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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

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