Sirolimus
Mechanism :
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 G1 to the S phase of the cell cycle.
Indication :
- Kidney transplant rejection prophylaxis
Contraindications :
Hypersensitivity to drug/class/component, Lung transplant use, Liver transplant use.
Caution if hepatic impairment, renal impairment, concurrent nephrotoxic agent use, delayed graft function, BMI >30 kg/m², hyperlipidemia.
Dosing :
>13 years, <40 kg:
Start with 3 mg/m² PO after kidney transplant and then maintenance dose of 1 mg/m² PO once daily. Max: 40 mg/day.
>13 years, >40 kg:
Start: 6 mg PO after transplant and then a maintenance dose of 2 mg PO once daily. Max: 40 mg/day.
Adjust dose based on trough levels. Adjust maintenance dose no more frequently than every 7-14 days.
Adverse Effect :
Serious Reactions: Immunosuppression, malignancy, lymphoma, infection, PML, BK virus-associated nephropathy, nephrotic syndrome, hemolytic uremic syndrome, TTP, thrombotic microangiopathy, venous thromboembolism, myelosuppression, hypersensitivity reaction, anaphylaxis/anaphylactoid reaction, angioedema, exfoliative dermatitis, impaired wound healing, lymphocele, ascites, pericardial effusion, pleural effusion, interstitial lung disease, hepatotoxicity, hypokalemia, osteonecrosis.
Common Reactions: Peripheral edema, hyperlipidemia, hypertension, constipation, diarrhea, headache, fever, anemia, nausea, arthralgia, thrombocytopenia, acne, rash, proteinuria, tachycardia, stomatitis, leukopenia, abnormal healing, hypokalemia, epistaxis, pyelonephritis, ovarian cysts, menstrual disorder.
Interaction :
Contraindicated:
Adenovirus vaccine, live; BCG live intravesical; Cidofovir; Influenza nasal vaccine, live; Ketoconazole; Measles/mumps/rubella vaccine, live; Mifepristone; Posaconazole; Rotavirus vaccine, live; Smallpox vaccine (live vaccinia virus); Streptozocin; Typhoid vaccine, live; Varicella vaccine, live; Voriconazole; Yellow fever vaccine, live; Zoster vaccine, live.
Renal Dose :
Dose in Renal Impairment GFR (mL/min)
| 20-50 | Dose as in normal renal function |
| 10-20 | Dose as in normal renal function |
| <10 | Dose as in normal renal function |
Dose in Patients undergoing Renal Replacement Therapies
| CAPD | Unlikely to be dialysed. Dose as in normal renal function |
| HD | Not dialysed. Dose as in normal renal function |
| HDF/High flux | Unknown dialysability. Dose as in normal renal function |
| CAV/VVHD | Unlikely to be dialysed. Dose as in normal renal function |
Hepatic Dose :
There is no change of dose in loading dose.
Mild to moderate hepatic impairment: The maintenance dose should be reduced by one-third.
Severe hepatic impairment: The maintenance dose should be reduced by 50%.