Livertox

DRUG RECORD

 

SIROLIMUS

 

Introduction

Sirolimus is macrocyclic antibiotic with potent immunosuppressive activity that is used alone or in combination with calcineurin inhibitors to prevent cellular rejection after organ 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.

Background

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 transplantation alone or in combination with calcineurin inhibitors or corticosteroids.  Sirolimus is available as tablets of 1 and 2 mg and in an oral solution of 1 mg/mL 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.

Hepatotoxicity

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.  Hepatic artery thrombosis has been reported to be more common with sirolimus therapy after liver transplantation, but this association is still controversial.

 

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, everolimus, mycophenolate mofetil, sirolimus and tacrolimus, as well as azathioprine and corticosteroids.

References regarding the safety and potential hepatotoxicity of the cyclosporine, everolimus, mycophenolate mofetil, sirolimus and tacrolimus are provided together at the end of the Overview section on drugs used to prevent transplant rejection.

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

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

 

Top of page

 

REPRESENTATIVE TRADE NAMES
Sirolimus – Rapamune®

 

DRUG CLASS
Transplant Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

Top of page

DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Sirolimus	53123-88-9	C51-H79-N-O13

Top of page

 

 

1. Recent References on Sirolimus

2. Trials on Sirolimus

Top of page