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DRUG RECORD

 

TACROLIMUS

OVERVIEW
Tacrolimus


Introduction

Tacrolimus is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after transplantation.  Tacrolimus therapy can be associated with mild serum enzyme elevations, and it has been linked to rare instances of clinically apparent cholestatic liver injury.


Background

Tacrolimus (ta kroe' li mas), also known as FK506, is a macrolide antibiotic which also has profound immunosuppressive properties, particularly affecting T cells and the cellular immune response.  Tacrolimus acts as a calcineurin inhibitor which is responsible for activating an important signal transduction molecule in the pathway of T cell activation.  The result of the inhibition is a decrease in maturation of T lymphocytes and reduction in lymphokine production, including IL-2.  Tacrolimus was approved for use in the United States in 1994 and rapidly became an important part of the primary regimen of immunosuppression after allogenic transplantation.  Current indications are for prevention of organ rejection after transplantation.  It is also used off label as therapy of active and recalcitrant forms of autoimmune diseases.  Tacrolimus is available as capsules of 0.5, 1 and 5 mg in several generic forms and under the brand name of Prograf.  It is also available in extended release forms and as a solution for intravenous administration (5 mg/mL).  Because of variability in individual pharmacokinetics of tacrolimus, the maintenance dose varies greatly and proper dosing requires monitoring for drug levels, which is also important because of its many dose dependent side effects and drug-drug interactions.  Common side effects of tacrolimus include headache, dizziness, paresthesias, neuropathy, hypertension, nephropathy, diabetes, acne, hirsuitism and opportunistic infections.

 

Hepatotoxicity

Tacrolimus therapy is associated with mild to moderate elevations in serum aminotransferase levels in 5% to 10% of patients.  These elevations are usually mild, asymptomatic and self-limited, but are occasionally persistent and require dose modification.  Tacrolimus has also been implicated in instances of cholestatic hepatitis, but clinically apparent liver injury is rare.  Because tacrolimus is used in the context of organ transplantation and often in liver transplantation, the causes of liver test abnormalities arising during therapy are many, and drug induced liver injury due to tacrolimus is sufficiently rare that its clinical features and typical course have not been defined.


Mechanism of Injury

Tacrolimus undergoes extensive hepatic metabolism largely via the cytochrome P450 system (CYP 3A4) and is susceptible to many drug-drug interactions.  Liver test abnormalities during therapy may be due to direct hepatotoxicity, its effects on levels of other medications, or its effects on the immune system.


Outcome and Management

The liver injury due to tacrolimus is usually mild and self-limiting and responses rapidly to dose adjustment or drug discontinuation.  Other calcineurin inhibitors and immunosuppressants are generally tolerated, but rare instances of cross sensitivity to hepatic injury by cyclosporine and tacrolimus have been reported.

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

References regarding the safety and potential hepatotoxicity of the cyclosporine, 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 Drugs; Antirheumatic Agents, Major Immunosuppressive Agents


Other Drugs in the Class, Transplant Drugs:  Cyclosporine, Everolimus, Mycophenolate, Sirolimus

 

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PRODUCT INFORMATION
Tacrolimus


REPRESENTATIVE TRADE NAMES
Tacrolimus – Generic, Prograf®


DRUG CLASS
Transplant Drugs

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Tacrolimus 109581-93-3 C44-H69-N-O12.H2-O Tacrolimus Chemical Structure

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OTHER REFERENCE LINKS
Tacrolimus
  1. PubMed logoRecent References on Tacrolimus

  2. Clinical Trials logoTrials on Tacrolimus

  3. TOXLINE logoTOXLINE Citations on Tacrolimus

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