Selective immunosuppressant, mTOR inhibitor
Brand names: Rapamune
Updated · Methodology
Second line
mTOR inhibitor for maintenance immunosuppression after organ transplantation. AEMPS positions sirolimus as an alternative or adjunct to calcineurin inhibitors to reduce nephrotoxicity.
Sources
ICD-10: Z94 · ICD-11: QB63
Sirolimus (rapamycin) binds FKBP-12 and blocks the mTORC1 complex (mammalian target of rapamycin complex 1), halting T-cell progression from G1 to S phase and suppressing cytokine-driven proliferation. It is used after kidney transplantation, in lymphangioleiomyomatosis, and in neuroendocrine tumours. Sirolimus is a CYP3A4 and P-glycoprotein substrate with a very narrow therapeutic window (target trough 4–12 ng/mL depending on indication). Strong CYP3A4 inhibitors or inducers shift concentrations sharply, so therapy proceeds under whole-blood level monitoring.
EMA summary of product characteristics (section 4.6): there are no or limited data on sirolimus use in pregnant women. Animal studies have shown reproductive toxicity, and the potential risk for humans is unknown. Sirolimus should not be used during pregnancy unless clearly necessary, and effective contraception is used during treatment and for 12 weeks after it stops.
Not compatible. Hale L4. No human milk transfer data; potential immunosuppressive effect on the infant. AEMPS contraindicates breastfeeding during sirolimus therapy.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Sirolimus is cleared by CYP3A4, and grapefruit juice inhibits this enzyme. The Rapamune SmPC says to avoid grapefruit juice and not to use it to dilute the oral solution: only water or orange juice. More sirolimus in the blood means more of its adverse effects, such as high cholesterol and triglycerides, mouth ulcers, anaemia and slow wound healing. The dose is guided by blood levels, and grapefruit throws them off.
Source: EMA: Ficha técnica de Rapamune 1 mg/ml solución oral (sirolimus) (2026)
10 pairs found. Sorted from critical to minor.
Mechanism
Sirolimus is a CYP3A4 sensitive substrate, P-gp substrate, NTI. Cobicistat raises concentration 10+ fold with severe toxicity: nephrotoxicity, hepatotoxicity, cytopenia.
Symptoms
Rising creatinine, thrombocytopenia, hepatitis within days.
Management
Combination contraindicated. For HIV in transplant patient – regimen without cobicistat.
Sources
Mechanism
Both are mTOR inhibitors. Combined use produces dual blockade with severe immunosuppression and toxicity. No clinical indication for co-use.
Symptoms
Severe immunosuppression, infections, pneumonitis.
Management
Combination contraindicated.
Sources
Mechanism
Ketoconazole strongly inhibits CYP3A4 and P-glycoprotein, the routes that clear sirolimus. In the sirolimus SmPC (Rapamune), repeated ketoconazole doses raised sirolimus AUC 10.9-fold and Cmax 4.4-fold. The label for oral ketoconazole (Ketoconazole Esteve) lists sirolimus among contraindicated combinations. The sirolimus SmPC does not recommend the pair, and the sirolimus label says to avoid it.
Symptoms
Severe immunosuppression.
Management
Combination contraindicated.
Sources
Mechanism
Posaconazole strongly inhibits CYP3A4, the enzyme that clears sirolimus. In the posaconazole SmPC (Noxafil), repeated posaconazole doses raised sirolimus Cmax a mean 6.7-fold and AUC 8.9-fold, with a range of 3.1 to 17.5-fold. The posaconazole label lists sirolimus as a contraindication. The does not recommend the combination and asks to avoid it whenever possible.
Symptoms
Rising creatinine, thrombocytopenia, hepatotoxicity within 5 days.
Management
The combination is not used. If a transplant patient on sirolimus needs posaconazole, a transplant specialist reviews the immunosuppressive regimen. For unavoidable co-administration the posaconazole SmPC advises a large immediate cut in the sirolimus dose and very frequent trough monitoring: at baseline, during co-administration and when posaconazole stops. If the patient is switched to tacrolimus, its dose also depends on posaconazole: per the SmPC it is reduced to about one third of the current dose and then adjusted by blood levels.
Sources
Mechanism
Ritonavir is the strongest CYP3A4 inhibitor. Sirolimus rises 15-fold.
Symptoms
Acute nephrotoxicity, thrombotic microangiopathy.
Management
Combination contraindicated. For HIV in transplant patient – ARV regimen without ritonavir or cobicistat.
Sources
Mechanism
Voriconazole is a strong CYP3A4 inhibitor, the main enzyme for sirolimus. Sirolimus levels rise 11-fold causing severe toxicity: nephrotoxicity, hepatotoxicity, cytopenias, thrombotic microangiopathy. Vfend Section 4.3 – strict contraindication.
Symptoms
Within 3–7 days – rising creatinine and transaminases, thrombocytopenia, oedema, haematuria.
Management
Combination contraindicated. For severe aspergillosis in a transplant patient, switch sirolimus to tacrolimus with a 50% dose reduction and blood-level monitoring. Alternative antifungal: isavuconazole with weaker CYP3A4 inhibition.
Sources
Mechanism
Sirolimus is cleared by CYP3A4 in the gut and liver and by P-glycoprotein. Clarithromycin strongly inhibits CYP3A4, so sirolimus blood levels rise. The sirolimus SmPC (Rapamune) lists clarithromycin among strong inhibitors it does not recommend combining with, and the sirolimus label says to avoid the pair. The labels give no figure for this specific pair; for ketoconazole, another strong CYP3A4 inhibitor, the sirolimus SmPC reports a 10.9-fold rise in AUC.
Symptoms
Rising creatinine, thrombocytopenia, hepatitis within 5–7 days.
Management
The combination is avoided. Clarithromycin is replaced by an antibiotic with less effect on sirolimus, usually azithromycin if the spectrum fits. If clarithromycin cannot be avoided, per the sirolimus SmPC trough sirolimus levels are measured during co-administration and after clarithromycin stops, and the sirolimus dose follows the result. The patient's clinical status and renal function are checked on the same schedule. A transplant specialist runs the regimen.
Sources
Mechanism
Isavuconazole is a moderate CYP3A4 inhibitor. Sirolimus rises 1.5-2 fold.
Symptoms
Nephrotoxicity.
Management
Reduce sirolimus by 50% with blood level monitoring.
Sources
Mechanism
Itraconazole is a strong inhibitor of CYP3A4 and P-glycoprotein, and sirolimus is cleared through both. The pair has not been studied directly: the itraconazole SmPC says a rise in sirolimus levels is likely and does not recommend the combination. The sirolimus SmPC and the label also advise against strong CYP3A4 inhibitors and name itraconazole. No label lists the pair as a contraindication.
Symptoms
Acute nephrotoxicity, hepatotoxicity, cytopenia.
Management
Avoid the combination during itraconazole therapy and for 2 weeks after it, as the itraconazole SmPC and the label state. For a fungal infection in a patient on sirolimus, the FDA sirolimus label advises an antifungal with lower interaction potential. If itraconazole is still needed, measure sirolimus blood levels more often and reduce or pause the dose according to the result.
Sources
Mechanism
Strong CYP3A4 + P-gp inducer. Sirolimus falls 70% – rejection risk.
Symptoms
Rejection signs.
Management
Alternative TB regimen. If rifampicin necessary – triple sirolimus dose.
Sources
Verbatim lines from the interaction sections, in the language of the label
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp: Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole…»FDA, section 7 · Open on DailyMed
«Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp: Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole…»FDA, section 7 · Open on DailyMed
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp: Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole…»FDA, section 7 · Open on DailyMed
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp: Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole…»FDA, section 7 · Open on DailyMed
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp: Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole…»FDA, section 7 · Open on DailyMed
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Los inhibidores del CYP3A4 pueden reducir el metabolismo de sirolimus y aumentar los niveles en sangre de sirolimus. Estos inhibidores incluyen ciertos antifúngicos (p.ej., clotrimazol, fluconazol…»AEMPS, section 4.5 · Open on CIMA
«Sirolimus es extensamente metabolizado en la pared intestinal y en el hígado por la isoenzima CYP3A4. Sirolimus es también un sustrato de la bomba de flujo multifármaco, la glicoproteína P (gp P)…»AEMPS, section 4.5 · Open on CIMA
«Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp: Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole…»FDA, section 7 · Open on DailyMed
«Agentes inmunosupresores (solo pacientes con trasplante renal): Durante la administración concomitante de Rapamune y ciclosporina debe monitorizarse la función renal. En pacientes que presentan…»AEMPS, section 4.4 · Open on CIMA
«Diltiazem (inhibidor de CYP3A4): La administración oral simultánea de 10 mg de solución oral de Rapamune y 120 mg de diltiazem, afectó significativamente la biodisponibilidad de sirolimus. Los…»AEMPS, section 4.5 · Open on CIMA
«Eritromicina (inhibidor de CYP3A4): La administración de múltiples dosis de eritromicina y sirolimus solución oral aumentó significativamente la tasa y el grado de absorción de ambos medicamentos…»AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la HMG-CoA reductasa: En los ensayos clínicos, la administración concomitante de Rapamune con inhibidores de la HMG-CoA reductasa y/AEMPS, section 4.4 · Open on CIMA
«Inhibidores de la HMG-CoA reductasa: En los ensayos clínicos, la administración concomitante de Rapamune con inhibidores de la HMG-CoA reductasa y/AEMPS, section 4.4 · Open on CIMA
«Angioedema: La administración concomitante de Rapamune e inhibidores de la enzima convertidora de angiotensina (ECA) ha desencadenado reacciones tipo edema angioneurótico. Niveles elevados de…»AEMPS, section 4.4 · Open on CIMA
«CONTRAINDICATIONS: • Coadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of: • Sirolimus: ( 4.2 , 7.2 )»FDA, section 4 · Open on DailyMed
«Sirolimus»AEMPS, section 4.3 · Open on CIMA
«CONTRAINDICATIONS: Coadministration of voriconazole tablets with sirolimus is contraindicated because voriconazole tablets significantly increase sirolimus concentrations [see Drug Interactions (7)…»FDA, section 4 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: Immunosuppressants : e.g. cyclosporine, tacrolimus, sirolimus Immunosuppressant/FDA, section 7 · Open on DailyMed
«Inmunosupresores (ciclosporina, sirolimus) : diltiazem aumenta los niveles de ciclosporina circulante. Se ha observado una interacción significativa entre diltiazem y la ciclosporina en pacientes con…»AEMPS, section 4.5 · Open on CIMA
«Posaconazol es un potente inhibidor del CYP3A4. La administración concomitante de posaconazol con sustratos de CYP3A4 puede causar aumentos importantes en la exposición a sustratos de CYP3A4 tal y…»AEMPS, section 4.5 · Open on CIMA
«Effects of Ranolazine on Other Drugs: Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of ranolazine extended-release tablets to 20 mg once daily, when ranolazine is…»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for…»FDA, section 7 · Open on DailyMed
«Número de veces que cambia la exposición con ciclosporina: Se observaron elevaciones de la creatinina sérica en los estudios en los que se utilizaba everolimus o sirolimus en combinación con dosis…»AEMPS, section 4.5 · Open on CIMA
«Interacciones basadas en CYP3A: Se pueden considerar ajustes de dosis y cuando sea posible, las concentraciones séricas de los fármacos metabolizados principalmente por CYP3A se deben controlar de…»AEMPS, section 4.5 · Open on CIMA
«El uso concomitante de clotrimazol vaginal junto con tacrolimus orales (FK-506; inmunosupresores) podrían producir un aumento de los niveles plasmáticos de tacrolimus y similarmente con sirolimus…»AEMPS, section 4.5 · Open on CIMA
«Established and Other Potentially Significant Interactions: Immuno-suppressants: cyclosporine everolimus sirolimus tacrolimus ↑ immuno-suppressants These immunosuppressant agents are metabolized by…»FDA, section 7 · Open on DailyMed
«INMUNOSUPRESORES: Ciclosporina Sirolimus Tacrolimus Everolimus»AEMPS, section 4.5 · Open on CIMA
«Interacción con medicamentos que son metabolizados por el CYP 3A4: Dronedarona podría aumentar las concentraciones plasmáticas de inmunosupresores (tacrolimus, sirolimus, everolimus y ciclosporina)…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: • CYP3A substrates with a narrow therapeutic index (e.g., sirolimus and tacrolimus): Monitor and adjust dosage of concomitant drug as needed when used with MULTAQ. ( 7.3 )»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immunosuppressant Dose adjustments of the…»FDA, section 7 · Open on DailyMed
«Inmunosupresores (p. ej.: ciclosporina, everolimus, sirolimus y tacrolimus): Sirolimus: Fluconazol aumenta la concentración plasmática de sirolimus debido, presumiblemente, a la inhibición del…»AEMPS, section 4.5 · Open on CIMA
«Hipersensibilidad/AEMPS, section 4.4 · Open on CIMA
«Inhibidores de mTOR o vildagliptina: Es posible que se produzca un aumento del riesgo de angioedema en pacientes que toman medicamentos concomitantes como inhibidores de mTOR (p. ej. temsirolimus…»AEMPS, section 4.5 · Open on CIMA
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Sirolimus is evaluated for the following indications with varying evidence strength: Transplant rejection prophylaxis (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of Sirolimus (≥ 1 in 100): Hypertriglyceridaemia and hypercholesterolaemia, Hypertension, Anaemia, thrombocytopenia, leukopenia, Oedema, Stomatitis and mouth ulcers, Acne. See the Safety section for uncommon and serious reactions.
EMA summary of product characteristics (section 4.6): there are no or limited data on sirolimus use in pregnant women. Animal studies have shown reproductive toxicity, and the potential risk for humans is unknown. Sirolimus should not be used during pregnancy unless clearly necessary, and effective contraception is used during treatment and for 12 weeks after it stops.
Not compatible. Hale L4. No human milk transfer data; potential immunosuppressive effect on the infant. AEMPS contraindicates breastfeeding during sirolimus therapy.
Sirolimus is contraindicated in: Hypersensitivity to sirolimus; Severe active infections; Severe hypertriglyceridaemia; Co-administration with grapefruit and grapefruit juice. Full list in the Safety section.
Direct links to regulator labels. Open in a new tab.
Tacrolimus, Ustekinumab, Adalimumab, Azathioprine, Leflunomide, Mycophenolate mofetil, Ciclosporin, Dimethyl Fumarate