Sirolimus

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. • 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.

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.

Sirolimus is to be administered orally once daily, consistently with or without food. 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 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. • Sirolimus Following CsA Withdrawal: 2–4 months post-transplantation, withdraw CsA over 4–8 weeks.

Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus. Hypersensitivity to sirolimus

Boxed warning (immunosuppression, use is not recommended in liver or lung transplant patients •): Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. • 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.

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.

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. • Therapeutic drug monitoring and dose reduction for sirolimus should be considered when sirolimus is co-administered with cannabidiol. • See full prescribing information for complete list of clinically significant drug interactions.

Sirolimus oral solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles). A syringe (amber color) and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). Sirolimus oral solution provided in bottles may develop a slight haze when refrigerated. If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears.