SIROLIMUS
Clinical safety rating: avoid
Contraindicated (not allowed)
Sirolimus is an immunosuppressant that forms a complex with FKBP12, which inhibits the mechanistic target of rapamycin (mTOR), a key regulator of cell cycle progression and proliferation. This inhibition blocks signal transduction from cytokine and growth factor receptors, thereby suppressing T-cell activation and proliferation.
| Metabolism | Sirolimus is extensively metabolized by CYP3A4 and CYP3A5 isoenzymes in the liver and intestinal wall. It is a substrate of P-glycoprotein (P-gp) efflux transporter. |
| Excretion | Primarily fecal (91%) with minimal renal excretion (2.2% as metabolites). |
| Half-life | Terminal half-life approximately 57-63 hours in adults, allowing once-daily dosing; longer in hepatic impairment. |
| Protein binding | Approximately 92% bound to albumin, alpha-1-acid glycoprotein, and lipoproteins. |
| Volume of Distribution | Vd approximately 5.6-14.7 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability approximately 15-20% (high interindividual variability, 10-35%). |
| Onset of Action | Oral: therapeutic effect (immunosuppression) within days to weeks; peak inhibition of mTOR occurs within hours to days. |
| Duration of Action | Duration of immunosuppression persists for the dosing interval (24 hours) with steady state achieved within 5-7 days. |
| Molecular Weight | 914.2 |
Loading dose of 6 mg orally on day 1, followed by 2 mg orally once daily; or 3 mg orally on day 1, followed by 1 mg orally once daily. Maintenance dosing adjusted to achieve trough concentrations of 4-20 ng/mL. For de novo renal transplant recipients: 6 mg loading dose then 2 mg/day.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment required for renal impairment. However, monitor renal function closely due to potential for nephrotoxicity when combined with calcineurin inhibitors. |
| Liver impairment | Mild to moderate hepatic impairment (Child-Pugh class A or B): reduce maintenance dose by approximately 33% (e.g., 1 mg/day instead of 2 mg/day). Severe hepatic impairment (Child-Pugh class C): reduce maintenance dose by approximately 50% (e.g., 0.5 mg/day or 1 mg every other day). Monitor trough concentrations. |
| Pediatric use | Age 13 years and older: same as adult dosing. For children <13 years: dosing based on body surface area (BSA), typically 1-3 mg/m²/day, with loading dose of 3-6 mg/m² on day 1. Adjust to target trough of 4-20 ng/mL. |
| Geriatric use | No specific dose adjustment recommended, but start at lower end of dosing range due to potential for decreased hepatic function and increased sensitivity. Monitor renal function and trough concentrations carefully. |
| 1st trimester | Avoid use in the first trimester due to teratogenic effects observed in animal studies and potential for fetal harm. |
| 2nd trimester | Avoid use in the second trimester unless absolutely necessary; may cause fetal growth restriction and oligohydramnios. |
| 3rd trimester | Avoid use in the third trimester due to risk of neonatal immune suppression and renal dysfunction. |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause hyperlipidemia and immunosuppression.
| Placental transfer | Sirolimus crosses the placenta, as evidenced by measurable levels in fetal plasma and amniotic fluid. Degree of transfer is moderate (maternal:fetal ratio ~0.5–1.0). |
| Breastfeeding | Sirolimus is excreted into human breast milk in low concentrations. Due to potential for immunosuppression and adverse effects in the nursing infant, breastfeeding is not recommended during therapy. Consider alternative feeding methods. |
■ FDA Black Box Warning
Increased risk of immunosuppression-related infections, lymphomas, and other malignancies. Sirolimus is not recommended for use in liver or lung transplant patients due to higher mortality and graft loss.
| Common Effects | Stomatitis |
| Serious Effects |
Hypersensitivity to sirolimus or any of its componentsUse with strong CYP3A4 inducers (e.g., rifampin, rifabutin) due to reduced efficacyLactation (per manufacturer recommendation)
| Precautions | Increased susceptibility to infections and development of lymphoma; angioedema; impaired wound healing; interstitial lung disease; nephrotoxicity; hyperlipidemia; new-onset diabetes mellitus; proteinuria; and increased risk of thrombosis in renal allograft recipients with delayed graft function. |
| Food/Dietary |
Loading safety data…
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Pregnancy category C. First trimester: Potential for embryotoxicity and teratogenicity based on animal studies (increased resorptions, malformations). Second and third trimesters: Risk of intrauterine growth restriction (IUGR), oligohydramnios, and spontaneous abortion. Distal risk uncertain; limited human data. |
| Fetal Monitoring | Monitor maternal sirolimus trough levels, renal function, blood pressure, and proteinuria. Fetal monitoring with prenatal ultrasound for growth parameters and amniotic fluid index. Assess for IUGR and oligohydramnios. Monitor for maternal hypertension and preeclampsia. |
| Fertility Effects | Reversible impairment of spermatogenesis in males (reduced sperm count and motility) and menstrual irregularities in females. May delay conception; ovulation may be suppressed. Use with caution in patients attempting to conceive. |
| Grapefruit and grapefruit juice can significantly increase sirolimus levels; avoid entirely. High-fat meals may decrease absorption, but taking with food consistently is acceptable. Ethanol should be avoided as it may increase hepatotoxicity risk. |
| Clinical Pearls | Sirolimus is a potent immunosuppressant used primarily in renal transplantation. Monitor trough levels closely (therapeutic range 5-15 ng/mL). Avoid concurrent use with strong CYP3A4 inducers or inhibitors. Sirolimus may cause hyperlipidemia, so monitor lipid profiles regularly. It is associated with an increased risk of lymphocele formation post-transplant. Use with caution in patients with impaired liver function. |
| Patient Advice | Take sirolimus exactly as prescribed, usually once daily with or without food, but consistently the same way each day. · Do not crush, chew, or break the tablets; swallow them whole. · Avoid grapefruit and grapefruit juice as they can increase sirolimus levels and risk of side effects. · Report any signs of infection (fever, sore throat, cough) or unusual bleeding/bruising to your doctor immediately. · Women of childbearing potential should use effective contraception during treatment and for 12 weeks after stopping sirolimus. · Regular blood tests are necessary to monitor drug levels, kidney function, cholesterol, and triglycerides. · Do not take any over-the-counter medications, herbal supplements (e.g., St. John's wort), or other drugs without consulting your doctor. |