following conversion to sirolimus. There was also no benefit with respect to renal function and a greater incidence of proteinuria was observed after conversion to sirolimus [see Clinical Studies (14.4) ] .

6.5 Pediatric Renal Transplant Patients 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 (14.6) ]. The use of sirolimus 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.

6.6 Patients with Lymphangioleiomyomatosis Safety was assessed in a controlled trial involving 89 patients with lymphangioleiomyomatosis, 46 of whom were treated with sirolimus [ see Clinical Studies (14.7) ]. The adverse drug reactions observed in this trial were consistent with the known safety profile for renal transplant patients receiving sirolimus, with the addition of weight decreased which was reported at a greater incidence with sirolimus when compared to placebo. Adverse reactions occurring at a frequency of ≥ 20% in the sirolimus treatment group and greater than placebo include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia and hypercholesterolemia.

6.7 Post-marketing Experience The following adverse reactions have been identified during post-approval use of sirolimus in transplant patients. 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) and fluid accumulation. Digestive System – Ascites. Hematological/Lymphatic – 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 (5.4) ]. Infections – Tuberculosis. BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including sirolimus. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including sirolimus [ see Warnings and Precautions (5.10) ]. Clostridium difficile enterocolitis. Metabolic/Nutritional – Liver function test abnormal, AST/SGOT increased, ALT/SGPT increased, hypophosphatemia, hyperglycemia, diabetes mellitus. Nervous system - Posterior reversible encephalopathy syndrome. 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 sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the sirolimus trough concentration increases [ see Warnings and Precautions (5.11) ]; pulmonary hemorrhage; pleural effusion; alveolar proteinosis. Skin – Neuroendocrine carcinoma of the skin (Merkel cell carcinoma) [ see Warnings and Precautions (5.18) ] , exfoliative dermatitis [ see Warnings and Precautions (5.4) ]. Urogenital – Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis, ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia). Azoospermia has been reported with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases.

6.1 Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal Transplantation The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [ see Clinical Studies (14.1) ]. 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 sirolimus oral solution 2 mg/day, 208 received sirolimus oral solution 5 mg/day, and 124 received placebo is presented in Table 1 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 sirolimus 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 (14.1) ]. In general, adverse reactions related to the administration of sirolimus 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 sirolimus oral solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of sirolimus 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. TABLE 1: ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥ 20% IN AT LEAST ONE OF THE SIROLIMUS TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥ 12 MONTHS POST-TRANSPLANTATION (STUDY 2) a –––Sirolimus Oral Solution––– 2 mg/day 5 mg/day Placebo Adverse Reaction (n = 218) (n = 208) (n = 124) Peripheral edema 54 58 48 Hypertriglyceridemia 45 57 23 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, diabetes mellitus. 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 sirolimus [ see Warnings and Precautions (5.8) ], ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia). 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 sirolimus 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 sirolimus 2 mg and sirolimus 5 mg compared with azathioprine and placebo controls. Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42% to 52% of patients enrolled in the sirolimus arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other sirolimus renal transplant studies, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels [ see Warnings and Precautions (5.7) ]. Abnormal Healing Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary). Malignancies Table 2 below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [ see Clinical Studies (14.1) ]. At 24 months (Study 1) and 36 months (Study 2) post-transplant, there were no significant differences among treatment groups. TABLE 2: INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANT a,b Sirolimus Oral Solution 2 mg/day Sirolimus Oral Solution 5 mg/day Azathioprine 2 to 3 mg/kg/day Placebo Study 1 Study 2 Study 1 Study 2 Study 1 Study 2 Malignancy (n = 284) (n = 227) (n = 274) (n = 219) (n = 161) (n = 130) Lymphoma/lymphoproliferative disease 0.7 1.8 1.1 3.2 0.6 0.8 Skin Carcinoma Any Squamous Cell c 0.4 2.7 2.2 0.9 3.8 3 Any Basal Cell c 0.7 2.2 1.5 1.8 2.5 5.3 Melanoma 0 0.4 0 1.4 0 0 Miscellaneous/Not Specified 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.

6.2 Sirolimus 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 sirolimus as a maintenance regimen following cyclosporine withdrawal, and 215 patients received sirolimus with cyclosporine therapy [ see Clinical Studies (14.2) ]. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg sirolimus 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 (14.2) ] is presented in Table 3. 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 sirolimus 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 sirolimus with cyclosporine group had a pre-transplantation history of skin carcinoma. TABLE 3: INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANT a,b Malignancy Nonrandomized Sirolimus with Cyclosporine Therapy Sirolimus Following Cyclosporine Withdrawal (n = 95) (n = 215) (n = 215) Lymphoma/lymphoproliferative disease 1.1 1.4 0.5 Skin Carcinoma Any Squamous Cell c 3.2 3.3 2.3 Any Basal Cell c 3.2 6.5 2.3 Melanoma 0 0.5 0 Miscellaneous/Not Specified 1.1 0.9 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.

6.3 High-Immunologic Risk Renal Transplant Patients Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [ see Clinical Studies (14.3) ]. Overall, the incidence and nature of adverse reactions was similar to those seen in previous combination studies with sirolimus. The incidence of malignancy was 1.3% at 12 months.

6.4 Conversion from Calcineurin Inhibitors to Sirolimus in Maintenance Renal Transplant Population The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population have not been established [ see Clinical Studies (14.4) ]. In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (initial target sirolimus concentrations of 12 ng/mL to 20 ng/mL, and then 8 ng/mL to 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 sirolimus 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 25.9% (15/58) versus 13.8% (4/29), graft loss (excluding death with functioning graft loss) was 22.4% (13/58) versus 31.0% (9/29), and death was 15.5% (9/58) versus 3.4% (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 sirolimus conversion arm. Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus 2.0% (11/551) and comparator 0.4% (1/273) treatment groups was observed with 2:1 randomization scheme. In a second study evaluating the safety and efficacy of conversion from tacrolimus to sirolimus 3 to 5 months post-kidney transplant, a higher rate of adverse events, discontinuations due to adverse events, acute rejection, and new onset diabetes mellitus was observed following conversion to sirolimus. There was also no benefit with respect to renal function and a greater incidence of proteinuria was observed after conversion to sirolimus [see Clinical Studies (14.4) ] .

6.5 Pediatric Renal Transplant Patients 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 (14.6) ]. The use of sirolimus 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.

6.7 Post-marketing Experience The following adverse reactions have been identified during post-approval use of sirolimus in transplant patients. 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) and fluid accumulation. Digestive System – Ascites. Hematological/Lymphatic – 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 (5.4) ]. Infections – Tuberculosis. BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including sirolimus. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including sirolimus [ see Warnings and Precautions (5.10) ]. Clostridium difficile enterocolitis. Metabolic/Nutritional – Liver function test abnormal, AST/SGOT increased, ALT/SGPT increased, hypophosphatemia, hyperglycemia, diabetes mellitus. Nervous system - Posterior reversible encephalopathy syndrome. 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 sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the sirolimus trough concentration increases [ see Warnings and Precautions (5.11) ]; pulmonary hemorrhage; pleural effusion; alveolar proteinosis. Skin – Neuroendocrine carcinoma of the skin (Merkel cell carcinoma) [ see Warnings and Precautions (5.18) ] , exfoliative dermatitis [ see Warnings and Precautions (5.4) ]. Urogenital – Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis, ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia). Azoospermia has been reported with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases.

Pregnancy: Based on animal data can cause fetal harm ( 5.15 , 8.1 ). Lactation: Potential for serious adverse effects in breastfed infants based on mechanism of action ( 8.2 ). Females and Males of Reproductive Potential: May impair fertility ( 8.1 . 8.3, 13.1 ).

8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action, sirolimus can cause fetal harm when administered to a pregnant woman [ see Data, Clinical Pharmacology (12.1) ]. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses [ see Data ]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Sirolimus crossed the placenta and was toxic to the conceptus. In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day 6 to 15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg). The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose of 2 mg). The NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone. In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day 6 to 18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of 0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e. embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg). In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.

8.2 Lactation Risk Summary It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [ see Clinical Pharmacology (12.1) ] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sirolimus and any potential adverse effects on the breastfed child from sirolimus.

8.3 Females and Males of Reproductive Potential Contraception Females should not be pregnant or become pregnant while receiving sirolimus. Advise females of reproductive potential that animal studies have been shown sirolimus to be harmful to the developing fetus. Females of reproductive potential are recommended to use highly effective contraceptive method. Effective contraception must be initiated before sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped [ see Warnings and Precautions (5.15) and Use in Specific Populations (8.1) ]. Infertility Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment with sirolimus [ see Adverse Reactions (6.7) and Nonclinical Toxicology (13.1) ]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of sirolimus. Azoospermia has been reported in males with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases.

8.4 Pediatric Use Renal Transplant The safety and efficacy of sirolimus in pediatric patients < 13 years have not been established. The safety and efficacy of sirolimus oral solution has been established for prophylaxis of organ rejection in renal transplantation in children ≥ 13 years judged to be at low- to moderate-immunologic risk. Use of sirolimus oral solution in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of sirolimus oral solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [ see Clinical Pharmacology (12.3) ]. 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 sirolimus oral solution 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 (14.6) ]. Lymphangioleiomyomatosis The safety and efficacy of sirolimus oral solution in pediatric patients <18 years have not been established.

8.5 Geriatric Use Clinical studies of sirolimus oral solution 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.

8.6 Patients with Hepatic Impairment The maintenance dose of sirolimus should be reduced in patients with hepatic impairment [ see Dosage and Administration (2.7) and Clinical Pharmacology (12.3) ].

8.7 Patients with Renal Impairment Dosage adjustment is not required in patients with renal impairment [ see Dosage and Administration (2.8) and Clinical Pharmacology (12.3) ].

8.6 Patients with Hepatic Impairment The maintenance dose of sirolimus should be reduced in patients with hepatic impairment [ see Dosage and Administration (2.7) and Clinical Pharmacology (12.3) ].

8.7 Patients with Renal Impairment Dosage adjustment is not required in patients with renal impairment [ see Dosage and Administration (2.8) and Clinical Pharmacology (12.3) ].

12.1 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 G 1 to the S phase of the cell cycle. Mammalian target of rapamycin (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. 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. Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

12.2 Pharmacodynamics Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [ see Clinical Studies (14.1) ]. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [ see Dosage and Administration (2.5) ].

12.3 Pharmacokinetics Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4. TABLE 4: MEAN ± SD STEADY-STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW- TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS 2 MG DAILY a,b Multiple-Dose (daily dose) Solution Tablets C max (ng/mL) 14.4 ± 5.3 15.0 ± 4.9 t max (hr) 2.1 ± 0.8 3.5 ± 2.4 AUC (ng

• h/mL) 194 ± 78 230 ± 67 C min (ng/mL) c 7.1 ± 3.5 7.6 ± 3.1 CL/F (mL/h/kg) 173 ± 50 139 ± 63 a: In presence of cyclosporine administered 4 hours before sirolimus dosing. b: Based on data collected at months 1 and 3 post-transplantation. c: Average C min over 6 months. Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUC τ,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 [ see Dosage and Administration (2.3 , 2.5 ) and Warning and Precautions (5.17) ]. Absorption Following administration of sirolimus oral solution, the mean times to peak concentration (t max ) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus oral solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus oral solution to stable renal transplant patients, are dose-proportional between 3 mg/m 2 and 12 mg/m 2 . Food Effects To minimize variability in sirolimus concentrations, sirolimus oral solution should be taken consistently with or without food [ see Dosage and Administration (2) ]. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23% to 35%, compared with fasting. The effect of food on the mean sirolimus C max was inconsistent depending on the sirolimus dosage form evaluated. Distribution The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α 1 -acid glycoprotein, and lipoproteins. Metabolism Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations [ see Warnings and Precautions (5.20) and Drug Interactions (7) ]. 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. 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 [ 14 C] 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. The mean ± SD terminal elimination half-life (t ½ ) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies The following sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies for prophylaxis of organ rejection in de novo renal transplant patients [ see Clinical Studies (14) ]. TABLE 5: SIROLIMUS WHOLE BLOOD TROUGH CONCENTRATIONS OBSERVED IN RENAL TRANSPLANT PATIENTS ENROLLED IN PHASE 3 STUDIES Year 1 Year 3 Patient Population (Study number) Treatment Mean (ng/mL) 10 th to 90 th percentiles (ng/mL) Mean (ng/mL) 10 th to 90 th percentiles (ng/mL) Low-to-moderate risk Sirolimus (2 mg/day) + CsA 7.2 3.6 to 11 – – (Studies 1 & 2) Sirolimus (5 mg/day) + CsA 14 8 to 22 – – Low-to-moderate risk Sirolimus + CsA 8.6 5 to 13 a 9.1 5.4 to 14 (Study 3) Sirolimus alone 19 14 to 22 a 16 11 to 22 High risk (Study 4) Sirolimus + CsA 15.7 11.8 11.5 5.4 to 27.3 b 6.2 to 16.9 c 6.3 to 17.3 d – – a: Months 4 through 12 b: Up to Week 2; observed CsA C min was 217 (56 to 432) ng/mL c: Week 2 to Week 26; observed CsA C min range was 174 (71 to 288) ng/mL d: Week 26 to Week 52; observed CsA C min was 136 (54.5 to 218) ng/mL The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration [ see Dosage and Administration (2.1) and Drug Interactions (7.1) ]. Lymphangioleiomyomatosis In a clinical trial of patients with lymphangioleiomyomatosis, the median whole blood sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9.0 ng/mL; n = 37). Pharmacokinetics in Specific Populations Hepatic Impairment Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean C max . As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t 1/2 , and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg). The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild-to-moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment [ see Dosage and Administration (2.5) ]. It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment [ see Dosage and Administration (2.7) ]. 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 in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment [ see Dosage and Administration (2.6) ]. Pediatric Renal Transplant Patients 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 ng/mL to 20 ng/mL for the 21 children receiving tablets, or 5 ng/mL to 15 ng/mL for the one child receiving oral solution. The children aged 6 to 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/m 2 ). The children aged 12 to 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/m 2 ). 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. See Table 6 below. TABLE 6: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE-DOSE CONCENTRATION CONTROL) a,b Age (y) n Body weight (kg) C max,ss (ng/mL) t max,ss (h) C min,ss (ng/mL) AUC т,ss (ng
• h/mL) CL/F c (mL/h/kg) CL/F c (L/h/m 2 ) 6 to 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 to 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 (m 2 ). Table 7 below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function. TABLE 7: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC PATIENTS WITH END-STAGE KIDNEY DISEASE MAINTAINED ON HEMODIALYSIS OR PERITONEAL DIALYSIS (1 mg/m 2 , 3 mg/m 2 , 9 mg/m 2 , 15 mg/m 2 SINGLE-DOSE)* Age Group (y) n t max (h) t 1/2 (h) CL/F/WT (mL/h/kg) 5 to 11 9 1.1 ± 0.5 71 ± 40 580 ± 450 12 to 18 11 0.79 ± 0.17 55 ± 18 450 ± 232 * All subjects received sirolimus oral solution. Geriatric Clinical studies of sirolimus 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 sirolimus oral solution or tablets, sirolimus trough concentration data in renal transplant patients > 65 years of age were similar to those in the adult population 18 to 65 years of age. Gender Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t 1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended. Race In the phase 3 trials for the prophylaxis of organ rejection following renal transplantation using sirolimus solution or tablets and cyclosporine oral solution [MODIFIED] (e.g., Neoral ® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral ® Soft Gelatin Capsules) [ see Clinical Studies (14) ], there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation. Drug-Drug Interactions Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below. Cyclosporine: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [ see Dosage and Administration (2.2) and Drug Interactions (7.1) ]. In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus tablets either simultaneously or 4 hours after a 300-mg dose of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean C max and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus C max and AUC were both increased by only 33% compared with administration of sirolimus alone. In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus oral solution either simultaneously or 4 hours after a 300 mg dose of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean C max and AUC of sirolimus, following simultaneous administration were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C max and AUC were increased by only 37% and 80%, respectively, compared with administration of sirolimus alone. In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus oral solution alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C max and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean C max and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone. Mean cyclosporine C max and AUC were not significantly affected when sirolimus oral solution was given simultaneously or when administered 4 hours after Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral ® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration. In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5 mg/m 2 /day, 1.5 mg/m 2 /day, and 3 mg/m 2 /day was administered simultaneously with Sandimmune ® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (% CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune ® Oral Solution (cyclosporine oral solution) administration. However, the % CV was higher (range 85.9% to 165%) than those from previous studies. Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary [ see Drug Interactions (7.4) ]. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus C max , t max , and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady-state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus C max and AUC were increased 4.4- and 4.2-fold respectively and t max was increased by 0.4 hr. Erythromycin C max and AUC were increased 1.6- and 1.7-fold, respectively, and t max was increased by 0.3 hr. Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus C max , t max , and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t ½ of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. Rifampin: Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly decreased sirolimus AUC and C max by about 82% and 71%, respectively. Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary; [ see Drug Interactions (7.4) ]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady-state to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus C max and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in t max . The C max and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and t max was decreased by 1.2 hr. Drugs Which May Be Co-administered Without Dose Adjustment Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. Sirolimus and these drugs may be co-administered without dose adjustments. Acyclovir Atorvastatin Digoxin Glyburide Nifedipine Norgestrel/ethinyl estradiol (Lo/Ovral ® ) Prednisolone Sulfamethoxazole/trimethoprim (Bactrim ® ) Other Drug-Drug Interactions Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered. Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to): Calcium channel blockers: nicardipine. Antifungal agents: clotrimazole, fluconazole. Antibiotics: troleandomycin. Gastrointestinal prokinetic agents: cisapride, metoclopramide. Other drugs: bromocriptine, cimetidine, danazol, letermovir, protease inhibitors (e.g., for HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir) . Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to): Anticonvulsants: carbamazepine, phenobarbital, phenytoin. Antibiotics: rifapentine. Other Drug-Food Interactions Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with or used for dilution of sirolimus [ see Dosage and Administration (2.9) and Drug Interactions (7.3) ]. Drug-Herb Interactions St. John’s Wort ( Hypericum perforatum ) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John’s Wort in patients receiving sirolimus could result in reduced sirolimus concentrations [ see Drug Interactions (7.4) ].

Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4. TABLE 4: MEAN ± SD STEADY-STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW- TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS 2 MG DAILY a,b Multiple-Dose (daily dose) Solution Tablets C max (ng/mL) 14.4 ± 5.3 15.0 ± 4.9 t max (hr) 2.1 ± 0.8 3.5 ± 2.4 AUC (ng

• h/mL) 194 ± 78 230 ± 67 C min (ng/mL) c 7.1 ± 3.5 7.6 ± 3.1 CL/F (mL/h/kg) 173 ± 50 139 ± 63 a: In presence of cyclosporine administered 4 hours before sirolimus dosing. b: Based on data collected at months 1 and 3 post-transplantation. c: Average C min over 6 months. Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUC τ,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 [ see Dosage and Administration (2.3 , 2.5 ) and Warning and Precautions (5.17) ]. Absorption Following administration of sirolimus oral solution, the mean times to peak concentration (t max ) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus oral solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus oral solution to stable renal transplant patients, are dose-proportional between 3 mg/m 2 and 12 mg/m 2 . Food Effects To minimize variability in sirolimus concentrations, sirolimus oral solution should be taken consistently with or without food [ see Dosage and Administration (2) ]. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23% to 35%, compared with fasting. The effect of food on the mean sirolimus C max was inconsistent depending on the sirolimus dosage form evaluated. Distribution The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α 1 -acid glycoprotein, and lipoproteins. Metabolism Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations [ see Warnings and Precautions (5.20) and Drug Interactions (7) ]. 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. 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 [ 14 C] 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. The mean ± SD terminal elimination half-life (t ½ ) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies The following sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies for prophylaxis of organ rejection in de novo renal transplant patients [ see Clinical Studies (14) ]. TABLE 5: SIROLIMUS WHOLE BLOOD TROUGH CONCENTRATIONS OBSERVED IN RENAL TRANSPLANT PATIENTS ENROLLED IN PHASE 3 STUDIES Year 1 Year 3 Patient Population (Study number) Treatment Mean (ng/mL) 10 th to 90 th percentiles (ng/mL) Mean (ng/mL) 10 th to 90 th percentiles (ng/mL) Low-to-moderate risk Sirolimus (2 mg/day) + CsA 7.2 3.6 to 11 – – (Studies 1 & 2) Sirolimus (5 mg/day) + CsA 14 8 to 22 – – Low-to-moderate risk Sirolimus + CsA 8.6 5 to 13 a 9.1 5.4 to 14 (Study 3) Sirolimus alone 19 14 to 22 a 16 11 to 22 High risk (Study 4) Sirolimus + CsA 15.7 11.8 11.5 5.4 to 27.3 b 6.2 to 16.9 c 6.3 to 17.3 d – – a: Months 4 through 12 b: Up to Week 2; observed CsA C min was 217 (56 to 432) ng/mL c: Week 2 to Week 26; observed CsA C min range was 174 (71 to 288) ng/mL d: Week 26 to Week 52; observed CsA C min was 136 (54.5 to 218) ng/mL The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration [ see Dosage and Administration (2.1) and Drug Interactions (7.1) ]. Lymphangioleiomyomatosis In a clinical trial of patients with lymphangioleiomyomatosis, the median whole blood sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9.0 ng/mL; n = 37). Pharmacokinetics in Specific Populations Hepatic Impairment Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean C max . As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t 1/2 , and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg). The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild-to-moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment [ see Dosage and Administration (2.5) ]. It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment [ see Dosage and Administration (2.7) ]. 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 in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment [ see Dosage and Administration (2.6) ]. Pediatric Renal Transplant Patients 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 ng/mL to 20 ng/mL for the 21 children receiving tablets, or 5 ng/mL to 15 ng/mL for the one child receiving oral solution. The children aged 6 to 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/m 2 ). The children aged 12 to 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/m 2 ). 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. See Table 6 below. TABLE 6: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE-DOSE CONCENTRATION CONTROL) a,b Age (y) n Body weight (kg) C max,ss (ng/mL) t max,ss (h) C min,ss (ng/mL) AUC т,ss (ng
• h/mL) CL/F c (mL/h/kg) CL/F c (L/h/m 2 ) 6 to 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 to 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 (m 2 ). Table 7 below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function. TABLE 7: SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC PATIENTS WITH END-STAGE KIDNEY DISEASE MAINTAINED ON HEMODIALYSIS OR PERITONEAL DIALYSIS (1 mg/m 2 , 3 mg/m 2 , 9 mg/m 2 , 15 mg/m 2 SINGLE-DOSE)* Age Group (y) n t max (h) t 1/2 (h) CL/F/WT (mL/h/kg) 5 to 11 9 1.1 ± 0.5 71 ± 40 580 ± 450 12 to 18 11 0.79 ± 0.17 55 ± 18 450 ± 232 * All subjects received sirolimus oral solution. Geriatric Clinical studies of sirolimus 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 sirolimus oral solution or tablets, sirolimus trough concentration data in renal transplant patients > 65 years of age were similar to those in the adult population 18 to 65 years of age. Gender Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t 1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended. Race In the phase 3 trials for the prophylaxis of organ rejection following renal transplantation using sirolimus solution or tablets and cyclosporine oral solution [MODIFIED] (e.g., Neoral ® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral ® Soft Gelatin Capsules) [ see Clinical Studies (14) ], there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation. Drug-Drug Interactions Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below. Cyclosporine: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [ see Dosage and Administration (2.2) and Drug Interactions (7.1) ]. In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus tablets either simultaneously or 4 hours after a 300-mg dose of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean C max and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus C max and AUC were both increased by only 33% compared with administration of sirolimus alone. In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus oral solution either simultaneously or 4 hours after a 300 mg dose of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean C max and AUC of sirolimus, following simultaneous administration were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C max and AUC were increased by only 37% and 80%, respectively, compared with administration of sirolimus alone. In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus oral solution alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C max and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean C max and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone. Mean cyclosporine C max and AUC were not significantly affected when sirolimus oral solution was given simultaneously or when administered 4 hours after Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral ® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral ® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration. In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5 mg/m 2 /day, 1.5 mg/m 2 /day, and 3 mg/m 2 /day was administered simultaneously with Sandimmune ® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (% CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune ® Oral Solution (cyclosporine oral solution) administration. However, the % CV was higher (range 85.9% to 165%) than those from previous studies. Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary [ see Drug Interactions (7.4) ]. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus C max , t max , and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady-state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus C max and AUC were increased 4.4- and 4.2-fold respectively and t max was increased by 0.4 hr. Erythromycin C max and AUC were increased 1.6- and 1.7-fold, respectively, and t max was increased by 0.3 hr. Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus C max , t max , and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t ½ of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. Rifampin: Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly decreased sirolimus AUC and C max by about 82% and 71%, respectively. Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary; [ see Drug Interactions (7.4) ]. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady-state to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus C max and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in t max . The C max and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and t max was decreased by 1.2 hr. Drugs Which May Be Co-administered Without Dose Adjustment Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. Sirolimus and these drugs may be co-administered without dose adjustments. Acyclovir Atorvastatin Digoxin Glyburide Nifedipine Norgestrel/ethinyl estradiol (Lo/Ovral ® ) Prednisolone Sulfamethoxazole/trimethoprim (Bactrim ® ) Other Drug-Drug Interactions Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended [ see Warnings and Precautions (5.20) and Drug Interactions (7.2) ]. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered. Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to): Calcium channel blockers: nicardipine. Antifungal agents: clotrimazole, fluconazole. Antibiotics: troleandomycin. Gastrointestinal prokinetic agents: cisapride, metoclopramide. Other drugs: bromocriptine, cimetidine, danazol, letermovir, protease inhibitors (e.g., for HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir) . Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to): Anticonvulsants: carbamazepine, phenobarbital, phenytoin. Antibiotics: rifapentine. Other Drug-Food Interactions Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with or used for dilution of sirolimus [ see Dosage and Administration (2.9) and Drug Interactions (7.3) ]. Drug-Herb Interactions St. John’s Wort ( Hypericum perforatum ) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John’s Wort in patients receiving sirolimus could result in reduced sirolimus concentrations [ see Drug Interactions (7.4) ].