Brand
name: Prograf
( Immunosuppressant )
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Manufacturer: ASTELLAS PHARMA US manufactures Prograf ( Immunosuppressant
).
Uses:
The uses of Prograf ( Immunosuppressant
) include:
Prograf is an immunosuppressant used to prevent rejection after
a liver or kidney transplant. It may also be used to treat other
conditions as
determined by your doctor
ROGRAF®
Prograf Tacrolimus capsules
Prograf Tacrolimus injection (for intravenous infusion only)
WARNING
Increased susceptibility to infection and the possible development
of lymphoma may result from immunosuppression. Only physicians experienced
in immunosuppressive therapy and management of organ transplant patients
should prescribe Prograf. Patients receiving the drug should be managed
in facilities equipped and staffed with adequate laboratory and supportive
medical resources. The physician responsible for maintenance therapy
should have complete information requisite for the follow-up of the
patient.
DESCRIPTION
Prograf is available for oral administration as capsules (Prograf Tacrolimus
capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous
Prograf Tacrolimus. Inactive ingredients include lactose, hydroxypropyl methylcellulose,
croscarmellose sodium, and magnesium stearate. The 0.5 mg capsule shell
contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule
shell contains gelatin and titanium dioxide, and the 5 mg capsule shell
contains gelatin, titanium dioxide and ferric oxide.
Prograf is also available as a sterile solution (Prograf Tacrolimus injection)
containing the equivalent of 5 mg anhydrous Prograf Tacrolimus in 1 mL for
administration by intravenous infusion only. Each mL contains polyoxyl
60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol,
USP, 80.0% v/v. Prograf injection must be diluted with 0.9% Sodium
Chloride Injection or 5% Dextrose Injection before use.
The chemical structure of Prograf Tacrolimus is:
Prograf Tacrolimus has an empirical formula of C44H69NO12 H2O and a formula
weight of 822.03. Prograf Tacrolimus appears as white crystals or crystalline
powder. It is practically insoluble in water, freely soluble in ethanol,
and very soluble in methanol and chloroform.
Mechanism of Action
Prograf Tacrolimus prolongs the survival of the host and transplanted graft
in animal transplant models of liver, kidney, heart, bone marrow, small
bowel and pancreas, lung and trachea, skin, cornea, and limb.
In animals, Prograf Tacrolimus has been demonstrated to suppress some humoral
immunity and, to a greater extent, cell-mediated reactions such as
allograft rejection, delayed type hypersensitivity, collagen-induced
arthritis, experimental allergic encephalomyelitis, and graft versus
host disease.
Prograf Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism
of action is not known. Experimental evidence suggests that Prograf Tacrolimus
binds to an intracellular protein, FKBP-12. A complex of Prograf Tacrolimus-FKBP-12,
calcium, calmodulin, and calcineurin is then formed and the phosphatase
activity of calcineurin inhibited. This effect may prevent the dephosphorylation
and translocation of nuclear factor of activated T-cells (NF-AT), a
nuclear component thought to initiate gene transcription for the formation
of lymphokines (such as interleukin-2, gamma interferon). The net result
is the inhibition of T-lymphocyte activation (i.e., immunosuppression).
Pharmacokinetics
Prograf Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic
parameters (mean±S.D.) of Prograf Tacrolimus have been determined following
intravenous (IV) and/or oral (PO) administration in healthy volunteers,
and in kidney transplant, liver transplant, and heart transplant patients.Due
to intersubject variability in Prograf Tacrolimus pharmacokinetics, individualization
of dosing regimen is necessary for optimal therapy. (See DOSAGE AND
ADMINISTRATION). Pharmacokinetic data indicate that whole blood concentrations
rather than plasma concentrations serve as the more appropriate sampling
compartment to describe Prograf Tacrolimus pharmacokinetics.
Absorption
Absorption of Prograf Tacrolimus from the gastrointestinal tract after oral
administration is incomplete and variable. The absolute bioavailability
of Prograf Tacrolimus was 17±10% in adult kidney transplant patients
(N=26), 22±6% in adult liver transplant patients (N=17), 23±9%
in adult heart transplant patients (N=11) and 18±5% in healthy
volunteers (N=16).
A single dose study conducted in 32 healthy volunteers established
the bioequivalence of the 1 mg and 5 mg capsules. Another single dose
study in 32 healthy volunteers established the bioequivalence of the
0.5 mg and 1 mg capsules. Prograf Tacrolimus maximum blood concentrations (Cmax)
and area under the curve (AUC) appeared to increase in a dose-proportional
fashion in 18 fasted healthy volunteers receiving a single oral dose
of 3, 7, and 10 mg.
In 18 kidney transplant patients, Prograf Tacrolimus trough concentrations
from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated
well with the AUC (correlation coefficient 0.93). In 24 liver transplant
patients over a concentration range of 10 to 60 ng/mL, the correlation
coefficient was 0.94. In 25 heart transplant patients over a concentration
range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after
an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.
Food Effects
The rate and extent of Prograf Tacrolimus absorption were greatest under fasted
conditions. The presence and composition of food decreased both the
rate and extent of Prograf Tacrolimus absorption when administered to 15 healthy
volunteers.
The effect was most pronounced with a high-fat meal (848 kcal, 46%
fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax
was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate)
decreased mean AUC and mean Cmax by 28% and 65%, respectively.
In healthy volunteers (N=16), the time of the meal also affected Prograf Tacrolimus
bioavailability. When given immediately following the meal, mean Cmax
was reduced 71%, and mean AUC was reduced 39%, relative to the fasted
condition. When administered 1.5 hours following the meal, mean Cmax
was reduced 63%, and mean AUC was reduced 39%, relative to the fasted
condition.
In 11 liver transplant patients, Prograf administered 15 minutes after
a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC
(27±18%) and Cmax (50±19%), as compared to a fasted state.
Distribution
The plasma protein binding of Prograf Tacrolimus is approximately 99% and
is independent of concentration over a range of 5-50 ng/mL. Prograf Tacrolimus
is bound mainly to albumin and alpha-1-acid glycoprotein, and has a
high level of association with erythrocytes. The distribution of Prograf Tacrolimus
between whole blood and plasma depends on several factors, such as
hematocrit, temperature at the time of plasma separation, drug concentration,
and plasma protein concentration. In a U.S. study, the ratio of whole
blood concentration to plasma concentration averaged 35 (range 12 to
67).
Metabolism
Prograf Tacrolimus is extensively metabolized by the mixed-function oxidase
system, primarily the cytochrome P-450 system (CYP3A). A metabolic
pathway leading to the formation of 8 possible metabolites has been
proposed. Demethylation and hydroxylation were identified as the primary
mechanisms of biotransformation in vitro. The major metabolite identified
in incubations with human liver microsomes is 13-demethyl Prograf Tacrolimus.
In in vitro studies, a 31-demethyl metabolite has been reported to
have the same activity as Prograf Tacrolimus.
Special Populations
Pediatric
Pharmacokinetics of Prograf Tacrolimus have been studied in liver transplantation
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 48.4±27.9 ng/mL, respectively. The absolute
bioavailability was 31±24%.
Whole blood trough concentrations from 31 patients less than 12 years
old showed that pediatric patients needed higher doses than adults
to achieve similar Prograf Tacrolimus trough concentrations. (See DOSAGE AND
ADMINISTRATION).
Renal Insufficiency: Prograf 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 Prograf Tacrolimus in patients with renal dysfunction
was similar to that in normal volunteers (see previous table).
Hepatic Insufficiency: Prograf 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
Prograf Tacrolimus in patients with mild hepatic dysfunction was not substantially
different from that in normal volunteers (see previous table). Prograf Tacrolimus
pharmacokinetics were studied in 6 patients with severe 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 Prograf 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 Prograf Tacrolimus doses to attain
similar trough concentrations. (See DOSAGE AND ADMINISTRATION.)
Gender : A formal study to evaluate the effect of gender on Prograf
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, liver and
heart 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 1-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 1-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 3 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 1 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.
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 Prograf 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 Prograf Tacrolimus trough concentrations were within the pre-defined
target range (i.e., 5-15 ng/mL) in 74-86% of the patients in the Prograf Tacrolimus
treatment arm.
