Prograf (Page 4 of 12)

Heart Transplantation

Two open-label, randomized, comparative studies evaluated the safety and efficacy of Prograf-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a Phase 3 study conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine in combination with Prograf or cyclosporine modified for 18 months. In a 3-arm study conducted in the US, 331 patients received corticosteroids and Prograf plus sirolimus, Prograf plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.

In the European Phase 3 study, patient/graft survival at 18 months posttransplant was similar between treatment arms, 91.7% in the tacrolimus group and 89.2% in the cyclosporine group. In the US study, patient and graft survival at 12 months was similar with 93.5% survival in the Prograf plus MMF group and 86.1% survival in the cyclosporine modified plus MMF group. In the European study, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100-200 ng/mL) at Day 122 and beyond in 32-68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5-15 ng/mL) in 74-86% of the patients in the tacrolimus treatment arm.

The US study contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose Prograf; however, this regimen was associated with increased risk of wound healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended (see WARNINGS).

INDICATIONS AND USAGE

Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. It is recommended that Prograf be used concomitantly with adrenal corticosteroids. Because of the risk of anaphylaxis, Prograf injection should be reserved for patients unable to take Prograf capsules orally. In heart and kidney transplant recipients, it is recommended that Prograf be used in conjunction with azathioprine or mycophenolate mofetil (MMF). The safety and efficacy of the use of Prograf with sirolimus has not been established (see CLINICAL STUDIES).

CONTRAINDICATIONS

Prograf is contraindicated in patients with a hypersensitivity to tacrolimus. Prograf injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).

WARNINGS

(See boxed WARNING)

Post-Transplant Diabetes Mellitus

Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of Prograf-treated kidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study (See Tables Below). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM.

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in the Phase III study

* use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.
Status of PTDM *	Prograf	CBIR
Patients without pretransplant history of diabetes mellitus.	151	151
New onset PTDM *, 1st Year	30/151 (20%)	6/151 (4%)
Still insulin dependent at one year in those without prior history of diabetes.	25/151 (17%)	5/151 (3%)
New onset PTDM * post 1 year	1	0
Patients with PTDM * at 2 years	16/151 (11%)	5/151 (3%)

Development of Post Transplant Diabetes Mellitus by Race and by Treatment Group during First Year Post Kidney Transplantation in the Phase III study

* use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.
Patient Race	Prograf		CBIR
	No. of Patients at Risk	Patients Who Developed PTDM *	No. of Patients At Risk	Patients Who Developed PTDM *
Black	41	15 (37%)	36	3 (8%)
Hispanic	17	5 (29%)	18	1 (6%)
Caucasian	82	10 (12%)	87	1 (1%)
Other	11	0 (0%)	10	1 (10%)
Total	151	30 (20%)	151	6 (4%)

Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of Prograf-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post transplant, in the U.S. and European randomized studies, respectively (See Table below). Hyperglycemia was associated with the use of Prograf in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

* use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus. † Patients without pretransplant history of diabetes mellitus.
Status of PTDM *	US Study		European Study
	Prograf	CBIR	Prograf	CBIR
Patients at risk †	239	236	239	249
New Onset PTDM *	42 (18%)	30 (13%)	26 (11%)	12 (5%)
Patients still on insulin at 1 year	23 (10%)	19 (8%)	18 (8%)	6 (2%)

Insulin-dependent post-transplant diabetes mellitus was reported in 13% and 22% of Prograf-treated heart transplant patients receiving mycophenolate mofetil or azathioprine and was reversible in 30% and 17% of these patients at one year post transplant, in the US and European randomized studies, respectively (See Table below). Hyperglycemia defined as two fasting plasma glucose levels ≥126 mg/dL was reported with the use of Prograf plus mycophenolate mofetil or azathioprine in 32% and 35% of heart transplant recipients in the US and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients

* use of insulin for 30 or more consecutive days without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus. † Patients without pretransplant history of diabetes mellitus. ‡ 7-12 months for the US Study.
Status of PTDM *	US Study			European Study
	Prograf/Sirolimus	Prograf/MMF	Cyclosporine/MMF	Prograf/AZA	Cyclosporine/AZA
Patients at risk †	85	75	83	132	138
New Onset PTDM *	21 (25%)	10 (13%)	6 (7%)	29 (22%)	5 (4%)
Patients still on insulin at 1 year ‡	10 (12%)	7 (9%)	1 (1%)	24 (18%)	4 (3%)