Sirolimus is an immunosuppressant medicine used to prevent rejection after kidney transplantation. It reduces the activity of the immune system so the body does not attack the transplanted kidney.
Also known as: Sirolimus, Rapamune
Sirolimus + ketoconazole: ketoconazole reduces sirolimus metabolism (CYP3A4/P-gp), increasing its levels and the toxicity risk (QUADRO 2).
Sirolimus is metabolised by CYP3A4 and is a P-glycoprotein substrate; ketoconazole strongly inhibits both pathways and can increase sirolimus concentrations several-fold, with a risk of nephrotoxicity, myelosuppression and hyperlipidaemia. QUADRO 2 of Annex 7 records this interaction in the azole antifungal section. The combination should be avoided; if unavoidable, substantially reduce the sirolimus dose and monitor serum levels and renal function. The elderly and patients with hepatic or renal dysfunction are the most vulnerable. Prefer antifungals with less enzyme inhibition when possible.
Ketoconazole + sirolimus: CYP3A4 and P-gp inhibition — marked sirolimus increase and toxicity; avoid or markedly reduce the dose.
Sirolimus is a CYP3A4/P-gp substrate; azole antifungals (ketoconazole, itraconazole, voriconazole) inhibit its metabolism, increasing concentrations (QUADRO 2, Azole antifungals).
Monitor sirolimus levels, renal function and signs of infection.
Elevated sirolimus levels (nephrotoxicity, hyperlipidaemia, myelosuppression) with ketoconazole.
Avoid the combination whenever possible; if unavoidable, monitor sirolimus levels and adjust the dose.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Azole antifungals)
Sirolimus + verapamil: verapamil reduces sirolimus metabolism, increasing its levels and the toxicity risk (QUADRO 2).
Verapamil inhibits CYP3A4 and P-glycoprotein, reducing sirolimus metabolism and efflux and increasing its plasma concentrations. QUADRO 2 of Annex 7 records this interaction in the calcium channel blocker section. The rise in levels can occur within the first days and present with nephrotoxicity, infections or anaemia. The risk is higher in transplant patients and the elderly. When starting verapamil, consider reducing the sirolimus dose and monitor serum levels and renal function; prefer other calcium channel blockers when possible.
Verapamil + sirolimus: CYP3A4 and P-gp inhibition — increased sirolimus; reduce dose and monitor levels.
Verapamil (CYP3A4/P-gp inhibitor) reduces sirolimus metabolism — increased concentrations (QUADRO 2, Calcium channel blockers: "Sirolimus: reduced sirolimus metabolism with diltiazem, nicardipine, verapamil").
Monitor renal function and signs of sirolimus toxicity.
Elevated sirolimus levels after starting verapamil.
Monitor sirolimus levels when starting verapamil; adjust the dose as needed.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Calcium channel blockers)
The sirolimus label instructs: "Do not take sirolimus with grapefruit juice". Grapefruit juice inhibits CYP3A4 and P-glycoprotein, raising sirolimus concentrations and the risk of toxicity.
Do not take sirolimus with grapefruit juice; keep dosing consistent (always with or always without food).
DailyMed/FDA (NIH/NLM) — approved Sirolimus tablet label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6a85ad01-8144-4d9c-e053-2991aa0a4f85
Rapamune label: "It is recommended that the maintenance dose of sirolimus tablets be reduced by approximately one third in patients with mild or moderate hepatic impairment". Sirolimus metabolism is hepatic (CYP3A4) and hepatic impairment increases exposure.
Reduce the maintenance dose by approximately one third in mild to moderate hepatic impairment; monitor levels when available.
DailyMed/FDA (NIH/NLM) — approved Sirolimus/Rapamune label, Patients with Hepatic Impairment section (8.6): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57fb4d90-3ccb-4a69-af1e-53be83f7a504
Rapamune label: "by approximately one half in patients with severe hepatic impairment". In severe hepatic impairment the recommended reduction is about half of the maintenance dose.
Reduce the maintenance dose by approximately half in severe hepatic impairment; monitor levels and liver function.
DailyMed/FDA (NIH/NLM) — approved Sirolimus/Rapamune label, Patients with Hepatic Impairment section (8.6): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57fb4d90-3ccb-4a69-af1e-53be83f7a504
FDA label (8.1): based on animal studies and the mechanism of action, sirolimus can cause fetal harm; limited data in pregnant women, insufficient to inform the risk of adverse developmental outcomes.
May cause fetal harm (animal data + mechanism); use only if benefit justifies risk.
No specific breastfeeding data in the label; assess risk/benefit.
Not applicable (no specific contraception requirements in the label).
DailyMed/FDA (NIH/NLM) — approved Sirolimus label (MYLAN), section 8.1: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5908cd1a-fc5a-462f-99ed-1d8983e253c9 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 2, Drugs and Breastfeeding: It is not known whether it is harmful.
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Immunosuppressant (mTOR inhibitor): blocks T-lymphocyte activation and proliferation and antibody production — a mechanism distinct from other immunosuppressants; CYP3A4 and P-gp substrate (FDA label 12.1/7).
mTOR inhibition (via FKBP-12 complex) — blockade of cytokine receptor signal transduction in T lymphocytes.
Oral absorption; the label recommends consistent administration with or without food (Table 4, section 12.3).
CYP3A4 metabolism (substrate); cyclosporine (CYP3A4/P-gp inhibitor) increases concentrations — administer sirolimus 4 h after cyclosporine (7.1).
Long half-life of approximately 57-63 hours (12.3).
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
