Sirolimus is macrocyclic antibiotic with potent immunosuppressive activity that is used alone or in combination with calcineurin inhibitors and corticosteroids to prevent cellular rejection after renal transplantation. Sirolimus therapy can be associated with mild serum enzyme elevations and it has been linked to rare instances of clinically apparent cholestatic liver injury.


Sirolimus (sir oh' li mus) is a macrocyclic lactone antibiotic which also has profound immunosuppressive properties particularly affecting T cells and the cellular immune response. Sirolimus binds to the same intracellular receptor as tacrolimus and cyclosporine, but does not inhibit calcineurin, but rather blocks the “mammalian target of rapamycin” (mTOR) which interrupts signaling pathways for several cytokines and growth factors including IL2. The result of the inhibition is inactivation of T cells. Sirolimus was approved for use in the United States in 1999 and current indications are for prevention of organ rejection after renal transplantation alone or in combination with calcineurin inhibitors or corticosteroids. It is also approved as therapy for lymphangioleiomyomatosis. Sirolimus has not been approved for use in liver or lung transplantation but is used off-label for prevention of rejection after other forms of organ transplantation after failure or intolerance to tacrolimus. Sirolimus is available as tablets of 0.5, 1 and 2 mg and in an oral solution of 1 mg/mL generically and under the brand name of Rapamune. After a loading dose, the usual maintenance dose in adults is 2 mg (~1 mg/m2) once daily. Sirolimus has less nephrotoxicity than the calcineurin inhibitors. Common side effects of sirolimus include anxiety, weakness, depression, dizziness, headache, gastrointestinal upset, oral ulcers, edema, bone marrow suppression and rash. Uncommon but potentially severe adverse events include hyperlipidemia, renal dysfunction, severe and opportunistic infections, embryo-fetal toxicity, infertility and hypersensitivity reactions. Sirolimus should be prescribed only by physicians with experience in immunosuppression and management of its complications.


Serum enzyme elevations occur in a proportion of patients taking sirolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Rare instances of cholestatic hepatitis have been reported with sirolimus use, but the clinical features of the clinically apparent liver injury due to this agent have not been well defined. Most published cases of liver injury attributed to sirolimus occurred in patients exposed to other potentially hepatotoxic agents or who have other underlying possible causes of the abnormalities such as sepsis, cancer or parenteral nutrition. Hepatic artery thrombosis has been reported to be more common with sirolimus therapy after liver transplantation, but this association is still controversial.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

Sirolimus undergoes extensive hepatic metabolism, largely via the cytochrome P450 system (CYP 3A4) and drug-drug interactions are common. Sirolimus may interfere with wound healing, which has been the usual reason cited for the increased rate of hepatic artery thrombosis with its use.

Outcome and Management

The liver injury associated with sirolimus therapy is usually mild and transient, resolving on its own or with dose modification or discontinuation. Sirolimus has not been linked to cases of acute liver failure or vanishing bile duct syndrome. There does not appear to be cross sensitivity to the hepatic injury between sirolimus and the other agents used for prevention of transplant rejection.

Agents used specifically for the prophylaxis against allograft rejection include cyclosporine, mycophenolate mofetil, sirolimus and tacrolimus, as well as azathioprine and corticosteroids.

Drug Class: Transplant Agents; Antirheumatic Agents, Major Immunosuppressive Agents

Other Drugs in the Class, Transplant Agents: Cyclosporine, Mycophenolate, Tacrolimus



Sirolimus – Generic, Rapamune®


Transplant Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 17 February 2020

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    (Expert review of hepatotoxicity published in 1999; cyclosporine therapy was associated with a high rate of cholestatic liver enzyme elevations ranging from 4-86% and occasional instances of cholestatic hepatitis, some features of which were reproducible in animal models; tacrolimus, sirolimus, and mycophenolate are not discussed).
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