Tacrolimus Gains FDA Approval for Use in Heart Recipients


The Food and Drug Administration has approved the immunosuppressant tacrolimus for preventing rejection in heart transplant recipients, on the basis of studies that found similar rates of patient and graft survival in patients on tacrolimus-based regimens and cyclosporine-based regimens.

Tacrolimus, marketed as Prograf by Astellas Pharma US, was previously approved for preventing rejection in kidney and liver transplant recipients and has been increasingly used off label for heart transplant recipients over the past several years.

During this time, “tacrolimus has been gaining favor as the first-line drug of choice,” said Dr. Jon Kobashigawa, medical director of the University of California, Los Angeles, heart transplant program, where a switch from a cyclosporine-based regimen to a tacrolimus-based regimen, usually with mycophenolate mofetil (MMF), was made about 5 years ago. After reports found it effective in reversing recurrent or refractory rejection, its use for primary prevention was studied in several trials, which demonstrated that a tacrolimus-based regimen was at least as effective as cyclosporine-based regimens, he said in an interview.

Two studies published in April in the American Journal of Transplantation demonstrated that the tacrolimus-based regimen was more effective in reducing rejection and had fewer side effects than did the cyclosporine-based regimen, said Dr. Kobashigawa, a principal investigator of one of these studies. He has received research grants and speaker honoraria from Astellas, and is on the company's scientific advisory board.

The incidence of rejection has decreased significantly at the UCLA program since the switch to tacrolimus and MMF, which “seems to have the best profile in terms of efficacy and lowest side effects,” he said. The major side effect differences with a tacrolimus-based regimen compared with cyclosporine are decreases in renal dysfunction, hyperlipidemia, and hypertension, which “all play a role in long-term outcome.”

Centers in the United States that still use cyclosporine-based regimens for heart transplant recipients will find it easier to switch now that heart transplantation is a primary indication, which will help insurance coverage, he said.

Prograf is marketed in Europe and Japan and is commercially available in about 70 countries, according to Astellas, the company that was created from the merger of Fujisawa Pharmaceutical Co. and Yamanouchi Pharmaceutical Co. last year. The U.S. approval pertains to both the capsule and intravenous formulations.

According to information provided by Astellas and the FDA, the March approval was based on two open-label, randomized studies comparing tacrolimus-based and cyclosporine-based immunosuppression in 645 primary orthotopic heart transplant recipients. In the European study, nearly 92% of patients and grafts had survived 18 months after transplantation, compared with nearly 90% of those who received cyclosporine-based regimens. In the U.S. study, 94% of patients and grafts survived at 12 months after transplantation, compared with 86% among those on the cyclosporine-based regimen.

Tacrolimus is associated with an increased risk of neurotoxicity, renal function impairment, infection, and posttransplant diabetes, and is associated with an increased risk of malignancies, “notably of nonmelanoma skin cancers,” the FDA statement said.

Another regimen for preventing heart transplant rejection—a combination of everolimus (a proliferation signal inhibitor) and cyclosporine—is under review at the FDA, but uncertainty over its adverse renal effects has held up approval in the United States. Data on the revised regimen from an ongoing European study are expected to be available by the end of this year.


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