Такролимус

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

|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

|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%)|

* 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.

Prograf can cause neurotoxicity and nephrotoxicity, particularly when used

in high doses. Nephrotoxicity was reported in approximately 52% of kidney

transplantation patients and in 40% and 36% of liver transplantation

patients receiving Prograf in the U.S. and European randomized trials,

respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seen

early after transplantation, characterized by increasing serum creatinine

and a decrease in urine output. Patients with impaired renal function

should be monitored closely as the dosage of Prograf may need to be

reduced. In patients with persistent elevations of serum creatinine who are

unresponsive to dosage adjustments, consideration should be given to

changing to another immunosuppressive therapy. Care should be taken in

using tacrolimus with other nephrotoxic drugs. In particular, to avoid

excess nephrotoxicity, Prograf should not be used simultaneously with

cyclosporine. Prograf or cyclosporine should be discontinued at least 24

hours prior to initiating the other. In the presence of elevated Prograf or

cyclosporine concentrations, dosing with the other drug usually should be

further delayed.

Mild to severe hyperkalemia was reported in 31% of kidney transplant

recipients and in 45% and 13% of liver transplant recipients treated with

Prograf in the U.S. and European randomized trials, respectively, and may

require treatment (see ADVERSE REACTIONS). Serum potassium levels should be

monitored and potassium-sparing diuretics should not be used during Prograf

therapy (see PRECAUTIONS).

Neurotoxicity, including tremor, headache, and other changes in motor

function, mental status, and sensory function were reported in

approximately 55% of liver transplant recipients in the two randomized

studies. Tremor occurred more often in Prograf-treated kidney transplant

patients (54%) compared to cyclosporine-treated patients. The incidence of

other neurological events in kidney transplant patients was similar in the

two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been

associated with high whole-blood concentrations of tacrolimus and may

respond to dosage adjustment. Seizures have occurred in adult and pediatric

patients receiving Prograf (see ADVERSE REACTIONS). Coma and delirium also

have been associated with high plasma concentrations of tacrolimus.

As in patients receiving other immunosuppressants, patients receiving

Prograf are at increased risk of developing lymphomas and other

malignancies, particularly of the skin. The risk appears to be related to

the intensity and duration of immunosuppression rather than to the use of

any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-

Barr Virus (EBV) infection has been reported in immunosuppressed organ

transplant recipients. The risk of LPD appears greatest in young children

who are at risk for primary EBV infection while immunosuppressed or who are

switched to Prograf following long-term immunosuppression therapy. Because

of the danger of oversuppression of the immune system which can increase

susceptibility to infection, combination immunosuppressant therapy should

be used with caution.

A few patients receiving Prograf injection have experienced anaphylactic

reactions. Although the exact cause of these reactions is not known, other

drugs with castor oil derivatives in the formulation have been associated

with anaphylaxis in a small percentage of patients. Because of this

potential risk of anaphylaxis, Prograf injection should be reserved for

patients who are unable to take Prograf capsules.

Patients receiving Prograf injection should be under continuous observation

for at least the first 30 minutes following the start of the infusion and

at frequent intervals thereafter. If signs or symptoms of anaphylaxis

occur, the infusion should be stopped. An aqueous solution of epinephrine

should be available at the bedside as well as a source of oxygen.

PRECAUTIONS:

General

Hypertension is a common adverse effect of Prograf therapy (see ADVERSE

REACTIONS). Mild or moderate hypertension is more frequently reported than

severe hypertension. Antihypertensive therapy may be required; the control

of blood pressure can be accomplished with any of the common

antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-

sparing diuretics should be avoided. While calcium-channel blocking agents

can be effective in treating Prograf-associated hypertension, care should

be taken since interference with tacrolimus metabolism may require a dosage

reduction (see Drug Interactions).

Renally and Hepatically Impaired Patients

For patients with renal insufficiency some evidence suggests that lower

doses should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND

ADMINISTRATION).

The use of Prograf in liver transplant recipients experiencing post-

transplant hepatic impairment may be associated with increased risk of

developing renal insufficiency related to high whole-blood levels of

tacrolimus. These patients should be monitored closely and dosage

adjustments should be considered. Some evidence suggests that lower doses

should be used in these patients (see DOSAGE AND ADMINISTRATION).

Myocardial Hypertrophy

Myocardial hypertrophy has been reported in association with the

administration of Prograf, and is generally manifested by

echocardiographically demonstrated concentric increases in left ventricular

posterior wall and interventricular septum thickness. Hypertrophy has been

observed in infants, children and adults. This condition appears reversible

in most cases following dose reduction or discontinuance of therapy. In a

group of 20 patients with pre- and post-treatment echocardiograms who

showed evidence of myocardial hypertrophy, mean tacrolimus whole blood

concentrations during the period prior to diagnosis of myocardial

hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2

years), 4 to 46 ng/mL in children (N=7, age 2 to 15 years) and 11 to 24

ng/mL in adults (N=3, age 37 to 53 years).

In patients who develop renal failure or clinical manifestations of

ventricular dysfunction while receiving Prograf therapy, echocardiographic

evaluation should be considered. If myocardial hypertrophy is diagnosed,

dosage reduction or discontinuation of Prograf should be considered.

Information for Patients

Patients should be informed of the need for repeated appropriate laboratory

tests while they are receiving Prograf. They should be given complete

dosage instructions, advised of the potential risks during pregnancy, and

informed of the increased risk of neoplasia. Patients should be informed

that changes in dosage should not be undertaken without first consulting

their physician.

Patients should be informed that Prograf can cause diabetes mellitus and

should be advised of the need to see their physician if they develop

frequent urination, increased thirst or hunger.

Laboratory Tests

Serum creatinine, potassium, and fasting glucose should be assessed

regularly. Routine monitoring of metabolic and hematologic systems should

be performed as clinically warranted.

Drug Interactions

Due to the potential for additive or synergistic impairment of renal

function, care should be taken when administering Prograf with drugs that

may be associated with renal dysfunction. These include, but are not

limited to, aminoglycosides, amphotericin B, and cisplatin. Initial

clinical experience with the co-administration of Prograf and cyclosporine

resulted in additive/synergistic nephrotoxicity. Patients switched from

cyclosporine to Prograf should receive the first Prograf dose no sooner

than 24 hours after the last cyclosporine dose. Dosing may be further

delayed in the presence of elevated cyclosporine levels.

Drugs That May Alter Tacrolimus Concentrations

Since tacrolimus is metabolized mainly by the CYP3A enzyme systems,

substances known to inhibit these enzymes may decrease the metabolism or

increase bioavailability of tacrolimus as indicated by increased whole

blood or plasma concentrations. Drugs known to induce these enzyme systems

may result in an increased metabolism of tacrolimus or decreased

bioavailability as indicated by decreased whole blood or plasma

concentrations. Monitoring of blood concentrations and appropriate dosage

adjustments are essential when such drugs are used concomitantly.

|s: | | | | |

| | | | |n |

| | | | |n |

| | | | | |

|nal | |Drugs | | |

|e | | | | |

| | | | | |

|30±8%) was | | | | |

|n (200 mg). | | | | |

|(0.430±0.129L| | | | |

|0.148±0.043L/| | | | |

|s: | | | | |

|ts | | | |Preparations |

*This table is not all inclusive.

St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein.

Since tacrolimus is a substrate for CYP3A4, there is the potential that the

use of St. John's Wort in patients receiving Prograf could result in

reduced tacrolimus levels.

In a study of 6 normal volunteers, a significant decrease in tacrolimus

oral bioavailability (14±6% vs. 7±3%) was observed with concomitant

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