SIROLIMUS

1 INDICATIONS AND USAGE 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 2–4 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 is an mTOR inhibitor indicated for the treatment of patients with lymphangioleiomyomatosis ( 1.3 ). 1.1 Prophylaxis of Organ Rejection in Renal Transplantation Sirolimus 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recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [ see Dosage and Administration (2.2) ].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 be used in combination with cyclosporine and corticosteroids for the first year following transplantation [ see Dosage and Administration (2.3) , 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 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 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) , Clinical Studies (14.6) ]. The safety and efficacy of de novo use of sirolimus 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 in maintenance renal transplant patients have not been established [ see Clinical Studies (14.4) ]. 1.3 Treatment of Patients with Lymphangioleiomyomatosis Sirolimus is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

2 DOSAGE AND ADMINISTRATION Sirolimus is to be administered orally once daily, consistently with or without food [ see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) ]. Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use. 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 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 and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg ( 2.2 ). • Sirolimus Following CsA Withdrawal: 2–4 months post-transplantation, withdraw CsA over 4–8 weeks ( 2.2 ). In renal transplant patients at high-immunologic risk: • Sirolimus 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 dose is 2 mg/day ( 2.4 ). • Adjust the sirolimus dose to achieve sirolimus trough concentrations between 5–15 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 should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [ see Drug Interactions (7.2) ]. Frequent sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus 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 dose = current dose × (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 × (new maintenance dose - current maintenance dose). The maximum sirolimus 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 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 siroli …

3 DOSAGE FORMS AND STRENGTHS • Tablets: 0.5 mg, 1 mg, 2 mg ( 3.1 ). 3.1 Sirolimus Tablets • 0.5 mg, tan, triangular-shaped tablets marked "RAPAMUNE 0.5 mg" on one side. • 1 mg, white, triangular-shaped tablets marked "RAPAMUNE 1 mg" on one side. • 2 mg, yellow-to-beige triangular-shaped tablets marked "RAPAMUNE 2 mg" on one side.

4 CONTRAINDICATIONS Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [ see Warnings and Precautions (5.4) ]. Hypersensitivity to sirolimus ( 4 ).

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. • Increased susceptibility to infection, lymphoma, and malignancy [ see Boxed Warning , Warnings and Precautions (5.1) ] • Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients [ see Boxed Warning , Warnings and Precautions (5.2) ] • Bronchial anastomotic dehiscence in lung transplant patients [ see Boxed Warning , 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 Greenstone LLC Professional Information Services at 1-877-446-3679 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 th …

7 DRUG INTERACTIONS 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 should be considered when sirolimus 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) , 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) , Clinical Pharmacology (12.3) ]. 7.3 Grapefruit Juice Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with sirolimus [ see 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) , Warnings and Precautions (5.21) ].

8 USE IN SPECIFIC POPULATIONS • 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 2–4% and 15–20%, 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 6–15). 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 6–18). 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 …

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.

11 DESCRIPTION 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][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4 H ,6 H ,31 H )-pentone. Its molecular formula is C 51 H 79 NO 13 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. Sirolimus is available as a tan, triangular-shaped tablet containing 0.5 mg sirolimus, as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus. The inactive ingredients in sirolimus tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl -alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide. Chemical structure

10 OVERDOSAGE 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 [ see Adverse Reactions (6) ]. 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 50 was greater than 800 mg/kg.

16 HOW SUPPLIED/STORAGE AND HANDLING Since sirolimus is not absorbed through the skin, there are no special precautions. Do not use sirolimus after the expiration date. The expiration date refers to the last day of that month. 16.1 Sirolimus Tablets Sirolimus Tablets are available as follows: • NDC 59762-1001-1, 0.5 mg, tan, triangular-shaped tablets marked "RAPAMUNE 0.5 mg" on one side; bottle containing 100 tablets. • NDC 59762-1002-1, 1 mg, white, triangular-shaped tablets marked "RAPAMUNE 1 mg" on one side; bottle containing 100 tablets. • NDC 59762-1003-1, 2 mg, yellow-to-beige triangular-shaped tablets marked "RAPAMUNE 2 mg" on one side; bottle containing 100 tablets. Sirolimus Tablets should be stored at 20°C to 25°C [USP Controlled Room Temperature] (68°F to 77°F). Dispense in a tight, light-resistant container as defined in the USP.