Prograf - FK506 - Tacrolimus

by William E. Berquist, MD

For further information on Prograf, please see:

Tacrolimus: The New Anti-Rejection Drug for Liver Transplant Recipients

C.L.A.S.S. Notes, Fall 1995 -- Tacrolimus is the first new medication since cyclosporine for liver transplants in both adults and children. Previously designated FK506, tacrolimus is also known by the trade name Prograf®. It is an immunosuppressive drug which blocks the immune system from recognizing and destroying a transplanted liver. Today, tacrolimus is being used more often at liver transplant centers as both an initial and maintenance immunosuppressive. Tacrolimus was licensed to Fujisawa, USA, on April 8, 1994, by the US Food and Drug Administration.

In 1984, tacrolimus was discovered as a derivative of a fungus growing in Japan. By 1989 it was being used in experiments to treat rejection in liver transplant patients in Pittsburgh. Recently, two large trials were completed in the U.S. (12 centers, 520 patients) and Europe (8 centers and 545 patients). Compared to cyclosporine, tacrolimus was as effective with regard to both patient and graft survival outcomes. What made tacrolimus particularly attractive was that the incidence of rejection and the need for additional steroids (prednisone) or OKT3 (an antibody made against certain white blood cells in the human immune system that recognizes transplanted organs and causes rejection) was considerably less in the tacrolimus patients. Side effects were similar in both groups with regard to kidney dysfunction. The tacrolimus patients had lower cholesterol levels and fewer problems of high blood pressure compared to cyclosporine.

With experience and time, transplant centers have discovered additional benefits of tacrolimus. The long-term effectiveness of tacrolimus in preventing rejection has permitted transplant centers to wean some patients totally off of prednisone. Because of the lower risk of hypertension, very few patients on tacrolimus need medication for blood pressure. Gum swelling and increased body hair that occurs with cyclosporine have not been seen with tacrolimus.

The possible side effects of tacrolimus are:

  • Kidney: Decrease kidney function: high potassium and creatinine; low bicarbonate levels.
  • Neurologic: Headaches, difficulty sleeping, tremors (shaking), overstimulation, numbness and tingling, vivid dreams, seizures.
  • Immunologic: Increased risk of complications with viral infections and lymphoproliferative disease.
  • Gastrointestinal: Nausea, vomiting, loss of appetite, and diarrhea.
  • Endocrine: Increased blood sugar.
  • Cardiac: Arrhythmia, cardiomyopathy.

Most of these side effects are dose-related. The blood level of tacrolimus is helpful in adjusting the dose such that rejection can be prevented by a sufficient dose and side effects prevented by the lowest therapeutic dose. Just as with cyclosporine, regular blood tests to measure liver functions and drug levels are necessary.

The development of fever, lymphadenopathy, lethargy and positive tests of EBV infection (Epstein-Barr virus) may herald the development of lymphoproliferative disease, also known as LPD. If EBV is detected early, antiviral therapy such as ganciclovir and decreasing or discontinuing tacrolimus have been successful in preventing LPD.

The presence of food in the stomach may result in impaired absorption and decreased drug levels of tacrolimus. Therefore, it is recommended that it be taken an hour before and two hours after a meal. Tacrolimus comes in capsules of .5 mg, 1 mg and 5 mg. Fujisawa does not make Prograf liquid; however, hospital pharmacies are able to prepare it as a liquid suspension. Generally, diarrhea does not affect drug levels. Tacrolimus is cleared by the liver. Levels of tacrolimus in the blood may also be affected by liver function status.

Tacrolimus is accepted as an effective immunosuppressive drug as evidenced by successful treatment of liver rejection after conversion from cyclosporine therapy. Some cases of chronic liver rejection with loss of bile ducts have responded to tacrolimus. Indications to convert from cyclosporine to tacrolimus or tacrolimus would include persistent acute or chronic rejection and aggravating side effects due to cyclosporine. Due to the potential for kidney toxicity, it has not found favor as a routine immunosuppressive for kidney transplantation.

Today, tacrolimus or Prograf is another step toward a more perfect immunosuppressive, anti-rejection drug. Side effects often can be controlled by careful monitoring and dose adjustment. The addition of tacrolimus to the menu of available medications has been most welcomed and has helped to achieve the current excellent long-term success of children following liver transplantation.

Dr. Berquist is Chief, Division of Gastroenterology and Liver Transplantation at Lucile Packard Children's Hospital at Stanford and chairman of the C.L.A.S.S. Scientific Advisory Committee.