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 (FKBP12), 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.

Rapamune is an mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in
patients aged ≥13 years receiving renal transplants:

o Patients at low- to moderate-immunologic risk: Use initially with cyclosporine (CsA) and corticosteroids. CsA withdrawal is recommended 2–4 months after transplantation.
o 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 .

Rapamune is an mTOR inhibitor indicated for the treatment of patients with lymphangioleiomyomatosis.

Renal Transplant Patients:

• 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 Rapamune maintenance dose to achieve sirolimus trough concentrations within the targetrange.
• Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment.

In renal transplant patients at low-to moderate-immunologic risk:

• Rapamune and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg.
• Rapamune Following CsA Withdrawal: 2–4 months post-transplantation, withdraw CsA over 4–8 weeks.

In renal transplant patients at high-immunologic risk:

• Rapamune 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.

Lymphangioleiomyomatosis Patients:

• Administer once daily by mouth, consistently with or without food.
• Recommended initial Rapamune dose is 2 mg/day.
• Adjust the Rapamune dose to achieve sirolimus trough concentrations between 5–15 ng/mL.
• Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment.

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.

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.

Hypersensitivity to Rapamune.

Hypersensitivity Reactions
Angioedema
Fluid Accumulation and Impairment of Wound Healing 
Hyperlipidemia
Decline in Renal Function 
Proteinuria 
Latent Viral Infections 
Interstitial Lung Disease/Non-Infectious Pneumonitis 
De Novo Use Without Cyclosporine 
Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/ Thrombotic Thrombocytopenic Purpura/ Thrombotic Microangiopathy 
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 Rapamune
Male Infertility: Azoospermia or oligospermia may occur 
Immunizations: Avoid live vaccines