patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037

mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of

distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and

0.138±0.071 L/hr/kg, respectively. Following oral administration to 9

patients, mean AUC and Cmax were 337±167 ng•hr/mL and 43.4±27.9 ng/mL,

respectively. The absolute bioavailability was 31± 21%.

Whole blood trough concentrations from 31 patients less than 12 years old

showed that pediatric patients needed higher doses than adults to achieve

similar tacrolimus trough concentrations. (See DOSAGE AND ADMINISTRATION).

Renal and Hepatic Insufficiency

The mean pharmacokinetic parameters for tacrolimus following single

administrations to patients with renal and hepatic impairment are given in

the following table.

|Population |Dose |AUC 0-t |tЅ |V |Cl |

|(No. of | |(ng·hr/mL|(hr) |(L/kg|(L/hr/kg)|

|Patients) | |) | |) | |

|Renal |0.02 |393±123 |26.3±9.2 |1.07 |0.038 |

|Impairment |mg/kg/4h|(t = | | |±0.014 |

|(n=12) |r |60hr) | |±0.20| |

| |IV | | | | |

|Mild Hepatic |0.02 |367±107 |60.6±43.8 |3.1 |0.042 |

|Impairment |mg/kg/4h|(t=72hr) |Range: 27.8 - |±1.6 |±0.02 |

|(n=6) |r | |141 | | |

| |IV | | | | |

| |7.7 mg |488±320 |66.1±44.8 |3.7 |0.034 |

| |PO |(t = |Range: 29.5 - |±4.7*|±0.019* |

| | |72hr) |138 | | |

|Severe Hepatic |0.02 |762±204 |198±158 |3.9 |0.017 |

|Impairment |mg/kg/4h|(t=120hr)|Range: 81-436 |±1.0 |±0.013 |

|(n=6, IV) |r | | | | |

| |IV (n=2)| | | | |

| | | | | | |

| |0.01 |289±117 | | | |

| |mg/kg/8h|(t=144hr)| | | |

| |r | | | | |

| |IV (n=4)| | | | |

| | | | | | |

|Severe Hepatic |8 mg PO |658 |119±35 |3.1 |0.016 |

|Impairment |(n=1) |(t=120hr)|Range: 85-178 |±3.4*|±0.011* |

|(n=5, PO)† | | | | | |

| |5mg PO |533±156 | | | |

| |(n=4) |(t=144hr)| | | |

| |4 mg PO | | | | |

| |(n=1) | | | | |

|* corrected for bioavailability |

|† 1 patient did not receive the PO dose |

Renal Insufficiency:

Tacrolimus pharmacokinetics following a single IV administration were

determined in 12 patients (7 not on dialysis and 5 on dialysis, serum

creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their

kidney transplant. The pharmacokinetic parameters obtained were similar for

both groups.

The mean clearance of tacrolimus in patients with renal dysfunction was

similar to that in normal volunteers (see previous table).

Hepatic Insufficiency:

Tacrolimus pharmacokinetics have been determined in six patients with mild

hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral

administrations. The mean clearance of tacrolimus in patients with mild

hepatic dysfunction was not substantially different from that in normal

volunteers (see previous table). Tacrolimus pharmacokinetics were studied

in 6 patients with sever hepatic dysfunction (mean Pugh score: >10). The

mean clearance was substantially lower in patients with severe hepatic

dysfunction, irrespective of the route of administration.

Race

A formal study to evaluate the pharmacokinetic disposition of tacrolimus in

Black transplant patients has not been conducted. However, a retrospective

comparison of Black and Caucasian kidney transplant patients indicated that

Black patients required higher tacrolimus doses to attain similar trough

concentrations. (See DOSAGE AND ADMINISTRATION).

Gender

A formal study to evaluate the effect of gender on tacrolimus

pharmacokinetics has not been conducted, however, there was no difference

in dosing by gender in the kidney transplant trial. A retrospective

comparison of pharmacokinetics in healthy volunteers, and in kidney and

liver transplant patients indicated no gender-based differences.

Clinical Studies

Liver Transplantation

The safety and efficacy of Prograf-based immunosuppression following

orthotopic liver transplantation were assessed in two prospective,

randomized, non-blinded multicenter studies. The active control groups were

treated with a cyclosporine-based immunosuppressive regimen. Both studies

used concomitant adrenal corticosteroids as part of the immunosuppressive

regimens. These studies were designed to evaluate whether the two regimens

were therapeutically equivalent, with patient and graft survival at 12

months following transplantation as the primary endpoints. The Prograf-

based immunosuppressive regimen was found to be equivalent to the

cyclosporine-based immunosuppressive regimens.

In one trial, 529 patients were enrolled at 12 clinical sites in the United

States; prior to surgery, 263 were randomized to the Prograf-based

immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive

regimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used,

while 2 sites used different control protocols. This trial excluded

patients with renal dysfunction, fulminant hepatic failure with Stage IV

encephalopathy, and cancers; pediatric patients (< 12 years old) were

allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in

Europe; prior to surgery, 270 were randomized to the Prograf-based

immunosuppressive regimen and 275 to CBIR. In this study, each center used

its local standard CBIR protocol in the active-control arm. This trial

excluded pediatric patients, but did allow enrollment of subjects with

renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy,

and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the Prograf-based treatment

groups were equivalent to those in the CBIR treatment groups in both

studies. The overall one-year patient survival (CBIR and Prograf-based

treatment groups combined) was 88% in the U.S. study and 78% in the

European study. The overall one-year graft survival (CBIR and Prograf-based

treatment groups combined) was 81% in the U.S. study and 73% in the

European study. In both studies, the median time to convert from IV to oral

Prograf dosing was 2 days.

Because of the nature of the study design, comparisons of differences in

secondary endpoints, such as incidence of acute rejection, refractory

rejection or use of OKT3 for steroid-resistant rejection, could not be

reliably made.

Kidney Transplantation

Prograf-based immunosuppression following kidney transplantation was

assessed in a Phase III randomized, multicenter, non-blinded, prospective

study. There were 412 kidney transplant patients enrolled at 19 clinical

sites in the United States. Study therapy was initiated when renal function

was stable as indicated by a serum creatinine < 4 mg/dL (median of 4 days

after transplantation, range 1 to 14 days). Patients less than 6 years of

age were excluded.

There were 205 patients randomized to Prograf-based immunosuppression and

207 patients were randomized to cyclosporine-based immunosuppression. All

patients received prophylactic induction therapy consisting of an

antilymphocyte antibody preparation, corticosteroids and azathioprine.

Overall one year patient and graft survival was 96.1% and 89.6%,

respectively and was equivalent between treatment arms.

Because of the nature of the study design, comparisons of differences in

secondary endpoints, such as incidence of acute rejection, refractory

rejection or use of OKT3 for steroid-resistant rejection, could not be

reliably made.

INDICATIONS AND USAGE:

Prograf is indicated for the prophylaxis of organ rejection in patients

receiving allogeneic liver or kidney 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.

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.)

Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in

20% of Prograf-treated kidney transplant patients without pretransplant

history of diabetes millitus in the Phase III study below (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 two

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

|Status of PTDM* |Prograf |CBIR |

|Patients without pretransplant history of |151 |151 |

|diabetes mellitus. | | |

|New onset PTDM*, 1st Year |30/151 |6/151 |

| |(20%) |(4%) |

|Still insulin dependent at one year in those |25/151(17|5/151 |

|without prior |%) |(3%) |

|history of diabetes. | | |

|New onset PTDM* post 1 year |1 |0 |

|Patients with PTDM* at 2 years |16/151 |5/151 |

| |(11%) |(3%) |

|*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. |

Development of Post Transplant Diabetes Mellitus by Race

and by Treatment Group during First Year Post Kidney Transplantation in the

Phase III Study

|Patient |Prograf | |CBIR | |

|Race | | | | |

| |No. of |Patients Who |No. of |Patients Who |

| |Patients |Developed |Patients |Developed |

| |at Risk |PTDM* |at Risk |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%) |

|* 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. |

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 one 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 One Year in Liver Transplant Recipients

|Status of PTDM* |US Study| |European| |

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