SIROLIMUS

Clinical safety rating: avoid

Contraindicated (not allowed)

How it works

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.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause hyperlipidemia and immunosuppression.

Breastfeeding	Milk/plasma ratio is unknown. Small molecular weight and high lipid solubility suggest excretion into breast milk. Potential for immunosuppression and growth inhibition in the infant. Contraindicated during breastfeeding due to potential serious adverse effects; avoid use.
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.

Warnings & precautions

■ 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.

Side Effect Profile

Common Effects	Stomatitis
Serious Effects

Absolute Contraindications

Hypersensitivity to sirolimus or its derivatives; use in liver or lung transplant patients (black box warning); concomitant use with strong CYP3A4 inducers or inhibitors without dose adjustment; pregnancy (teratogenic effects observed in animal studies).

Clinical Precautions

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.

Clinical Tips & Counseling

Drug interactions

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