RAPAMUNE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for RAPAMUNE (RAPAMUNE).

How it works

Rapamycin (sirolimus) is an mTOR inhibitor that binds to FKBP-12 and inhibits mTOR complex 1 (mTORC1), thereby blocking IL-2 and other cytokine-mediated T-cell proliferation and activation.

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP3A5; it is a substrate of P-glycoprotein (ABCB1). Metabolites include hydroxy-, demethyl-, and didemethyl-sirolimus.
Excretion	Primarily fecal (91%) via biliary elimination; renal excretion accounts for ~2% as unchanged drug and metabolites.
Half-life	Mean terminal elimination half-life is 57 hours (range 45–75 hours) in stable renal transplant patients; prolongs to ~110 hours in hepatic impairment.
Protein binding	~92% bound primarily to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Vd/F = 12 L/kg (range 5–25 L/kg); extensive extravascular distribution due to high tissue binding, particularly to erythrocytes and tissues.
Bioavailability	Mean oral bioavailability is ~14–15% (range 10–20%), significantly increased by high-fat meals; not available in parenteral form.
Onset of Action	Oral: Peak immunosuppressive effect occurs within 3–5 days after starting therapy; clinical rejection prophylaxis onset is delayed due to T-cell inhibition kinetics.
Duration of Action	Immunosuppressive effects persist for 12–24 hours after a single dose, but full trough-level monitoring is required due to long half-life; steady state reached in 6–16 days.

Classification & Brands

Action Class	Immunosuppressant- mTOR inhibitors
Brand Substitutes	Rapolax 1mg Tablet, Rocas 1mg Tablet, Emtor 1mg Tablet, Limus 1mg Tablet, Rapasim 1 Tablet

Dosing & administration

For prophylaxis of organ rejection in renal transplant patients: initial dose of 6 mg orally once, then 2 mg orally once daily, with dose adjustments based on therapeutic drug monitoring targeting trough concentrations of 4-12 ng/mL (HPLC).

Dosage form	TABLET
Renal impairment	No specific GFR-based dose modifications are recommended; however, use with caution in patients with impaired renal function. Monitor renal function closely due to potential nephrotoxicity.
Liver impairment	For patients with mild to moderate hepatic impairment (Child-Pugh class A or B), reduce the initial dose by approximately one-third. For severe hepatic impairment (Child-Pugh class C), reduce the initial dose by approximately one-half. Titrate based on therapeutic drug monitoring.
Pediatric use	For pediatric patients (≥13 years) with body weight ≥40 kg: initial dose of 6 mg orally once, then 2 mg orally once daily. For pediatric patients with body weight <40 kg: initial dose of 3 mg/m² orally once, then 1 mg/m² orally once daily, adjusted to achieve target trough concentrations of 4-12 ng/mL.
Geriatric use	No specific dose adjustments are provided for elderly patients; use the same initial dosing as in younger adults with careful monitoring of renal function and sirolimus trough concentrations due to potential age-related decreases in clearance.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for RAPAMUNE (RAPAMUNE).

Breastfeeding	Contraindicated during breastfeeding. M/P ratio not determined; likely concentrated in breast milk due to high lipophilicity. Potential for immunosuppression and growth inhibition in the infant.
Teratogenic Risk	FDA Pregnancy Category D. First trimester: Increased risk of structural anomalies (e.g., cleft lip/palate, microtia). Second/third trimester: Risk of spontaneous abortion, low birth weight, and neonatal renal dysfunction.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Increased susceptibility to infection and possible development of lymphoma and other malignancies, particularly skin cancer, has been reported. Immunosuppression increases the risk of opportunistic infections. Use of sirolimus has been associated with bronchial anastomotic dehiscence in lung transplant patients; use in lung transplantation is not recommended.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to sirolimus or any component of the formulation; use in lung transplantation (bronchial dehiscence); use in pediatric liver transplantation (not studied).

Clinical Precautions

Precautions

Increased risk of infection, lymphoma, and other malignancies; interstitial lung disease (non-infectious pneumonitis); renal function impairment (especially when used with calcineurin inhibitors); wound healing complications; edema; hyperlipidemia; thrombotic microangiopathy; angioedema; exfoliative dermatitis.

Clinical Tips & Counseling

Drug interactions

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RAPAMUNE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for RAPAMUNE (RAPAMUNE).

How it works

Rapamycin (sirolimus) is an mTOR inhibitor that binds to FKBP-12 and inhibits mTOR complex 1 (mTORC1), thereby blocking IL-2 and other cytokine-mediated T-cell proliferation and activation.

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and CYP3A5; it is a substrate of P-glycoprotein (ABCB1). Metabolites include hydroxy-, demethyl-, and didemethyl-sirolimus.
Excretion	Primarily fecal (91%) via biliary elimination; renal excretion accounts for ~2% as unchanged drug and metabolites.
Half-life	Mean terminal elimination half-life is 57 hours (range 45–75 hours) in stable renal transplant patients; prolongs to ~110 hours in hepatic impairment.
Protein binding	~92% bound primarily to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Vd/F = 12 L/kg (range 5–25 L/kg); extensive extravascular distribution due to high tissue binding, particularly to erythrocytes and tissues.
Bioavailability	Mean oral bioavailability is ~14–15% (range 10–20%), significantly increased by high-fat meals; not available in parenteral form.
Onset of Action	Oral: Peak immunosuppressive effect occurs within 3–5 days after starting therapy; clinical rejection prophylaxis onset is delayed due to T-cell inhibition kinetics.
Duration of Action	Immunosuppressive effects persist for 12–24 hours after a single dose, but full trough-level monitoring is required due to long half-life; steady state reached in 6–16 days.

Classification & Brands

Action Class	Immunosuppressant- mTOR inhibitors
Brand Substitutes	Rapolax 1mg Tablet, Rocas 1mg Tablet, Emtor 1mg Tablet, Limus 1mg Tablet, Rapasim 1 Tablet

Dosing & administration

Dosage form	TABLET
Renal impairment	No specific GFR-based dose modifications are recommended; however, use with caution in patients with impaired renal function. Monitor renal function closely due to potential nephrotoxicity.
Liver impairment	For patients with mild to moderate hepatic impairment (Child-Pugh class A or B), reduce the initial dose by approximately one-third. For severe hepatic impairment (Child-Pugh class C), reduce the initial dose by approximately one-half. Titrate based on therapeutic drug monitoring.
Pediatric use	For pediatric patients (≥13 years) with body weight ≥40 kg: initial dose of 6 mg orally once, then 2 mg orally once daily. For pediatric patients with body weight <40 kg: initial dose of 3 mg/m² orally once, then 1 mg/m² orally once daily, adjusted to achieve target trough concentrations of 4-12 ng/mL.
Geriatric use	No specific dose adjustments are provided for elderly patients; use the same initial dosing as in younger adults with careful monitoring of renal function and sirolimus trough concentrations due to potential age-related decreases in clearance.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for RAPAMUNE (RAPAMUNE).

Breastfeeding	Contraindicated during breastfeeding. M/P ratio not determined; likely concentrated in breast milk due to high lipophilicity. Potential for immunosuppression and growth inhibition in the infant.
Teratogenic Risk	FDA Pregnancy Category D. First trimester: Increased risk of structural anomalies (e.g., cleft lip/palate, microtia). Second/third trimester: Risk of spontaneous abortion, low birth weight, and neonatal renal dysfunction.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to sirolimus or any component of the formulation; use in lung transplantation (bronchial dehiscence); use in pediatric liver transplantation (not studied).