RAPAMUNE

Sirolimus is an mTOR inhibitor immunosuppressive agent.

Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus.

The chemical name of sirolimus (also known as rapamycin) is (3 S,6 R,7 E,9 R,10 R,12 R,14 S,15 E,17 E,19 E,21 S,23 S,26 R,27 R,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S,3 R,4 R )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 H -pyrido[2,1-c] oxaazacyclohentriacontine-1,5,11,28,29 (4 H,6 H,31 H )-pentone.

Its molecular formula is

C 51 H 79 NO and its molecular weight is 914.2.

The structural formula of sirolimus is illustrated as follows.

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

Each sirolimus tablet intended for oral administration contains 0.5 mg or 1 mg or 2 mg of sirolimus.

In addition, each tablet contains the following inactive ingredients: citric acid monohydrate, crospovidone, glyceryl monooleate, hypromellose, lactose monohydrate, microcrystalline cellulose, poloxamer, polyethylene glycol, povidone, sucrose, talc, titanium dioxide and vitamin E acetate.

Additionally, each 0.5 mg tablet contains FD&C yellow #5 Aluminum Lake and iron oxide yellow and 2 mg tablet contains iron oxide black, iron oxide red and iron oxide yellow.

Sirolimus 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 months to 4 months after transplantation.

Patients at high-immunologic risk

Use in combination with CsA and corticosteroids for the first 12 months following transplantation.

Safety and efficacy of

CsA withdrawal has not been established in high risk patients.

Sirolimus is an mTOR inhibitor indicated for the treatment of patients with lymphangioleiomyomatosis. 1.1 Prophylaxis of Organ Rejection in Renal Transplantation Sirolimus tablets are 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that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn to 4 months after transplantation.

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 tablets be used in combination with cyclosporine and corticosteroids for the first year following transplantation. 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.

In patients at high-immunologic risk, the safety and efficacy of sirolimus tablets 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.

In pediatric patients, the safety and efficacy of sirolimus tablets have not been established in patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-immunologic risk.

The safety and efficacy of de novo use of sirolimus tablets without cyclosporine have not been established in renal transplant patients.

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus tablet s in maintenance renal transplant patients have not been established. 1.3 Treatment of Patients with Lymphangioleiomyomatosis Sirolimus tablets are indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

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 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.

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. 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 a: In presence of cyclosporine administered 4 hours before sirolimus dosing. b: Based on data collected at months and 3 post-transplantation. c: Average C min over 6 months.

Dose (daily dose) Solution Tablets C max (ng/mL) 14.4 ± 5.3 15 ± 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 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.

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 and 12 mg/m 2.

To minimize variability in sirolimus concentrations, both sirolimus oral solution and tablets should be taken consistently with or without food.

In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by to 35%, compared with fasting.

The effect of food on the mean sirolimus C max was inconsistent depending on the sirolimus dosage form evaluated.

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.

Sirolimus is extensively metabolized by

O-demethylation and/or hydroxylation.

Seven 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.

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.

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.

TABLE 5 SIROLIMUS WHOLE BLOOD TROUGH CONCENTRATIONS OBSERVED IN RENAL TRANSPLANT PATIENTS ENROLLED IN PHASE 3 STUDIES a: Months 4 through 12 b: Up to Week 2; observed CsA C min was 217 (56 to 432) ng/mL c: Week to Week 26; observed CsA C min range was 174 (71 to 288) ng/mL d: Week to Week 52; observed CsA C min was 136 (54.5 to 218) ng/mL Patient Population (Study number) Treatment Year 1 Year 3 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 (Studies 1 & 2) sirolimus (2 mg/day) + CsA 7.2 3.6 to 11 – – sirolimus (5 mg/day) + CsA 14 8 to 22 – – Low-to-moderate risk (Study 3) sirolimus + CsA 8.6 5 to 13 a 9.1 5.4 to 14 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 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.

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 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.

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.

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.

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 to 20 ng/mL for the 21 children receiving tablets, or to 15 ng/mL for the one child receiving oral solution.

The children aged 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 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.

Table 6 below.

TABLE 6 SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE-DOSE CONCENTRATION CONTROL) a,b a: sirolimus coadministered with cyclosporine oral solution [MODIFIED] (e.g., Neoral ® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral ® Soft Gelatin Capsules).

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

Increased susceptibility to infection, lymphoma, and malignancy Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients Bronchial anastomotic dehiscence in lung transplant patients Hypersensitivity reactions Exfoliative dermatitis Angioedema Fluid accumulation and impairment of wound healing Hypertriglyceridemia, hypercholesterolemia Decline in renal function in long-term combination of cyclosporine with sirolimus Proteinuria Interstitial lung disease Increased risk of calcineurin inhibitor-induced HUS/TTP/TMA Embryo-fetal toxicity Male infertility 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.

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.

To report SUSPECTED ADVERSE

REACTIONS, contact Zydus Pharmaceuticals (USA) Inc.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.

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 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.

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 a: Patients received cyclosporine and corticosteroids. –––Sirolimus Oral Solution––– Adverse Reaction 2 mg/day (n = 218) 5 mg/day (n = 208) Placebo (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 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.

System – Stomatitis.

System – Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia.

Metabolic/Nutritional – Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes mellitus.

System – Bone necrosis.

System – Pneumonia, epistaxis.

Skin – Melanoma, squamous cell carcinoma, basal cell carcinoma.

System – Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with sirolimus, 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.

The use of sirolimus in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.

In Studies 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 to 52% of patients enrolled in the sirolimus arms of Studies 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.

Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).

Table 2 below summarizes the incidence of malignancies in the two controlled trials (Studies and 2) for the prevention of acute rejection.

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 a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Patients may be counted in more than one category.

Solution 2 mg/day Sirolimus Oral Solution 5 mg/day Azathioprine to 3 mg/kg/day Placebo Malignancy Study 1 (n = 284) Study 2 (n = 227) Study 1 (n = 274) Study 2 (n = 219) Study 1 (n = 161) Study 2 (n = 130) Lymphoma/ lymphoproliferative disease 0.7 1.8 1.1 3.2 0.6 0.8 Skin Carcinoma Any Squamous 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 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.

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 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 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 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 a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued tre.

Reports of overdose with sirolimus have been received; however, experience has been limited.

In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section.

General supportive measures should be followed in all cases of overdose.

Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent.

In mice and rats, the acute oral LD was greater than 800 mg/kg.

Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus.

Hypersensitivity to sirolimus.

Sirolimus tablets are to be administered orally once daily, consistently with or without food.

Tablets should not be crushed, chewed or split.

Patients unable to take the tablets should be prescribed the solution and instructed in its use.

Administer once daily by mouth, consistently with or without food.

Administer the initial dose as soon as possible after transplantation and 4 hours after CsA.

Adjust the sirolimus maintenance dose to achieve sirolimus trough concentrations within the target-range.

Hepatic impairment

Reduce maintenance dose in patients with hepatic impairment.

In renal transplant patients at low-to moderate-immunologic risk: Sirolimus and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg.

Withdrawal: 2 months to 4 months post-transplantation, withdraw CsA over 4 weeks to 8 weeks.

In renal transplant patients at high-immunologic risk: Sirolimus and CsA Combination Therapy (for the first 12 months posttransplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg.

Recommended initial sirolimus dose is 2 mg/day.

Adjust the sirolimus dose to achieve sirolimus trough concentrations between to 15 ng/mL.

Therapeutic drug monitoring is recommended for all patients. 2.1 General Dosing Guidance for Renal Transplant Patients The initial dose of sirolimus tablets should be administered as soon as possible after transplantation.

It is recommended that sirolimus tablets be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) .

Frequent sirolimus tablets dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life.

Once sirolimus tablets maintenance dose is adjusted, patients should continue on the new maintenance dose for at least to 14 days before further dosage adjustment with concentration monitoring.

In most patients, dose adjustments can be based on simple proportion: new sirolimus tablets 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 loading dose = 3 x (new maintenance dose - current maintenance dose).

The maximum sirolimus tablets 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 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. 2.2 Renal Transplant Patients at Low.

• to Moderate-Immunologic Risk Sirolimus and Cyclosporine Combination Therapy For de novo renal transplant patients, it is recommended that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids.

A loading dose of sirolimus 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.

At to 4 months following transplantation, cyclosporine should be progressively discontinued over to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range.

Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased. 2.3 Renal Transplant Patients at High-Immunologic Risk In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation.

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 with cyclosporine, sirolimus 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 and 7, and the daily dose of sirolimus should thereafter be adjusted.

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.

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 dose should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured in to 20 days, with dosage adjustment to maintain concentrations between to 15 ng/mL.

In most patients, dose adjustments can be based on simple proportion: new sirolimus dose = current dose x (target concentration/current concentration).

Frequent sirolimus 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 maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 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 dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors.

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus 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.

Following cyclosporine withdrawal in transplant patients at low.

• to moderate-immunologic risk, the target sirolimus trough concentrations should be to 24 ng/mL for the first year following transplantation.

Thereafter, the target sirolimus concentrations should be 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.

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. 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 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 loading dose. 2.8 Patients with Renal Impairment Dosage adjustment is not needed in patients with impaired renal function.

Tablets, 0.5 mg are yellow, round, biconvex, coated tablets debossed with "1" in on one side and plain on other side and are supplied as follows: NDC: 70518-4376-00 NDC: 70518-4376-01 PACKAGING: 100 in 1 BOX INNER PACKAGING: 1 in 1 POUCH Since sirolimus is not absorbed through the skin, there are no special precautions.

However, if direct contact occurs with the skin or eyes, wash skin thoroughly with soap and water; rinse eyes with plain water.

Do not use Sirolimus

Tablets after the expiration date.

The expiration date refers to the last day of that month.

Store at 20°C to 25°C (68F° to 77°F) .

Use cartons to protect blister cards and strips from light.

Dispense in a tight, light-resistant container as defined in the USP.

Suite #4 Indiana, PA 1-724-465-8762.

Based on animal studies and the mechanism of action, sirolimus can cause fetal harm when administered to a pregnant woman.

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.

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 to 4% and to 20%, respectively.

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 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).

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 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.

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

The safety and efficacy of sirolimus oral solution and sirolimus tablets have 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 and sirolimus tablets 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.

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 or tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival.

The safety and efficacy of sirolimus in pediatric patients <18 years have not been established.

Clinical studies of sirolimus oral solution or tablets did not include sufficient numbers of patients ≥ 65 years to determine whether they respond differently from younger patients.

Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary.

Differences in responses between the elderly and younger patients have not been identified.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, or cardiac function, and of concomitant disease or other drug therapy.