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Такролимус

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

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 (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.)

| | | |Cmax |Tmax |AUC |tЅ |Cl |V |

| | | |(ng/mL|(hr) |(ng·hr/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 |

| |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 |

|Pts | | | | | | | | |

| | |PO |19.2 |3.0 |203*** |# |# |# |

| | |(0.2 |±10.3 | |±42 | | | |

| | |PO |24.2 |1.5 |288*** |# |# |# |

| | |(0.3 |±15.8 | |±93 | | | |

|Liver |17 |IV |— |— |3300*** |11.7 |0.053 |0.85 |

|Transp| |(0.05 | | | |±3.9 |±0.017 |±0.30 |

|Pts | |hr) | | | | | | |

| | |PO |68.5 |2.3 |519*** |# |# |# |

| | |(0.3 |±30.0 |±1.5 |±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

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 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 |tЅ |V |Cl |

|Patients) | |) | |) | |

|Renal |0.02 |393±123 |26.3±9.2 |1.07 |0.038 |

|Impairment |mg/kg/4h|(t = | | |±0.014 |

|(n=12) |r |60hr) | |±0.20| |

| |IV | | | | |

|Mild Hepatic |0.02 |367±107 |60.6±43.8 |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 |488±320 |66.1±44.8 |3.7 |0.034 |

| |PO |(t = |Range: 29.5 - |±4.7*|±0.019* |

| | |72hr) |138 | | |

|Severe Hepatic |0.02 |762±204 |198±158 |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 |289±117 | | | |

| |mg/kg/8h|(t=144hr)| | | |

| |r | | | | |

| |IV (n=4)| | | | |

| | | | | | |

|Severe Hepatic |8 mg PO |658 |119±35 |3.1 |0.016 |

|Impairment |(n=1) |(t=120hr)|Range: 85-178 |±3.4*|±0.011* |

|(n=5, PO)† | | | | | |

| |5mg PO |533±156 | | | |

| |(n=4) |(t=144hr)| | | |

| |(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 3.9±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 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

|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

|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.

|s: | | | | |

| | | | |n |

| | | | |n |

| | | | | |

|nal | |Drugs | | |

|e | | | | |

| | | | | |

|30±8%) was | | | | |

|n (200 mg). | | | | |

|(0.430±0.129L| | | | |

|0.148±0.043L/| | | | |

|s: | | | | |

|ts | | | |Preparations |

*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 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| |

| |(%) | |(%) | |

| |f |(N=250|(N=264) |(N=265) |

| |(N=250|) | | |

| |) | | | |

|Headache (see WARNINGS) |64 |60 |37 |26 |

|Tremor (see WARNINGS) |56 |46 |48 |32 |

|Insomnia |64 |68 |32 |23 |

|Paresthesia |40 |30 |17 |17 |

|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 |

|Hypertension (see PRECAUTIONS) |47 |56 |38 |43 |

|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 |

|Hyperkalemia (see WARNINGS) |45 |26 |13 |9 |

|Hypokalemia |29 |34 |13 |16 |

|Hyperglycemia (see WARNINGS) |47 |38 |33 |22 |

|Hypomagnesemia |48 |45 |16 |9 |

|Anemia |47 |38 |5 |1 |

|Leukocytosis |32 |26 |8 |8 |

|Thrombocytopenia |24 |20 |14 |19 |

|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 |

|Pleural Effusion |30 |32 |36 |35 |

|Atelectasis |28 |30 |5 |4 |

|Dyspnea |29 |23 |5 |4 |

|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.

|Transplant | | |n=56 | |

| |n=114 | | | |

|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 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.

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 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

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.