Medication Adverse Event Alert

February 27, 2007

ISSUE:	Increased incidence of grade IIIA acute rejection in heart transplant patients when switched from calcineurin inhibitor and CellCept combination therapy to Rapamune and CellCept combination therapy
MEDICATION:	CellCept® (mycophenolate mofetil), Roche Laboratories, Inc., in combination with Rapamune® (sirolimus), Wyeth Pharmaceuticals, Inc., in heart transplant patients

The following was posted on FDA Med Watch alert website dated February 22, 2007:
"Roche and FDA notified cardiac transplant healthcare practitioners about a clinical study (Heart Spare The Nephron) that was terminated due to an observed increased incidence of grade IIIA acute rejection in heart transplant patients switched from calcineurin inhibitor and CellCept to Rapamune (sirolimus) and CellCept at 12 weeks post heart transplantation. The safety and efficacy of CellCept in combination with sirolimus following withdrawal of initial calcineurin inhibitor therapy has not been established."

An excerpt of F Hoffman La-Roche's "Dear Health Care Provider" letter is provided below:
"Roche Laboratories Inc., following discussion with the U.S. Food and Drug Administration, would like to inform you of important safety information regarding the termination of the Heart Spare The Nephron (STN) clinical trial due to an observed increased incidence of grade IIIA acute rejection in heart transplant patients switched from a calcineurin inhibitor (CNI) in combination with CellCept® (mycophenolate mofetil) to Rapamune® (sirolimus) in combination with CellCept® at 12 weeks post heart transplantation.

The safety and efficacy of CellCept® in combination with sirolimus following withdrawal of initial calcineurin inhibitor therapy has not been established. The Heart STN clinical trial was designed to investigate whether renal function benefit could be achieved with the withdrawal of calcineurin inhibitor therapy followed by the introduction of sirolimus at 12 weeks post heart transplantation. Following heart transplantation, all patients received the immunosuppressive therapy for their center, including CellCept® in combination with either cyclosporine or tacrolimus, and corticosteroids. Fifteen patients had been randomized to one of two arms in the trial when this study was stopped prematurely. In the treatment group, seven heart transplant recipients were switched from CNI to sirolimus at 12 weeks post heart transplantation while maintaining CellCept® and corticosteroid therapy. In the control treatment arm, eight patients continued to receive CNI, CellCept® and corticosteroid therapy.

Of the seven patients randomized to the sirolimus, CellCept® and corticosteroid arm, four experienced a grade IIIA rejection within 5 weeks of discontinuing the CNI.3 Three of the four rejection episodes occurred at one center in the United States. Three of these patients responded well to treatment with corticosteroids and the fourth patient recovered after experiencing hemodynamic compromise. No cases of graft loss occurred. There were no similar episodes of rejection in patients receiving the calcineurin based regimen (CNI, CellCept® and corticosteroids).

F. Hoffmann-La Roche Ltd. terminated this clinical trial when these results were reported. There is limited data available from this study to draw a firm conclusion regarding the difference in the rejection rate between the two treatment arms. Should you have any questions or require additional information regarding the use of CellCept®, please contact the Roche Pharmaceuticals Service Center at 1-800-526-6367"