Instructions for sirolimus

1. Common name: Sirolimus

Product name:Rapamune

All names: sirolimus, sirolimus, rapamune, rapamune

2. Indications:

1. Sirolimus is suitable for preventing organ rejection (TR) in patients over 13 years old who have received kidney transplants.

For patients with low to moderate immune risk, it is recommended that rapamycin be used first in a combination regimen of cyclosporine and corticosteroids, with cyclosporine discontinued 2 months after transplantation; patients with high immune risk (defined as black In recipients and/or repeat kidney transplant recipients who have lost a previous allograft for immunological reasons and/or patients with high herd-reactive antibodies [peak PRA levels >80%]), rapamycin is recommended in combination with cyclosporine and corticosteroids during the first year after transplantation.

2. Sirolimus is also suitable for the treatment of patients with pulmonary lymphangioleiomyomatosis (LAM).

3. Usage and dosage:

1. Kidney transplant patients: Sirolimus can be taken orally once a day with or without food. Patients who cannot take sirolimus tablets should take sirolimus solution.

(1) Recommended dose: An initial dose of sirolimus should be given as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after taking cyclosporine oral solution (modified version) and/or cyclosporine capsules (modified version). Two milligrams (2 mg) of sirolimus oral solution has been shown to be clinically equivalent to 2 mg of sirolimus tablets; the two formulations are interchangeable at this dose.

Frequent rapamin dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because of the long half-life of sirolimus. Once the sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7-14 days before making further dose adjustments through concentration monitoring. In most patients, dose adjustments can be based on a simple ratio: new sirolimus dose = current dose × (target concentration/current concentration). When it is necessary to increase the sirolimus trough concentration, in addition to the new maintenance dose, a loading dose should also be considered: Sirolimus Loading dose = 3 × (new maintenance dose - current maintenance dose). The maximumdose of sirolimustaken on any day should not be exceeded40mg. If the estimated daily dose exceeds 40 mg due to an additional loading dose, the loading dose should be administered within 2 days. Sirolimus trough concentrations should be monitored for at least 3 to 4 days after the loading dose.

(2) Kidney transplant patients with low to moderate immune risk:

For primary renal transplant patients, sirolimus oral solution and tablets are recommended first in a regimen using cyclosporine and corticosteroids. A loading dose of sirolimus equivalent to three times the maintenance dose should be given, that is, a loading dose of 6 mg should be given before the daily maintenance dose of 2 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target range.

After transplantation 2 to 4 months after transplantation, cyclosporine should be gradually discontinued within 4 to 8 weeks, and the dose of sirolimus should be adjusted so that the whole blood trough concentration of sirolimus is within the target range. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued unless the dose of sirolimus is increased.

(3) Kidney transplant patients with high immune risk:

For patients at high immune risk, the use of sirolimus in combination with cyclosporine and corticosteroids is recommended for the first 12 months after transplantation. The safety and effectiveness of this combination in patients at high immune risk have not been studied beyond the first 12 months. Therefore, any adjustments to the immunosuppressive regimen during the first 12 months after transplantation should be considered based on the patient's clinical status.

For patients receiving combination therapy with sirolimus and cyclosporine, sirolimus treatment should be initiated with a loading dose of 15 mg on day 1 after transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be administered. The trough should be reached on days 5 to 7, after which the daily dose of sirolimus should be adjusted. The initial dose of cyclosporine should be 7 mg/kg/day in divided doses, and the dose should be adjusted subsequently to achieve target whole blood trough concentrations. The dose of prednisone should be at least 5 mg/day. Antibody induction therapy may be used.

2. Patients with lymphangioleiomyomatosis:

In patients with lymphangioleiomyomatosis, the initial dose of sirolimus should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured over 10 to 20 days, and the dose should be adjusted to maintain concentrations between 5 and 15 ng/mL.

3. Underweight patients: The initial dose of sirolimus for patients ≥13 years old weighing 40kg should be adjusted to 1 mg/m2/day based on body surface area, and the loading dose should be 3mg/m2.

4. Patients with liver function impairment: It is recommended that the maintenance dose of sirolimus be reduced by approximately one-third for patients with mild or moderate liver impairment, and by approximately half for patients with severe liver impairment. There is no need to modify the loading dose of sirolimus.

5. Drug monitoring: When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target range. After discontinuation of cyclosporine in transplant patients at low to moderate immune risk, the target trough sirolimus concentration in the first year after transplantation should be 16-24 ng/mL. Thereafter, the target concentration of sirolimus should be 12-20 ng/mL.

4. Adverse reactions:

The most common (≥30%) sirolimus adverse reactions observed in clinical studies for the prevention of organ rejection in kidney transplant recipients are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, increased creatinine, constipation, abdominal pain, diarrhea, headache, pyrexia, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.

The most common (≥20%) adverse reactions observed in clinical studies of sirolimus treatment of LAM were stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

5. Storage:

Rapamin tablets should be stored20°C to 25°C (68°F to 77°F), protected from light by using cartons on blister cards and paper strips, and packaged in sealed, light-proof containers.

6. Taboo:

Sirolimus is contraindicated in patients allergic to sirolimus.

7. Mechanism of action:

Sirolimus inhibits antigens and cytokines through a mechanism different from other immunosuppressantsActivation and proliferation of T lymphocytes caused by stimulation of (interleukin [IL]-2, IL-4, and IL-15). Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin FK-binding protein-12 (FKBP-12), producing an immunosuppressive complex. FKBP-12 complexSirolimushad no effect on calcineurin activity. This complex binds to and inhibits activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibitory effect inhibits cytokine-driven T cell proliferation, thereby inhibiting cell cycle progression from G1 to S phase. Mammalian rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability.

Lymphangioleiomyomatosis involves an infiltration of lung tissue by smooth muscle-like cells containing tuberous sclerosis complex (TSC) gene-inactivating mutations (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, leading to cell proliferation and the release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway, thereby inhibiting the proliferation of LAM cells.

SirolimusThe original drug has been launched in China and has entered the scope of Class B medical insurance. SpecificationsThe price of each box of 1mg*10 tablets is about 400 yuan. The domestic drug is only available to patients with anti-rejection reactions in organ transplantation. Patients who do not meet the conditions may not be able to purchase this drug. The original sirolimus drug has also been launched overseas. The price of the Turkish version of Specifications1mg*100 tablets per box is around RMB 2,000 (the price may fluctuate due to exchange rates). The ingredients of the original drugs marketed in China are basically the same as those of foreign original drugs. Currently, there are no generic sirolimus drugs produced in other countries.