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
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, |
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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