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                                 -2002.


                       Prograf Prescribing Information

WARNING
DESCRIPTION:
CLINICAL PHARMACOLOGY:
INDICATIONS AND USAGE:
CONTRAINDICATIONS:
WARNINGS:
PRECAUTIONS:
ADVERSE REACTIONS:
OVERDOSAGE:
DOSAGE AND ADMINISTRATION:
HOW SUPPLIED:
REFERENCE

Fujisawa
Revised: May 2002
Prograf

tacrolimus capsules

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 (tacrolimus
capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous
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 (tacrolimus injection)
containing the equivalent of 5 mg anhydrous 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.
Tacrolimus, previously known as FK506, is the active ingredient in Prograf.
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces
tsukubaensis. Chemically, tacrolimus is designated as [3S-
[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-
5,6,8,11,12, 13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-
dihydroxy-3- [2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14, 16-
dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-
c][1,4] oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate.


The chemical structure of tacrolimus is:

Tacrolimus has an empirical formula of C44H69NO12 H2O and a formula weight
of 822.05. 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.
CLINICAL PHARMACOLOGY:
Mechanism of Action
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, 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.
Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism
of action is not known. Experimental evidence suggests that tacrolimus
binds to an intracellular protein, FKBP-12. A complex of 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
Tacrolimus activity is primarily due to the parent drug. The
pharmacokinetic parameters (meanS.D.) of tacrolimus have been determined
following intravenous (IV) and oral (PO) administration in healthy
volunteers, kidney transplant and liver transplant patients. (See table
below.)



|Popula|N    |Route      |Parame|        |        |        |        |      |
|tion  |     |(Dose)     |ters  |        |        |        |        |      |
|      |     |           |Cmax  |Tmax    |AUC     |t      |Cl      |V     |
|      |     |           |(ng/mL|(hr)    |(nghr/m|(hr)    |(L/hr/kg|(L/kg)|
|      |     |           |)     |        |L)      |        |)       |      |
|Health|8    |IV         |      |        |598*    |34.2    |0.040   |1.91  |
|y     |     |(0.025     |     |       | 125   | 7.7   |0.009  |0.31 |
|Volunt|     |mg/kg/4hr) |      |        |        |        |        |      |
|eers  |     |           |      |        |        |        |        |      |
|      |16   |PO         |29.7  |1.6     |243**   |34.8    |0.041  |1.94 |
|      |     |(5 mg)     |7.2  |0.7    |73     |11.4   |0.008  |      |
|      |     |           |      |        |        |        |        |0.53 |
|Kidney|26   |IV         |      |        |294***  |18.8    |0.083   |1.41  |
|      |     |(0.02      |     |       |262    |16.7   |0.050  |0.66 |
|Transp|     |mg/kg/12hr)|      |        |        |        |        |      |
|lant  |     |           |      |        |        |        |        |      |
|Pts   |     |           |      |        |        |        |        |      |
|      |     |PO         |19.2  |3.0     |203***  |#       |#       |#     |
|      |     |(0.2       |10.3 |        |42     |        |        |      |
|      |     |mg/kg/day) |      |        |        |        |        |      |
|      |     |PO         |24.2  |1.5     |288***  |#       |#       |#     |
|      |     |(0.3       |15.8 |        |93     |        |        |      |
|      |     |mg/kg/day) |      |        |        |        |        |      |
|Liver |17   |IV         |     |       |3300*** |11.7    |0.053   |0.85  |
|Transp|     |(0.05      |      |        |        |3.9    |0.017  |0.30 |
|lant  |     |mg/kg/12   |      |        |2130   |        |        |      |
|Pts   |     |hr)        |      |        |        |        |        |      |
|      |     |PO         |68.5  |2.3     |519***  |#       |#       |#     |
|      |     |(0.3       |30.0 |1.5    |179    |        |        |      |
|      |     |mg/kg/day) |      |        |        |        |        |      |


  Corrected for individual bioavailability * AUC0-120 ** AUC0-72 *** AUC0-
                    inf  not applicable # not available
Due to intersubject variability in 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 tacrolimus pharmacokinetics.
Absorption
Absorption of tacrolimus from the gastrointestinal tract after oral
administration is incomplete and variable. The absolute bioavailability of
tacrolimus was 1710% in adult kidney transplant patients (N=26), 226% in
adult liver transplant patients (N=17), and 185% 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. 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, 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.
Food Effects: The rate and extent of tacrolimus absorption were greatest
under fasted conditions. The presence and composition of food decreased
both the rate and extent of 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 C max were decreased 37% and 77%, respectively; Tmax was
lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate)
decreased mean AUC and mean C max by 28% and 65%, respectively.
In healthy volunteers (N=16), the time of the meal also affected 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 (5019%), as compared to a fasted state.
Distribution
The plasma protein binding of tacrolimus is approximately 99% and is
independent of concentration over a range of 5-50 ng/mL. Tacrolimus is
bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level
of association with erythrocytes. The distribution of 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
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 tacrolimus. In in vitro studies,
a 31-demethyl metabolite has been reported to have the same activity as
tacrolimus.
Excretion
The mean clearance following IV administration of tacrolimus is 0.040,
0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplant
patients and adult liver transplant patients, respectively. In man, less
than 1% of the dose administered is excreted unchanged in urine.
In a mass balance study of IV administered radiolabeled tacrolimus to 6
healthy volunteers, the mean recovery of radiolabel was 77.812.7%. Fecal
elimination accounted for 92.41.0% and the elimination half-life based on
radioactivity was 48.115.9 hours whereas it was 43.511.6 hours based on
tacrolimus concentrations. The mean clearance of radiolabel was 0.0290.015
L/hr/kg and clearance of tacrolimus was 0.0290.009 L/hr/kg. When
administered PO, the mean recovery of the radiolabel was 94.930.7%. Fecal
elimination accounted for 92.630.7%, urinary elimination accounted for
2.31.1% and the elimination half-life based on radioactivity was 31.910.5
hours whereas it was 48.412.3 hours based on tacrolimus concentrations.
The mean clearance of radiolabel was 0.2260.116 L/hr/kg and clearance of
tacrolimus 0.1720.088 L/hr/kg.
Special Populations
Pediatric
Pharmacokinetics of 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 11.53.8 hours, 2.62.1 L/kg and
0.1380.071 L/hr/kg, respectively. Following oral administration to 9
patients, mean AUC and Cmax were 337167 nghr/mL and 43.427.9 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  |t            |V    |Cl       |
|(No. of        |        |(nghr/mL|(hr)          |(L/kg|(L/hr/kg)|
|Patients)      |        |)        |              |)    |         |
|Renal          |0.02    |393123  |26.39.2      |1.07 |0.038    |
|Impairment     |mg/kg/4h|(t =     |              |     |0.014   |
|(n=12)         |r       |60hr)    |              |0.20|         |
|               |IV      |         |              |     |         |
|Mild Hepatic   |0.02    |367107  |60.643.8     |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  |488320  |66.144.8     |3.7  |0.034    |
|               |PO      |(t =     |Range: 29.5 - |4.7*|0.019*  |
|               |        |72hr)    |138           |     |         |
|Severe Hepatic |0.02    |762204  |198158       |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    |289117  |              |     |         |
|               |mg/kg/8h|(t=144hr)|              |     |         |
|               |r       |         |              |     |         |
|               |IV (n=4)|         |              |     |         |
|               |        |         |              |     |         |
|Severe Hepatic |8 mg PO |658      |11935        |3.1  |0.016    |
|Impairment     |(n=1)   |(t=120hr)|Range: 85-178 |3.4*|0.011*  |
|(n=5, PO)     |        |         |              |     |         |
|               |5mg PO  |533156  |              |     |         |
|               |(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 3.91.6 and 12.02.4 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|      |
|                                    |        |        |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
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.
|*Drugs That  |             |             |             |             |
|May Increase |             |             |             |             |
|Tacrolimus   |             |             |             |             |
|Blood        |             |             |             |             |
|Concentration|             |             |             |             |
|s:           |             |             |             |             |
|Calcium      |             |Antifungal   |             |Macrolide    |
|Channel      |             |Agents       |             |Antibiotics  |
|Blockers     |             |             |             |             |
|diltiazem    |             |clotrimazole |             |clarithromyci|
|             |             |             |             |n            |
|nicardipine  |             |fluconazole  |             |erythromycin |
|nifedipine   |             |itraconazole |             |troleandomyci|
|             |             |             |             |n            |
|verapamil    |             |ketoconazole |             |             |
|             |             |             |             |             |
|Gastrointesti|             |Other        |             |             |
|nal          |             |Drugs        |             |             |
|Prokinetic   |             |             |             |             |
|Agents       |             |             |             |             |
|cisapride    |             |bromocriptine|             |             |
|metoclopramid|             |cimetidine   |             |             |
|e            |             |             |             |             |
|             |             |cyclosporine |             |             |
|             |             |danazol      |             |             |
|             |             |ethinyl      |             |             |
|             |             |estradiol    |             |             |
|             |             |methylprednis|             |             |
|             |             |olone        |             |             |
|             |             |omeprazole   |             |             |
|             |             |protease     |             |             |
|             |             |inhibitors   |             |             |
|             |             |nefazodone   |             |             |
|             |             |             |             |             |
|In a study of|             |             |             |             |
|6 normal     |             |             |             |             |
|volunteers, a|             |             |             |             |
|significant  |             |             |             |             |
|increase in  |             |             |             |             |
|tacrolimus   |             |             |             |             |
|oral         |             |             |             |             |
|bioavailabili|             |             |             |             |
|ty (145% vs.|             |             |             |             |
|308%) was   |             |             |             |             |
|observed with|             |             |             |             |
|concomitant  |             |             |             |             |
|ketoconazole |             |             |             |             |
|administratio|             |             |             |             |
|n (200 mg).  |             |             |             |             |
|The apparent |             |             |             |             |
|oral         |             |             |             |             |
|clearance of |             |             |             |             |
|tacrolimus   |             |             |             |             |
|during       |             |             |             |             |
|ketoconazole |             |             |             |             |
|administratio|             |             |             |             |
|n was        |             |             |             |             |
|significantly|             |             |             |             |
|decreased    |             |             |             |             |
|compared to  |             |             |             |             |
|tacrolimus   |             |             |             |             |
|alone        |             |             |             |             |
|(0.4300.129L|             |             |             |             |
|/hr/kg vs.   |             |             |             |             |
|0.1480.043L/|             |             |             |             |
|hr/kg).      |             |             |             |             |
|Overall, IV  |             |             |             |             |
|clearance of |             |             |             |             |
|tacrolimus   |             |             |             |             |
|was not      |             |             |             |             |
|significantly|             |             |             |             |
|changed by   |             |             |             |             |
|ketoconazole |             |             |             |             |
|co-administra|             |             |             |             |
|tion,        |             |             |             |             |
|although it  |             |             |             |             |
|was highly   |             |             |             |             |
|variable     |             |             |             |             |
|between      |             |             |             |             |
|patients.    |             |             |             |             |
|*Drugs That  |             |             |             |             |
|May Decrease |             |             |             |             |
|Tacrolimus   |             |             |             |             |
|Blood        |             |             |             |             |
|Concentration|             |             |             |             |
|s:           |             |             |             |             |
|Anticonvulsan|             |Antibiotics  |             |Herbal       |
|ts           |             |             |             |Preparations |
|carbamazepine|             |rifabutin    |             |St. John's   |
|             |             |             |             |Wort         |
|phenobarbital|             |rifampin     |             |             |
|phenytoin    |             |             |             |             |


*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 (146% vs. 73%) was observed with concomitant
rifampin administration (600 mg). In addition, there was a significant
increase in tacrolimus clearance (0.0360.008L/hr/kg vs.
0.0530.010L/hr/kg) with concomitant rifampin administration.
Interaction studies with drugs used in HIV therapy have not been conducted.
However, care should be exercised when drugs that are nephrotoxic (e.g.,
ganciclovir) or that are metabolized by CYP3A (e.g., ritonavir) are
administered concomitantly with tacrolimus. Tacrolimus may effect the
pharmacokinetics of other drugs (e.g. phenytoin) and increase their
concentration. Grapefruit juice affects CYP3A-mediated metabolism and
should be avoided (see DOSAGE AND ADMINISTRATION).
Other Drug Interactions
Immunosuppressants may affect vaccination. Therefore, during treatment with
Prograf, vaccination may be less effective. The use of live vaccines should
be avoided; live vaccines may include, but are not limited to measles,
mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1
Carcinogenesis, Mutagenesis and Impairment of Fertility
An increased incidence of malignancy is a recognized complication of
immunosuppression in recipients of organ transplants. The most common forms
of neoplasms are non-Hodgkin's lymphomas and carcinomas of the skin. As
with other immunosuppressive therapies, the risk of malignancies in Prograf
recipients may be higher than in the normal, healthy population.
Lymphoproliferative disorders associated with Epstein-Barr Virus infection
have been seen. It has been reported that reduction or discontinuation of
immunosuppression may cause the lesions to regress.
No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli)
or mammalian (Chinese hamster lung-derived cells) in vitro assays of
mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo
clastogenicity assays performed in mice; tacrolimus did not cause
unscheduled DNA synthesis in rodent hepatocytes.
Carcinogenicity studies were carried out in male and female rats and mice.
In the 80-week mouse study and in the 104-week rat study no relationship of
tumor incidence to tacrolimus dosage was found. The highest doses used in
the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times
(rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when
corrected for body surface area.
No impairment of fertility was demonstrated in studies of male and female
rats. Tacrolimus, given orally at 1.0 mg/kg (0.7 - 1.4X the recommended
clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area
corrections) to male and female rats, prior to and during mating, as well
as to dams during gestation and lactation, was associated with
embryolethality and with adverse effects on female reproduction. Effects on
female reproductive function (parturition) and embryolethal effects were
indicated by a higher rate of pre-implantation loss and increased numbers
of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the
recommended clinical dose range based on body surface area correction),
tacrolimus was associated with maternal and paternal toxicity as well as
reproductive toxicity including marked adverse effects on estrus cycles,
parturition, pup viability, and pup malformations.
Pregnancy: Category C
In reproduction studies in rats and rabbits, adverse effects on the fetus
were observed mainly at dose levels that were toxic to dams. Tacrolimus at
oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was
associated with maternal toxicity as well as an increase in incidence of
abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the
recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface
area corrections. At the higher dose only, an increased incidence of
malformations and developmental variations was also seen. Tacrolimus, at
oral doses of 3.2 mg/kg during organogenesis in rats, was associated with
maternal toxicity and caused an increase in late resorptions, decreased
numbers of live births, and decreased pup weight and viability. Tacrolimus,
given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X
the recommended clinical dose range based on body surface area corrections)
to pregnant rats after organogenesis and during lactation, was associated
with reduced pup weights.
No reduction in male or female fertility was evident.
There are no adequate and well-controlled studies in pregnant women.
Tacrolimus is transferred across the placenta. The use of tacrolimus during
pregnancy has been associated with neonatal hyperkalemia and renal
dysfunction. Prograf should be used during pregnancy only if the potential
benefit to the mother justifies potential risk to the fetus.
Nursing Mothers
Since tacrolimus is excreted in human milk, nursing should be avoided.
Pediatric Patients
Experience with Prograf in pediatric kidney transplant patients is limited.
Successful liver transplants have been performed in pediatric patients
(ages up to 16 years) using Prograf. The two randomized active-controlled
trials of Prograf in primary liver transplantation included 56 pediatric
patients. Thirty-one patients were randomized to Prograf-based and 25 to
cyclosporine-based therapies. Additionally, a minimum of 122 pediatric
patients were studied in an uncontrolled trial of tacrolimus in living
related donor liver transplantation. Pediatric patients generally required
higher doses of Prograf to maintain blood trough concentrations of
tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS:
Liver Transplantation
The principal adverse reactions of Prograf are tremor, headache, diarrhea,
hypertension, nausea, and renal dysfunction. These occur with oral and IV
administration of Prograf and may respond to a reduction in dosing.
Diarrhea was sometimes associated with other gastrointestinal complaints
such as nausea and vomiting.
Hyperkalemia and hypomagnesemia have occurred in patients receiving Prograf
therapy. Hyperglycemia has been noted in many patients; some may require
insulin therapy (see WARNINGS).
The incidence of adverse events was determined in two randomized
comparative liver transplant trials among 514 patients receiving tacrolimus
and steroids and 515 patients receiving a cyclosporine-based regimen
(CBIR). The proportion of patients reporting more than one adverse event
was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions
must be taken when comparing the incidence of adverse events in the U.S.
study to that in the European study. The 12-month posttransplant
information from the U.S. study and from the European study is presented
below. The two studies also included different patient populations and
patients were treated with immunosuppressive regimens of differing
intensities. Adverse events reported in > 15% in tacrolimus patients
(combined study results) are presented below for the two controlled trials
in liver transplantation:
 LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN > 15% OF PROGRAF-TREATED
                                  PATIENTS
|                                       |U.S.  |      |EUROPEAN|        |
|                                       |STUDY |      |STUDY   |        |
|                                       |(%)   |      |(%)     |        |
|                                       |Progra|CBIR  |Prograf |CBIR    |
|                                       |f     |(N=250|(N=264) |(N=265) |
|                                       |(N=250|)     |        |        |
|                                       |)     |      |        |        |
|Nervous System                         |      |      |        |        |
|Headache (see WARNINGS)                |64    |60    |37      |26      |
|Tremor (see WARNINGS)                  |56    |46    |48      |32      |
|Insomnia                               |64    |68    |32      |23      |
|Paresthesia                            |40    |30    |17      |17      |
|Gastrointestinal                       |      |      |        |        |
|Diarrhea                               |72    |47    |37      |27      |
|Nausea                                 |46    |37    |32      |27      |
|Constipation                           |24    |27    |23      |21      |
|LFT Abnormal                           |36    |30    |6       |5       |
|Anorexia                               |34    |24    |7       |5       |
|Vomiting                               |27    |15    |14      |11      |
|Cardiovascular                         |      |      |        |        |
|Hypertension (see PRECAUTIONS)         |47    |56    |38      |43      |
|Urogenital                             |      |      |        |        |
|Kidney Function Abnormal (see WARNINGS)|40    |27    |36      |23      |
|Creatinine Increased (see WARNINGS)    |39    |25    |24      |19      |
|BUN Increased (see WARNINGS)           |30    |22    |12      |9       |
|Urinary Tract Infection                |16    |18    |21      |19      |
|Oliguria                               |18    |15    |19      |12      |
|Metabolic and Nutritional              |      |      |        |        |
|Hyperkalemia (see WARNINGS)            |45    |26    |13      |9       |
|Hypokalemia                            |29    |34    |13      |16      |
|Hyperglycemia (see WARNINGS)           |47    |38    |33      |22      |
|Hypomagnesemia                         |48    |45    |16      |9       |
|Hemic and Lymphatic                    |      |      |        |        |
|Anemia                                 |47    |38    |5       |1       |
|Leukocytosis                           |32    |26    |8       |8       |
|Thrombocytopenia                       |24    |20    |14      |19      |
|Miscellaneous                          |      |      |        |        |
|Abdominal Pain                         |59    |54    |29      |22      |
|Pain                                   |63    |57    |24      |22      |
|Fever                                  |48    |56    |19      |22      |
|Asthenia                               |52    |48    |11      |7       |
|Back Pain                              |30    |29    |17      |17      |
|Ascites                                |27    |22    |7       |8       |
|Peripheral Edema                       |26    |26    |12      |14      |
|Respiratory System                     |      |      |        |        |
|Pleural Effusion                       |30    |32    |36      |35      |
|Atelectasis                            |28    |30    |5       |4       |
|Dyspnea                                |29    |23    |5       |4       |
|Skin and Appendages                    |      |      |        |        |
|Pruritus                               |36    |20    |15      |7       |
|Rash                                   |24    |19    |10      |4       |


  Less frequently observed adverse reactions in both liver transplantation
 and kidney transplantation patients are described under the subsection Less
                Frequently Reported Adverse Reactions below.
Kidney Transplantation
The most common adverse reactions reported were infection, tremor,
hypertension, decreased renal function, constipation, diarrhea, headache,
abdominal pain and insomnia.
Adverse events that occurred in > 15 % of Prograf-treated kidney transplant
patients are presented below:
    KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN > 15% OF PROGRAF-
                              TREATED PATIENTS
|                                                      |Prograf  |CBIR    |
|                                                      |(N=205)  |(N=207) |
|Nervous System                                        |         |        |
|Tremor (see WARNINGS)                                 |54       |34      |
|Headache (see WARNINGS)                               |44       |38      |
|Insomnia                                              |32       |30      |
|Paresthesia                                           |23       |16      |
|Dizziness                                             |19       |16      |
|Gastrointestinal                                      |         |        |
|Diarrhea                                              |44       |41      |
|Nausea                                                |38       |36      |
|Constipation                                          |35       |43      |
|Vomiting                                              |29       |23      |
|Dyspepsia                                             |28       |20      |
|Cardiovascular                                        |         |        |
|Hypertension (see PRECAUTIONS)                        |50       |52      |
|Chest Pain                                            |19       |13      |
|Urogenital                                            |         |        |
|Creatinine Increased (see WARNINGS)                   |45       |42      |
|Urinary Tract Infection                               |34       |35      |
|Metabolic and Nutritional                             |         |        |
|Hypophosphatemia                                      |49       |53      |
|Hypomagnesemia                                        |34       |17      |
|Hyperlipemia                                          |31       |38      |
|Hyperkalemia (see WARNINGS)                           |31       |32      |
|Diabetes Mellitus (see WARNINGS)                      |24       |9       |
|Hypokalemia                                           |22       |25      |
|Hyperglycemia (see WARNINGS)                          |22       |16      |
|Edema                                                 |18       |19      |
|Hemic and Lymphatic                                   |         |        |
|Anemia                                                |30       |24      |
|Leukopenia                                            |15       |17      |
|Miscellaneous                                         |         |        |
|Infection                                             |45       |49      |
|Peripheral Edema                                      |36       |48      |
|Asthenia                                              |34       |30      |
|Abdominal Pain                                        |33       |31      |
|Pain                                                  |32       |30      |
|Fever                                                 |29       |29      |
|Back Pain                                             |24       |20      |
|Respiratory System                                    |         |        |
|Dyspnea                                               |22       |18      |
|Cough Increased                                       |18       |15      |
|Musculoskeletal                                       |         |        |
|Arthralgia                                            |25       |24      |
|Skin                                                  |         |        |
|Rash                                                  |17       |12      |
|Pruritis                                              |15       |7       |


 Less frequently observed adverse reactions in both liver transplantion and
   kidney transplantation patients are described under the subsection Less
             Frequently Reported Adverse Reactions shown below.
Less Frequently Reported Adverse Reactions
The following adverse events were reported in the range of 3% to less than
15% incidence in either liver or kidney transplant recipients who were
treated with tacrolimus in the Phase 3 comparative trials.
NERVOUS SYSTEM: (see WARNINGS) abnormal dreams, agitation, amnesia,
anxiety, confusion, convulsion, depression, dizziness, emotional lability,
encephalopathy, hallucinations, hypertonia, incoordination, myoclonus,
nervousness, neuropathy, psychosis, somnolence, thinking abnormal; SPECIAL
SENSES: abnormal vision, amblyopia, ear pain, otitis media, tinnitus;
GASTROINTESTINAL: anorexia, cholangitis, cholestatic jaundice, dyspepsia,
dysphagia, esophagitis, flatulence, gastritis, gastrointestinal hemorrhage,
GGT increase, GI perforation, hepatitis, ileus, increased appetite,
jaundice, liver damage, liver function test abnormal, oral moniliasis,
rectal disorder, stomatitis; CARDIOVASCULAR: angina pectoris, chest pain,
deep thrombophlebitis, abnormal ECG, hemorrhage, hypotension, postural
hypotension, peripheral vascular disorder, phlebitis, tachycardia,
thrombosis, vasodilatation; UROGENITAL: (see WARNINGS) albuminuria,
cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney
tubular necrosis, nocturia, pyuria, toxic nephropathy, oliguria, urinary
frequency, urinary incontinence, vaginitis; METABOLIC/NUTRITIONAL:
acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased,
AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased,
dehydration, GGT increased, healing abnormal, hypercalcemia,
hypercholesterolemia, hyperlipemia, hyperphosphatemia, hyperuricemia,
hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia,
hypoproteinemia, lactic dehydrogenase increase, weight gain; ENDOCRINE:
(see PRECAUTIONS) Cushing's syndrome, diabetes mellitus; HEMIC/LYMPHATIC:
coagulation disorder, ecchymosis, hypochromic anemia, leukocytosis,
leukopenia, polycythemia, prothrombin decreased, serum iron decreased,
thrombocytopenia; MISCELLANEOUS: abdomen enlarged, abscess, accidental
injury, allergic reaction, cellulitis, chills, flu syndrome, generalized
edema, hernia, peritonitis, photosensitivity reaction, sepsis;
MUSCULOSKELETAL: arthralgia, cramps, generalized spasm, joint disorder, leg
cramps, myalgia, myasthenia, osteoporosis; RESPIRATORY: asthma, bronchitis,
cough increased, lung disorder, pneumothorax, pulmonary edema, pharyngitis,
pneumonia, respiratory disorder, rhinitis, sinusitis, voice alteration;
SKIN: acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes
simplex, hirsutism, skin discoloration, skin disorder, skin ulcer,
sweating.
There have been rare spontaneous reports of myocardial hypertrophy
associated with clinically manifested ventricular dysfunction in patients
receiving Prograf therapy (see PRECAUTIONS-Myocardial Hypertrophy).
Post Marketing
The following have been reported: increased amylase including pancreatitis,
hearing loss including deafness, leukoencephalopathy, thrombocytopenic
purpura, hemolytic-uremia syndrome, acute renal failure, Stevens-Johnson
syndrome, stomach ulcer, glycosuria, cardiac arrhythmia and
gastroenteritis.
OVERDOSAGE:
Limited overdosage experience is available. Acute overdosages of up to 30
times the intended dose have been reported. Almost all cases have been
asymptomatic and all patients recovered with no sequelae. Occasionally,
acute overdosage has been followed by adverse reactions consistent with
those listed in the ADVERSE REACTIONS section except in one case where
transient urticaria and lethargy were observed. Based on the poor aqueous
solubility and extensive erythrocyte and plasma protein binding, it is
anticipated that tacrolimus is not dialyzable to any significant extent;
there is no experience with charcoal hemoperfusion. The oral use of
activated charcoal has been reported in treating acute overdoses, but
experience has not been sufficient to warrant recommending its use. General
supportive measures and treatment of specific symptoms should be followed
in all cases of overdosage.
In acute oral and IV toxicity studies, mortalities were seen at or above
the following doses: in adult rats, 52X the recommended human oral dose; in
immature rats, 16X the recommended oral dose; and in adult rats, 16X the
recommended human IV dose (all based on body surface area corrections).
DOSAGE AND ADMINISTRATION:
Prograf injection (tacrolimus injection)
For IV Infusion Only
NOTE: Anaphylactic reactions have occurred with injectables containing
castor oil derivatives. See WARNINGS.
In patients unable to take oral Prograf capsules, therapy may be initiated
with Prograf injection. The initial dose of Prograf should be administered
no sooner than 6 hours after transplantation. The recommended starting dose
of Prograf injection is 0.03-0.05 mg/kg/day as a continuous IV infusion.
Adult patients should receive doses at the lower end of the dosing range.
Concomitant adrenal corticosteroid therapy is recommended early post-
transplantation. Continuous IV infusion of Prograf injection should be
continued only until the patient can tolerate oral administration of
Prograf capsules.
Preparation for Administration/Stability
Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5%
Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL
prior to use. Diluted infusion solution should be stored in glass or
polyethylene containers and should be discarded after 24 hours. The diluted
infusion solution should not be stored in a PVC container due to decreased
stability and the potential for extraction of phthalates. In situations
where more dilute solutions are utilized (e.g., pediatric dosing, etc.),
PVC-free tubing should likewise be used to minimize the potential for
significant drug adsorption onto the tubing. Parenteral drug products
should be inspected visually for particulate matter and discoloration prior
to administration, whenever solution and container permit. Due to the
chemical instability of tacrolimus in alkaline media, Prograf injection
should not be mixed or co-infused with solutions of pH 9 or greater (e.g.,
ganciclovir or acyclovir).
Prograf capsules (tacrolimus capsules)
   Summary of Initial Oral Dosage Recommendations and Typical Whole Blood
                            Trough Concentrations
|Patient Population       |Recommended   |Typical Whole Blood Trough    |
|                         |Initial       |Concentrations                |
|                         |Oral Dose*    |                              |
|Adult kidney transplant  |0.2 mg/kg/day |month 1-3 : 7-20 ng/mL        |
|patients                 |              |month 4-12 : 5-15 ng/mL       |
|Adult liver transplant   |0.10-0.15     |month 1-12 : 5-20 ng/mL       |
|patients                 |mg/kg/day     |                              |
|Pediatric liver          |0.15-0.20     |month 1-12 : 5-20 ng/mL       |
|transplant patients      |mg/kg/day     |                              |


                       *Note: two divided doses, q12h
Liver Transplantation
It is recommended that patients initiate oral therapy with Prograf capsules
if possible. If IV therapy is necessary, conversion from IV to oral Prograf
is recommended as soon as oral therapy can be tolerated. This usually
occurs within 2-3 days. The initial dose of Prograf should be administered
no sooner than 6 hours after transplantation. In a patient receiving an IV
infusion, the first dose of oral therapy should be given 8-12 hours after
discontinuing the IV infusion. The recommended starting oral dose of
Prograf capsules is 0.10-0.15 mg/kg/day administered in two divided daily
doses every 12 hours. Co-administered grapefruit juice has been reported to
increase tacrolimus blood trough concentrations in liver transplant
patients. (See Drugs That May Alter Tacrolimus Concentrations.)
Dosing should be titrated based on clinical assessments of rejection and
tolerability. Lower Prograf dosages may be sufficient as maintenance
therapy. Adjunct therapy with adrenal corticosteroids is recommended early
post transplant.
Dosage and typical tacrolimus whole blood trough concentrations are shown
in the table above; blood concentration details are described in Blood
Concentration Monitoring: Liver Transplantation below.
Kidney Transplantation
The recommended starting oral dose of Prograf is 0.2 mg/kg/day administered
every 12 hours in two divided doses. The initial dose of Prograf may be
administered within 24 hours of transplantation, but should be delayed
until renal function has recovered (as indicated for example by a serum
creatinine<4 mg/dL). Black patients may require higher doses to achieve
comparable blood concentrations. Dosage and typical tacrolimus whole blood
trough concentrations are shown in the table above; blood concentration
details are described in Blood Concentration Monitoring: Kidney
Transplantation below.
The data in kidney transplant patients indicate that the Black patients
required a higher dose to attain comparable trough concentrations compared
to Caucasian patients.

|Time After   |Caucasian|                  |Black    |                  |
|Transplant   |         |                  |n=56     |                  |
|             |n=114    |                  |         |                  |
|             |Dose     |Trough            |Dose     |Trough            |
|             |(mg/kg)  |Concentrations    |(mg/kg)  |Concentrations    |
|             |         |(ng/mL)           |         |(ng/mL)           |
|Day 7        |0.18     |12.0              |0.23     |10.9              |
|Month 1      |0.17     |12.8              |0.26     |12.9              |
|Month 6      |0.14     |11.8              |0.24     |11.5              |
|Month 12     |0.13     |10.1              |0.19     |11.0              |


                             Pediatric Patients
Pediatric liver transplantation patients without pre-existing renal or
hepatic dysfunction have required and tolerated higher doses than adults to
achieve similar blood concentrations. Therefore, it is recommended that
therapy be initiated in pediatric patients at a starting IV dose of 0.03-
0.05 mg/kg/day and a starting oral dose of 0.15-0.20 mg/kg/day. Dose
adjustments may be required. Experience in pediatric kidney transplantation
patients is limited.
Patients with Hepatic or Renal Dysfunction
Due to the reduced clearance and prolonged half-life, patients with severe
hepatic impairment (Pugh > 10) may require lower doses of Prograf. Close
monitoring of blood concentrations is warranted.
Due to the potential for nephrotoxicity, patients with renal or hepatic
impairment should receive doses at the lowest value of the recommended IV
and oral dosing ranges. Further reductions in dose below these ranges may
be required. Prograf therapy usually should be delayed up to 48 hours or
longer in patients with post-operative oliguria.
Conversion from One Immunosuppressive Regimen to Another
Prograf should not be used simultaneously with cyclosporine. Prograf or
cyclosporine should be discontinued at least 24 hours before initiating the
other. In the presence of elevated Prograf or cyclosporine concentrations,
dosing with the other drug usually should be further delayed.
Blood Concentration Monitoring
Monitoring of tacrolimus blood concentrations in conjunction with other
laboratory and clinical parameters is considered an essential aid to
patient management for the evaluation of rejection, toxicity, dose
adjustments and compliance. Factors influencing frequency of monitoring
include but are not limited to hepatic or renal dysfunction, the addition
or discontinuation of potentially interacting drugs and the posttransplant
time. Blood concentration monitoring is not a replacement for renal and
liver function monitoring and tissue biopsies.
Two methods have been used for the assay of tacrolimus, a microparticle
enzyme immunoassay (MEIA) and an ELISA. Both methods have the same
monoclonal antibody for tacrolimus. Comparison of the concentrations in
published literature to patient concentrations using the current assays
must be made with detailed knowledge of the assay methods and biological
matrices employed. Whole blood is the matrix of choice and specimens should
be collected into tubes containing ethylene diamine tetraacetic acid (EDTA)
anti-coagulant. Heparin anti-coagulation is not recommended because of the
tendency to form clots on storage. Samples which are not analyzed
immediately should be stored at room temperature or in a refrigerator and
assayed within 7 days; if samples are to be kept longer they should be deep
frozen at -20 C for up to 12 months.
Liver Transplantation
Although there is a lack of direct correlation between tacrolimus
concentrations and drug efficacy, data from Phase II and III studies of
liver transplant patients have shown an increasing incidence of adverse
events with increasing trough blood concentrations. Most patients are
stable when trough whole blood concentrations are maintained between 5 to
20 ng/mL. Long term posttransplant patients often are maintained at the low
end of this target range.
Data from the U.S. clinical trial show that tacrolimus whole blood
concentrations, as measured by ELISA, were most variable during the first
week post-transplantation. After this early period, the median trough blood
concentrations, measured at intervals from the second week to one year post-
transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.
Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus
document and several position papers regarding the therapeutic monitoring
of tacrolimus from the 1995 International Consensus Conference on
Immunosuppressive Drugs. Refer to these manuscripts for further discussions
of tacrolimus monitoring.
Kidney Transplantation
Data from the Phase III study indicates that trough concentrations of
tacrolimus in whole blood, as measured by IMx, were most variable during
the first week of dosing. During the first three months, 80% of the
patients maintained trough concentrations between 7-20 ng/mL, and then
between 5-15 ng/mL, through one-year.
The relative risk of toxicity is increased with higher trough
concentrations. Therefore, monitoring of whole blood trough concentrations
is recommended to assist in the clinical evaluation of toxicity.
HOW SUPPLIED:
|Prograf capsules (tacrolimus capsules) 0.5 mg                           |
|Oblong, light yellow, branded with red "0.5 mg" on the capsule cap and "|
|607" on the capsule body, supplied in 60-count bottles (NDC             |
|0469-0607-67), containing the equivalent of 0.5 mg anhydrous tacrolimus.|
|                                                                        |
|Prograf capsules (tacrolimus capsules) 1 mg                             |
|Oblong, white, branded with red "1 mg" on the capsule cap and " 617" on |
|the capsule body, supplied in 100-count bottles (NDC 0469-0617-71) and  |
|10 blister cards of 10 capsules (NDC 0469-0617-10), containing the      |
|equivalent of 1 mg anhydrous tacrolimus.                                |
|Prograf capsules (tacrolimus capsules) 5mg                              |
|Oblong, grayish/red, branded with white "5 mg" on the capsule cap and " |
|657" on the capsule body, supplied in 100-count bottles (NDC            |
|0469-0657-71) and 10 blister cards of 10 capsules (NDC 0469-0657-10),   |
|containing the equivalent of 5 mg anhydrous tacrolimus.                 |
|Store and Dispense                                                      |
|Store at 25 C (77 F); excursions permitted to15 C-30 C (59 F-86   |
|F).                                                                     |
|Prograf injection (tacrolimus injection) 5mg (for IV infusion only)     |
|Supplied as a sterile solution in 1 mL ampules containing the equivalent|
|of 5 mg of anhydrous tacrolimus per mL, in boxes of 10 ampules (NDC     |
|0469-3016-01).                                                          |
|Store and Dispense                                                      |
|Store between 5 C and 25 C (41 F and 77 F).                         |
|Made in Ireland                                                         |
|Prograf capsules (tacrolimus capsules) 0.5 mg                           |
|Oblong, light yellow, branded with red "0.5 mg" on the capsule cap and "|
|607" on the capsule body, supplied in 100-count plastic bottles (NDC    |
|0469-0607-73) containing the equivalent of 0.5 mg anhydrous tacrolimus. |
|Prograf capsules (tacrolimus capsules) 1 mg                             |
|Oblong, white, branded with red "1 mg" on the capsule cap and " 617" on |
|the capsule body, supplied in 100-count plastic bottles (NDC            |
|0469-0617-73) and 10 blister cards of 10 capsules (NDC 0469-0617-11),   |
|containing the equivalent of 1 mg anhydrous tacrolimus.                 |
|Prograf capsules (tacrolimus capsules) 5mg                              |
|Oblong, grayish/red, branded with white "5 mg" on the capsule cap and " |
|657" on the capsule body, supplied in 100-count plastic bottles (NDC    |
|0469-0657-73) and 10 blister cards of 10 capsules (NDC 0469-0657-11),   |
|containing the equivalent of 5 mg anhydrous tacrolimus                  |
|Store and Dispense                                                      |
|Store at 25C (77F); excursions permitted to 15C-30C (59F-86F).    |
|Made in Japan                                                           |


Manufactured for:

Fujisawa Healthcare, Inc.

Deerfield, IL 60015-2548
Rx only
ZL40305/06
REFERENCE
1. CDC: Recommendations of the Advisory Committee on Immunization
Practices: Use of vaccines and immune globulins in persons with altered
immunocompetence. MMWR 1993;42(RR-4):1-18.
http://www.fujisawa.com/medinfo/pi/pi_main_pg.htm

GENERIC NAME: tacrolimus
BRAND NAME: Prograf
DRUG CLASS AND MECHANISM: Tacrolimus is a drug that suppresses the immune
system and is used to prevent rejection of transplanted organs. Tacrolimus
accomplishes its immune-suppressing effecting by inhibiting an enzyme
(calcineurin) crucial for the multiplication of T-cells, cells that are
vital to the immune process. The use of oral tacrolimus allows
transplantation specialists to reduce the dose of steroids which are also
used to prevent rejection. This "steroid-sparing effect" is important
because of the many side effects that can occur when larger doses of
steroids are used for a long period of time. Tacrolimus was approved by the
FDA in April, 1994 for liver transplantation and also has been used in
patients for heart, kidney, small bowel, and bone marrow transplantation.
GENERIC AVAILABLE: No
PRESCRIPTION: Yes
PREPARATIONS: Tacrolimus is available as 1mg and 5mg capsules. It also is
available for intravenous use.
STORAGE: Tacrolimus should be stored at room temperature between 15 and
30C (59 and 86F).
PRESCRIBED FOR: Tacrolimus is used for the prevention of rejection of
transplanted organs.
DOSING: Oral tacrolimus is taken twice daily. Doses vary widely and are
based on blood tests that measure the amount of tacrolimus in the body.
Taking tacrolimus with food can reduce some of the abdominal pain that can
occur with this medicine; however, food can reduce the amount of tacrolimus
that is absorbed. This is especially true with fatty foods. Thus,
tacrolimus is best taken without food. If it must be taken with food, it
should be taken with non-fatty food.
DRUG INTERACTIONS: The destruction of tacrolimus by the body may be
inhibited by a large number of drugs, resulting in higher blood levels of
tacrolimus, and possibly increasing its side effects. Such drugs include
bromocriptine (Parlodel), cimetidine (Tagamet), cisapride (Propulsid),
clarithromycin (Biaxin), cyclosporine (Sandimmune; Neoral), danazol
(Danacrine), diltiazem (Cardizem; Tiazac), erythromycin, fluconazole
(Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), metoclopramide
(Reglan), methylprednisolone (Medrol), nicardipine (Cardene),
troleandomycin (Tao), and verapamil (Calan; Isoptin; Verelan; Covera-HS).
Grapefruit juice also may have a similar effect on tacrolimus and should be
avoided.
Other drugs can stimulate the break-down of tacrolimus, decreasing its
blood concentration and possibly reducing its effectiveness. Such drugs
include carbamazepine (Tegretol), nifedipine (Procardia; Adalat);
phenobarbital, phenytoin (Dilantin), rifabutin, and rifampin,
                                 tacrolimus
Live virus vaccines should be avoided while receiving tacrolimus or any
other medicine that suppresses the immune system since the vaccines may be
less effective.
Since tacrolimus can cause hyperkalemia (high potassium in the blood), the
use of tacrolimus with diuretics that also cause retention of potassium is
not recommended. Such diuretics include triamterene (found in Dyazide and
Maxzide), amiloride (found in Moduretic), and spironolactone (Aldactone).
Aluminum hydroxide, which is found in many antacids, binds tacrolimus in
the stomach. Aluminum-containing antacids should not be taken with
tacrolimus.
PREGNANCY: Tacrolimus crosses the placenta, but there have been no adequate
studies in pregnant women to assess the effects on the fetus. Among women
who have received tacrolimus while pregnant, high potassium levels and
kidney injury in newborns have been reported. Therefore, tacrolimus should
be used during pregnancy only when it is clearly needed.
NURSING MOTHERS: Tacrolimus passes into breast milk. It is recommended that
breast-feeding be discontinued while women are receiving oral tacrolimus.
SIDE EFFECTS: Tacrolimus is associated with many and various side effects.
These include baldness (which can occur in 1 in 5 patients who take it),
anemia (1 in 2), loss of appetite (1 in 3), diarrhea (3 of 4), high
concentrations of potassium in the blood (1 in 2), high blood presure (1 in
2), nausea (1 in 2), vomiting (1 in 4), tingling sensation in the
extremities (2 in 5), itching (1 in 3), tremor (1 in 2), fever (1 in 2),
headache (2 in 3), rash (1 in 4), high blood sugar concentrations (between
1 in 3 and 1 in 2), and abdominal pain (1in 4).
Other side effects may include confusion, painful joints, increased
sensitivity to light, blurred vision, insomnia, infection, jaundice
(yellowing of the skin due to effects on the liver), kidney injury, swollen
ankles, and seizures.

                 PROGRAF (tacrolimus) Capsules and Injection
                           July 25, 2001: Fujisawa
Revisions to the PRECAUTIONS and ADVERSE REACTIONS sections. A new
Patients Information leaflet is added to the PROGRAF Capsules labeling
PRECAUTIONS
*Drugs That May Decrease Tacrolimus Blood Concentrations:
Anticonvulsants Antibiotics
carbamazepine rifabutin
phenobarbital rifampin
phenytoin
Herbal Preparations
St. Johns Wort
*This table is not all inclusive.
St. Johns Wort (hypericum perforatum) induces CYP3A4 and P-glycoprotein.
Since tacrolimus is a substrate for CYP3A4, there is the potential that the
use of St. Johns Wort in patients receiving Prograf could result in
reduced tacrolimus levels.
ADVERSE REACTIONS
Post Marketing
The following have been reported: increased amylase including pancreatitis,
hearing loss including deafness, leukoencephalopathy, thrombocytopenic
purpura, hemolytic-uremic syndrome, acute renal failure, Stevens-Johnson
syndrome, stomach ulcer, glycosuria, and cardiac arrhythmia and
gastroenteritis.
Patient Information
PROGRAF
(tacrolimus capsules)
Read this important information before you start using PROGRAF [PRO-graf]
and each time you refill your prescription. This summary does not take the
place of talking with your transplant team.
Talk with your transplant team if you have any questions or want more
information about PROGRAF. You can also visit the Fujisawa Internet site at
www.fujisawa.com.
What Is PROGRAF?
PROGRAF is a medicine that slows down the bodys immune system. For this
reason, it works as an anti-rejection medicine.
PROGRAF helps patients who have had a liver or kidney transplant protect
their new organ and prevent it from being rejected by the body.
How Does PROGRAF Protect My New Organ?
The bodys immune system protects the body against anything that it does
not recognize as part of the body. For example, when the immune system
detects a virus or bacteria it tries to get rid of it to prevent infection.
When a person has a liver or kidney transplant, the immune system does not
recognize the new organ as a part of the body and tries to get rid of it,
too. This is called "rejection." PROGRAF protects your new organ by slowing
down the bodys immune system.
Who Should Not Take PROGRAF?
Do not take PROGRAF if you are allergic to any of the ingredients in
PROGRAF. The active ingredient is tacrolimus. Ask your doctor or pharmacist
about the inactive ingredients.
Tell your transplant team about all your health conditions, including
kidney and/or liver problems. Discuss with your transplant team the use of
any other prescription and non- prescription medications, including any
herbal or over-the-counter remedies that you may take while on Prograf. In
very rare cases you may not be able to take Prograf.
Tell your transplant team if you are pregnant, planning to have a baby or
are breastfeeding. Talk with your transplant doctor about possible effects
PROGRAF could have on your child. Do not nurse a baby while taking PROGRAF
since the medicine will be in the breast milk.
How Should I Take PROGRAF?
PROGRAF can protect your new kidney or liver only if you take the medicine
correctly.
Your new organ needs around-the-clock protection so your body does not
reject it. The success of your transplant depends a great deal upon how
well you help PROGRAF do its job. Here is what you can do to help.
Take PROGRAF exactly as prescribed
It is important to take PROGRAF capsules exactly as your transplant team
tells you to.
PROGRAF comes in several different strength capsules--0.5 mg, 1 mg and 5
mg. Your transplant team will tell you what dose to take and how often to
take it. Your transplant team may adjust your dose until they find what
works best for you.
Never change your dose on your own. Never stop taking PROGRAF even if you
are feeling well. However, if you feel poorly on Prograf, discuss this with
your transplant team.
Take PROGRAF two times a day, 12 hours apart
Try to pick times that will be easy for you. For example, if you take your
first dose at 7:00 a.m. you should take your second dose at 7:00 p.m. Do
not vary the times. You must take PROGRAF at the same times every day. If
you decide to take PROGRAF at 7:00 a.m. and 7:00 p.m., take it at these
same times every day. This will make sure you always have enough medicine
in your body to give your new organ the around-the-clock protection it
needs.
Take PROGRAF the same way each day
Some people prefer to take PROGRAF with food to help reduce possible
stomach upset. Whether you take PROGRAF with or without food, it is
important to take PROGRAF the same way every day. For example, if you take
PROGRAF with food, you should always take it with food. Do not eat
grapefruit or drink grapefruit juice in combination with your medicine
unless your transplant teams approves. Do not change the way you take this
medicine without telling
your transplant team, since this could change the amount of protection you
get from PROGRAF.
Take all your doses
It is important to take your doses twice a day exactly as prescribed by
your doctor. If you miss even two doses, your new liver or kidney could
lose the protection it needs to defend itself against rejection by your
body.
If you miss one dose, do not try to catch up on your own. Call your
transplant team right away for instructions on what to do.
If you travel and change time zones, be sure to ask your transplant team
how to adjust your dosage schedule so your new organ does not lose its
protection.
Plan ahead so that you do not run out of PROGRAF
Make sure you have your prescription for PROGRAF refilled and at home
before you need it. Circle the date on a calendar when you need to order
your refill. Allow extra time if you receive your medicines through the
mail.
Your transplant team will follow your progress and watch for early signs of
side effects. This is why you will have blood tests done often after your
transplant. On the days you are going to have a blood test to measure the
amount of PROGRAF in your body, your transplant team may ask you not to
take your morning dose until after the blood sample is taken. Check with
your transplant team before skipping this dose.
Can Other Medicines Affect How PROGRAF Works?
Some medicines and alcohol can affect how well PROGRAF works. After you
start taking PROGRAF:
Be sure to tell your transplant team, family doctor, dentist, pharmacist
and any other health care professional treating you the names of all the
medicines you are taking. This includes PROGRAF as well as all other
prescription medicines and non- prescription medicines, natural or herbal
remedies, nutritional supplements, and vitamins. This is the only way that
your health care team can help prevent drug interactions that could be
serious.
Always check with your transplant team before you start taking any new
medicine.
While you are taking PROGRAF, do not get any vaccinations without your
transplant teams approval. The vaccination may not work as well as it
should.
Liver transplant patients, including those taking PROGRAF, should not drink
alcohol.
What Are the Possible Side Effects of PROGRAF?
Tell your transplant team right away if you think you might be having a
side effect. Your transplant team will decide if it is a medicine side
effect or a sign that has nothing to do with the medicine but needs to be
treated. Infection or reduced urine can be signs of serious problems that
you should discuss with your transplant team.
Your transplant team will also follow your progress and watch for the early
signs of any side effects. This is why you will have blood tests done often
during the first few months after your transplant. On the days you are
going to have a blood test to measure the amount of PROGRAF in your body,
your transplant team may ask you not to take your morning dose until after
the blood sample is taken. Check skipping this dose.
For Kidney Transplant Patients:
The most common side effects of PROGRAF for kidney transplant patients are
infection, headache, tremors (shaking of the body), diarrhea, constipation,
nausea, high blood pressure, changes in the amount of urine, and trouble
sleeping.
Less common side effects are abdominal pain (stomach pain), numbness or
tingling in your hands or feet; loss of appetite; indigestion or "upset
stomach"; vomiting; urinary tract infections; fever; pain; swelling of the
hands, ankles or legs; shortness of breath or trouble breathing; cough; leg
cramps; heart "fluttering", palpitations or chest pain; unusual weakness or
tiredness; dizziness; confusion; changes in mood or emotions; itchy skin,
skin rash, and diabetes.
For Liver Transplant Patients:
The most common side effects of PROGRAF for liver transplant patients are
headache, tremors (shaking of the body), diarrhea, high blood pressure,
nausea and changes in the amount of urine.
Less common side effects are numbness or tingling in your hands or feet;
trouble sleeping; constipation; loss of appetite; vomiting; urinary tract
infections; fever; pain (especially in the back or abdomen [stomach area]);
swelling of the hands, ankles, legs or abdomen; shortness of breath or
trouble breathing; cough; unusual bruising; leg cramps; heart "fluttering"
or palpitations; unusual weakness or tiredness; confusion; changes in mood
or emotions; itchy skin, and skin rash.


""