RAPAMUNE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RAPAMUNE (RAPAMUNE).
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.
| 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. |
| Molecular Weight | 914.2 Da |
| Action Class | Immunosuppressant- mTOR inhibitors |
| Brand Substitutes | Rapolax 1mg Tablet, Rocas 1mg Tablet, Emtor 1mg Tablet, Limus 1mg Tablet, Rapasim 1 Tablet |
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. |
| 1st trimester | Use only if potential benefit justifies risk. Associated with increased risk of fetal loss and malformations in animal studies; limited human data. |
| 2nd trimester | Use only if potential benefit justifies risk. May cause fetal harm; consider alternative immunosuppressants. |
| 3rd trimester | Use only if potential benefit justifies risk. Potential for neonatal immunosuppression and other adverse effects. |
Clinical note
Comprehensive clinical and safety monograph for RAPAMUNE (RAPAMUNE).
| Placental transfer | Crosses the placenta; fetal concentrations are approximately 10-20% of maternal levels per limited human data. |
| Breastfeeding | Not recommended during breastfeeding due to potential for serious adverse effects in the nursing infant. Sirolimus is excreted in human milk; data suggest low levels but risks outweigh benefits. |
■ 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.
| Serious Effects |
Hypersensitivity to sirolimus or any component of the formulationConcurrent use with strong CYP3A4 inducers (e.g., rifampin) due to reduced efficacy
| 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. |
| Food/Dietary | Grapefruit and grapefruit juice increase sirolimus levels by inhibiting CYP3A4 and P-glycoprotein; avoid concurrent use. High-fat meals may slow absorption; take consistently with or without food to minimize variability. |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) or 'Avoid' |
| 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 | Monitor trough sirolimus levels (target 5-15 ng/mL) every 2-4 weeks. Assess maternal renal function, blood pressure, and glucose. Fetal ultrasound for anomalies and growth every 4-6 weeks. Neonatal monitoring for lymphoproliferative disorder and infections. |
| Fertility Effects | Reversible impairment of spermatogenesis in males (oligospermia, reduced sperm motility) and menstrual irregularities in females. May prolong time to conception; advise contraception during therapy. |
| Clinical Pearls | Rapamune (sirolimus) is an mTOR inhibitor used for prophylaxis of organ rejection in renal transplant patients. It is often used in combination with cyclosporine and corticosteroids during the first 12 months post-transplant. Monitor therapeutic drug levels (trough) between 5-15 ng/mL. Avoid use in de novo liver or lung transplant patients due to increased risk of hepatic artery thrombosis. Sirolimus prolongs the QT interval; monitor ECG in patients at risk. Dose adjustment required for hepatic impairment. Do not use in patients with severe hypersensitivity to sirolimus or its derivatives. |
| Patient Advice | Take exactly as prescribed; do not change dose or stop without consulting your doctor. · Swallow tablets whole; do not crush, chew, or split. · Take consistently with or without food; avoid grapefruit and grapefruit juice. · Report any signs of infection (fever, sore throat, cough), mouth ulcers, or skin changes. · Avoid live vaccines during treatment and discuss vaccination with your doctor. · Use effective contraception during and for 12 weeks after stopping therapy. · Keep all appointments for blood tests to monitor drug levels and organ function. · Avoid excessive sun exposure; use sunscreen and protective clothing. · Do not take any new medications (including OTC, herbal) without doctor approval. · Tell your doctor if you have high cholesterol/triglycerides, diabetes, or history of skin cancer. |