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Такролимус

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БАШКИРСКИЙ ГОСУДАРСТВЕННЫЙ МЕДИЦИНСКИЙ УНИВЕРСИТЕТ

КАФЕДРА ФАРМАКОЛОГИИ №1 , С КУРСОМ КЛИНИЧЕСКОЙ ФАРМАКОЛОГИИ

Зав. кафедры: д.м.н. профессор Алехин Е.К.

Зав. курсом: д.м.н. профессор Зарудий Ф.А.

Преподаватель: к.м.н. доцент Шигаев Н.И.

РЕФЕРАТ

«Такролимус»

Выполнил: студент лечебного факультета гр.№ Л-Б

УФА-2002г.

Prograf Prescribing Information

HYPERLINK \l “BOXED_WARNING” WARNING

HYPERLINK \l “DESCRIPTION:” DESCRIPTION:

HYPERLINK \l “CLINICAL” CLINICAL PHARMACOLOGY:

HYPERLINK \l “INDICATIONS” INDICATIONS AND USAGE:

HYPERLINK \l “CONTRAINDICATIONS:” CONTRAINDICATIONS:

HYPERLINK \l “WARNINGS:” WARNINGS:

HYPERLINK \l “PRECAUTIONS:” PRECAUTIONS:

HYPERLINK \l “ADVERSE_REACTIONS” ADVERSE REACTIONS:

HYPERLINK \l “OVERDOSAGE:” OVERDOSAGE:

HYPERLINK \l “DOSAGE” DOSAGE AND ADMINISTRATION:

HYPERLINK \l “HOW_SUPPLIED” HOW SUPPLIED:

HYPERLINK \l “REFERENCE” REFERENCE

INCLUDEPICTURE \d “images/07yell.jpg”

INCLUDEPICTURE \d “Image5.gif” Fujisawa

Revised: May 2002

Prograf®

tacrolimus capsules

tacrolimus injection (for intravenous infusion only)

PRIVATE

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*,26
aR*]]-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 (mean±S.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.)

PRIVATE Population N Route

(Dose) Parameters

Cmax

(ng/mL) Tmax

(hr) AUC

(ng·hr/mL) t1/2

(hr) Cl

(L/hr/kg) V

(L/kg)

Healthy

Volunteers 8 IV

(0.025 mg/kg/4hr)

— 598*

± 125 34.2

± 7.7 0.040

±0.009 1.91

±0.31

16 PO

(5 mg) 29.7

±7.2 1.6

±0.7 243**

±73 34.8

±11.4 0.041†

±0.008 1.94†

±0.53

Kidney

Transplant

Pts 26 IV

(0.02 mg/kg/12hr)

— 294***

±262 18.8

±16.7 0.083

±0.050 1.41

±0.66

PO

(0.2 mg/kg/day) 19.2

±10.3 3.0 203***

±42 # # #

PO

(0.3 mg/kg/day) 24.2

±15.8 1.5 288***

±93 # # #

Liver

Transplant

Pts 17 IV

(0.05 mg/kg/12 hr) — — 3300***

±2130 11.7

±3.9 0.053

±0.017 0.85

±0.30

PO

(0.3 mg/kg/day) 68.5

±30.0 2.3

±1.5 519***

±179 # # #

† 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 HYPERLINK \l “DOSAGE” 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 17±10% in adult kidney transplant patients (N=26),
22±6% in adult liver transplant patients (N=17), 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. 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 (50±19%), 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 77.8±12.7%.
Fecal elimination accounted for 92.4±1.0% and the elimination half-life
based on radioactivity was 48.1±15.9 hours whereas it was 43.5±11.6
hours based on tacrolimus concentrations. The mean clearance of
radiolabel was 0.029±0.015 L/hr/kg and clearance of tacrolimus was
0.029±0.009 L/hr/kg. When administered PO, the mean recovery of the
radiolabel was 94.9±30.7%. Fecal elimination accounted for 92.6±30.7%,
urinary elimination accounted for 2.3±1.1% and the elimination half-life
based on radioactivity was 31.9±10.5 hours whereas it was 48.4±12.3
hours based on tacrolimus concentrations. The mean clearance of
radiolabel was 0.226±0.116 L/hr/kg and clearance of tacrolimus
0.172±0.088 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 11.5±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 43.4±27.9 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 HYPERLINK \l
“DOSAGE” 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.

PRIVATE Population

(No. of Patients) Dose AUC 0-t

(ng·hr/mL) t1/2

(hr) V

(L/kg) Cl

(L/hr/kg)

Renal

Impairment

(n=12)

0.02

mg/kg/4hr

IV 393±123

(t = 60hr) 26.3±9.2 1.07

±0.20 0.038

±0.014

Mild Hepatic

Impairment

(n=6) 0.02

mg/kg/4hr

IV 367±107

(t=72hr) 60.6±43.8

Range: 27.8 – 141 3.1

±1.6 0.042

±0.02

7.7 mg

PO 488±320

(t = 72hr) 66.1±44.8

Range: 29.5 – 138 3.7

±4.7* 0.034

±0.019*

Severe Hepatic

Impairment

(n=6, IV) 0.02

mg/kg/4hr

IV (n=2)

762±204

(t=120hr) 198±158

Range: 81-436 3.9

±1.0 0.017

±0.013

0.01

mg/kg/8hr

IV (n=4)

289±117

(t=144hr)

Severe Hepatic

Impairment

(n=5, PO)† 8 mg PO

(n=1)

658

(t=120hr) 119±35

Range: 85-178 3.1

±3.4* 0.016

±0.011*

5mg PO

(n=4)

533±156

(t=144hr)

4 mg PO

(n=1)

PRIVATE * 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 3.9±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 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 HYPERLINK \l “DOSAGE”
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 TransplantationPrograf-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 HYPERLINK \l "BOXED_WARNING" 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 Mellitusand Insulin Use at 2 years in Kidney Transplant Recipients in the Phase III StudyPRIVATE Status of PTDM* Prograf CBIRPatients without pretransplant history of diabetes mellitus. 151 151New onset PTDM*, 1st Year 30/151 (20%) 6/151 (4%)Still insulin dependent at one year in those without priorhistory of diabetes. 25/151(17%) 5/151 (3%)New onset PTDM* post 1 year 1 0Patients with PTDM* at 2 years 16/151 (11%) 5/151 (3%)PRIVATE *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 Raceand by Treatment Group during First Year Post Kidney Transplantation in the Phase III StudyPRIVATE Patient Race PrografCBIRNo. of Patientsat Risk Patients WhoDeveloped PTDM* No. of Patientsat Risk Patients WhoDeveloped 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%)PRIVATE * 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 HYPERLINK \l "ADVERSE_REACTIONS" ADVERSE REACTIONS ).Incidence of Post Transplant Diabetes Mellitus and Insulin Useat One Year in Liver Transplant RecipientsPRIVATE Status of PTDM* US StudyEuropean StudyPrograf CBIR Prograf CBIRPatients at risk ** 239 236 239 249New 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 HYPERLINK \l "ADVERSE_REACTIONS" 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 HYPERLINK \l "ADVERSE_REACTIONS" ADVERSE REACTIONS ). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during Prograf therapy (see HYPERLINK \l "PRECAUTIONS:" 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 HYPERLINK \l "ADVERSE_REACTIONS" 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 HYPERLINK \l "ADVERSE_REACTIONS" 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:GeneralHypertension is a common adverse effect of Prograf therapy (see HYPERLINK \l "ADVERSE_REACTIONS" 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 HYPERLINK \l "Drug_Interactions" Drug Interactions ).Renally and Hepatically Impaired PatientsFor patients with renal insufficiency some evidence suggests that lower doses should be used (see HYPERLINK \l "CLINICAL" CLINICAL PHARMACOLOGY and HYPERLINK \l "DOSAGE" 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 HYPERLINK \l "DOSAGE" DOSAGE AND ADMINISTRATION ).HYPERLINK \l "Myocardial_Hypertrophy" Myocardial HypertrophyMyocardial 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 PatientsPatients 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 TestsSerum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metabolic and hematologic systems should be performed as clinically warranted.Drug InteractionsDue 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 HYPERLINK \l "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.PRIVATE *Drugs That May Increase Tacrolimus Blood Concentrations:CalciumChannelBlockersAntifungalAgentsMacrolideAntibioticsdiltiazemclotrimazoleclarithromycinnicardipinefluconazoleerythromycinnifedipineitraconazoletroleandomycinverapamilketoconazoleGastrointestinalProkineticAgentsOtherDrugscisapridebromocriptinemetoclopramidecimetidinecyclosporinedanazolethinyl estradiolmethylprednisoloneomeprazoleprotease inhibitorsnefazodoneIn a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129L/hr/kg vs. 0.148±0.043L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients.*Drugs That May Decrease Tacrolimus Blood Concentrations:AnticonvulsantsAntibioticsHerbal PreparationscarbamazepinerifabutinSt. John's Wortphenobarbitalrifampinphenytoin*This table is not all inclusive.St. John's Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving Prograf could result in reduced tacrolimus levels.In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008L/hr/kg vs. 0.053±0.010L/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 HYPERLINK \l "DOSAGE" DOSAGE AND ADMINISTRATION ).Other Drug InteractionsImmunosuppressants 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.1Carcinogenesis, Mutagenesis and Impairment of FertilityAn 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 CIn 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 MothersSince tacrolimus is excreted in human milk, nursing should be avoided.Pediatric PatientsExperience 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 HYPERLINK \l "DOSAGE" DOSAGE AND ADMINISTRATION ).ADVERSE REACTIONS:Liver TransplantationThe 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 HYPERLINK \l "WARNINGS:" 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

PRIVATE U.S. STUDY (%)

EUROPEAN STUDY (%)

Prograf

(N=250) CBIR

(N=250) Prograf

(N=264) CBIR

(N=265)

Nervous System

Headache (see HYPERLINK \l “WARNINGS:” WARNINGS ) 64 60 37 26

Tremor (see HYPERLINK \l “WARNINGS:” 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 HYPERLINK \l “PRECAUTIONS:” PRECAUTIONS ) 47 56 38
43

Urogenital

Kidney Function Abnormal (see HYPERLINK \l “WARNINGS:” WARNINGS ) 40
27 36 23

Creatinine Increased (see HYPERLINK \l “WARNINGS:” WARNINGS ) 39 25 24
19

BUN Increased (see HYPERLINK \l “WARNINGS:” WARNINGS ) 30 22 12 9

Urinary Tract Infection 16 18 21 19

Oliguria 18 15 19 12

Metabolic and Nutritional

Hyperkalemia (see HYPERLINK \l “WARNINGS:” WARNINGS ) 45 26 13 9

Hypokalemia 29 34 13 16

Hyperglycemia (see HYPERLINK \l “WARNINGS:” 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
HYPERLINK \l “Less_Frequent_AEs” 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

PRIVATE Prograf

(N=205) CBIR

(N=207)

Nervous System

Tremor (see HYPERLINK \l “WARNINGS:” WARNINGS ) 54 34

Headache (see HYPERLINK \l “WARNINGS:” 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 HYPERLINK \l “PRECAUTIONS:” PRECAUTIONS ) 50 52

Chest Pain 19 13

Urogenital

Creatinine Increased (see HYPERLINK \l “WARNINGS:” WARNINGS ) 45 42

Urinary Tract Infection 34 35

Metabolic and Nutritional

Hypophosphatemia 49 53

Hypomagnesemia 34 17

Hyperlipemia 31 38

Hyperkalemia (see HYPERLINK \l “WARNINGS:” WARNINGS ) 31 32

Diabetes Mellitus (see HYPERLINK \l “WARNINGS:” WARNINGS ) 24 9

Hypokalemia 22 25

Hyperglycemia (see HYPERLINK \l “WARNINGS:” 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
HYPERLINK \l “Less_Frequent_AEs” 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 HYPERLINK \l “WARNINGS:” 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 HYPERLINK \l
“WARNINGS:” 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 HYPERLINK \l “PRECAUTIONS:” 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 HYPERLINK \l “PRECAUTIONS:”
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 HYPERLINK \l “ADVERSE_REACTIONS”
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 HYPERLINK \l “WARNINGS:” 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

PRIVATE Patient Population Recommended Initial

Oral Dose* Typical Whole Blood Trough Concentrations

Adult kidney transplant patients 0.2 mg/kg/day month 1-3 : 7-20 ng/mL

month 4-12 : 5-15 ng/mL

Adult liver transplant patients 0.10-0.15 mg/kg/day month 1-12 : 5-20
ng/mL

Pediatric liver transplant patients 0.15-0.20 mg/kg/day month 1-12 :
5-20 ng/mL

*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 HYPERLINK \l “alter”
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: HYPERLINK \l “Liver_Transplant” 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: HYPERLINK \l "kidney_transplantation" 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.PRIVATE Time AfterTransplant Caucasiann=114Blackn=56Dose(mg/kg) TroughConcentrations(ng/mL) Dose(mg/kg) TroughConcentrations(ng/mL)Day 7 0.18 12.0 0.23 10.9Month 1 0.17 12.8 0.26 12.9Month 6 0.14 11.8 0.24 11.5Month 12 0.13 10.1 0.19 11.0Pediatric PatientsPediatric 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 DysfunctionDue 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:

PRIVATE Prograf capsules (tacrolimus capsules) 0.5 mg

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 ”
INCLUDEPICTURE \d “images/f.gif” 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 ”
INCLUDEPICTURE \d “images/f.gif” 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

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

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

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 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).

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.

HYPERLINK http://www.fujisawa.com/medinfo/pi/pi_main_pg.htm
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
30°C (59° and 86°F).

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 HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=1908” 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), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=839” cimetidine (Tagamet),
HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=816” cisapride
(Propulsid), HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=705”
clarithromycin (Biaxin), cyclosporine (Sandimmune; Neoral), danazol
(Danacrine), HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=713”
diltiazem (Cardizem; Tiazac), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=748” erythromycin , HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=739” fluconazole (Diflucan),
HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=836” itraconazole
(Sporanox), HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=770”
ketoconazole (Nizoral), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=821” metoclopramide (Reglan),
HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=906”
methylprednisolone (Medrol), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=712” nicardipine (Cardene),
troleandomycin (Tao), and HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=856” 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 HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=841”
carbamazepine (Tegretol), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=815” nifedipine (Procardia;
Adalat); phenobarbital, HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=740” 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 HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=1954” 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 HYPERLINK “/script/main/art.asp?li=MNI&ArticleKey=687”
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 HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=290” baldness (which can occur
in 1 in 5 patients who take it), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=2015” anemia (1 in 2), loss of
appetite (1 in 3), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=1900” 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), HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=504” 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, HYPERLINK
“/script/main/art.asp?li=MNI&ArticleKey=1899” 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
Patient’s 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. John’s Wort

*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.

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 body’s 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 body’s 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 body’s 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 team’s 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.

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