Рефераты. Такролимус

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| |

| | | |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%)|

* 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

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