Fujisawa
Revised: September 2004

• DESCRIPTION

• CLINICAL PHARMACOLOGY

• INDICATIONS AND USAGE

• CONTRAINDICATIONS

• WARNINGS

• PRECAUTIONS

• ADVERSE REACTIONS

• OVERDOSAGE

• DOSAGE AND ADMINISTRATION

• HOW SUPPLIED

• REFERENCES

Prograf

Prograf ( tacrolimus ) capsules

Prograf ( tacrolimus ) injection (for intravenous infusion only)

WARNING

Increased susceptibility to infection and the possible development of lymphoma may result from

immunosuppression. Only physicians experienced in immunosuppressive therapy and

management of organ transplant patients should prescribe Prograf. Patients receiving the drug

should be managed in facilities equipped and staffed with adequate laboratory and supportive

medical resources. The physician responsible for maintenance therapy should have complete

information requisite for the follow-up of the patient.

DESCRIPTION:

Prograf is available for oral administration as capsules (Prograf ( Prograf ( tacrolimus ) ) capsules) containing the

equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous Prograf ( Prograf ( tacrolimus ) ). Inactive ingredients include lactose,

hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. The 0.5 mg

capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell contains

gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and

ferric oxide.

Prograf is also available as a sterile solution (Prograf ( Prograf ( tacrolimus ) ) injection) containing the

equivalent of 5 mg anhydrous Prograf ( Prograf ( tacrolimus ) ) in 1 mL for administration by intravenous infusion only.

Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated

alcohol, USP, 80.0% v/v. Prograf injection must be diluted with 0.9% Sodium Chloride Injection

or 5% Dextrose Injection before use.

Prograf ( Prograf ( tacrolimus ) ), previously known as FK506, is the active ingredient in Prograf. Prograf ( Prograf ( tacrolimus ) ) is

a macrolide immunosuppressant produced by Streptomyces tsukubaensis.

Chemically, Prograf ( Prograf ( 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.

O

The chemical structure of Prograf ( Prograf ( tacrolimus ) ) is:

Prograf ( Prograf ( tacrolimus ) ) has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03.

Tacroliums 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

Prograf ( Prograf ( tacrolimus ) ) prolongs the survival of the host and transplanted graft in animal transplant models of

liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and

limb.

In animals, Prograf ( Prograf ( tacrolimus ) ) has been demonstated 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 encephalomyelitits, and graft

versus host disease.

Prograf ( Prograf ( tacrolimus ) ) inhibits T-lymphocyte activation, although the exact mechanism of action is

not known. Experimental evidence suggests that Prograf ( tacrolimus ) binds to an intracellular protein,

FKBP-12. A complex of Prograf ( tacrolimus )-FKBP-12, calcium, calmodulin, and calcineurin is then formed

and the phosphatase activity of calcineurin inhibited. This effect may prevent the

dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear

component thought to initiate gene transcription for the formation of lymphokines (such as

interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e.,

immunosuppression).

Due to intersubject variability in Prograf ( tacrolimus ) pharmacokinetics, individualization of dosing regimen

is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION). Pharmacokinetic

data indicate that whole blood concentrations rather than plasma concentrations serve as the

more appropriate sampling compartment to describe Prograf ( tacrolimus ) pharmacokinetics.

Absorption

Absorption of Prograf ( tacrolimus ) from the gastrointestinal tract after oral administration is incomplete and

variable. The absolute bioavailablility of Prograf ( 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. Tacroliums maximum blood concentration

(Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18

fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg.

In 18 kidney transplant patients, Prograf ( tacrolimus ) trough concentrations from 3 to 30 ng/mL

measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient

0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation

coefficient was 0.94.

Food Effects: The rate and extent of Prograf ( tacrolimus ) absorption were greatest under fasted

conditions. The presence and composition of food decreased both the rate and extent of

Prograf ( tacrolimus ) absorption when administered to 15 healthy volunteers.

The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and

Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A highcarbohydrate

meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28%

and 65%, respectively.

In healthy volunteers (N=16), the time of the meal also affected Prograf ( tacrolimus ) bioavailability.

When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was

reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal,

mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

In 11 liver transplant patients, Prograf administered 15 minutes after a high fat (400 kcal,

34% fat) breakfast, resulted in decreased AUC (27±18%) and Cmax (50±19%), as compared to a

fasted state.

Distribution

The plasma protein binding of Prograf ( tacrolimus ) is approximately 99% and is independent of

concentration over a range of 5-50 ng/mL. Prograf ( tacrolimus ) is bound mainly to albumin and alpha-1-

acid glycoprotein, and has a high level of association with erythrocytes. The distribution of

Prograf ( tacrolimus ) between whole blood and plasma depends on several factors, such as hematocrit,

temperature at the time of plasma separation, drug concentration, and plasma protein

concentration. In a U.S. study, the ratio of whole blood concentration to plasma concentration

averaged 35 (range 12 to 67).

Metabolism

Prograf ( tacrolimus ) is extensively metabolized by the mixed-function oxidase system, primarily the

cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible

metabolites has been proposed. Demethylation and hydroxylation were identified as the primary

mechanisms of biotransformation in vitro. The major metabolite identified in incubations with

human liver microsomes is 13-demethyl Prograf ( tacrolimus ). In in vitro studies, a 31-demethyl metabolite

has been reported to have the same activity as Prograf ( tacrolimus ).

Excretion

The mean clearance following IV administration of Prograf ( 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 Prograf ( 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 Prograf ( tacrolimus ) concentrations. The mean clearance of radiolabel was

0.029±0.015 L/hr/kg and clearance of Prograf ( 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 Prograf ( tacrolimus )

concentrations. The mean clearance of radiolabel was 0.226±0.116 L/hr/kg and clearance of

Prograf ( tacrolimus ) 0.172±0.088 L/hr/kg.

Special Populations

Pediatric

Pharmacokinetics of Prograf ( tacrolimus ) have been studied in liver transplantation patients, 0.7 to 13.2

years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients,

mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg

and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC

and Cmax were 337±167 ng·hr/mL and 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 Prograf ( tacrolimus ) trough

concentrations. (See DOSAGE AND ADMINISTRATION).

Renal and Hepatic Insufficiency

Prograf ( tacrolimus ) pharmacokinetics following a single IV administration were determined in 12

patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL,

respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were

similar for both groups.

The mean clearance of Prograf ( tacrolimus ) in patients with renal dysfunction was similar to that in

normal volunteers (see previous table).

Hepatic Insufficiency:

Prograf ( tacrolimus ) pharmacokinetics have been determined in six patients with mild hepatic

dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean

clearance of Prograf ( tacrolimus ) in patients with mild hepatic dysfunction was not substantially

different from that in normal volunteers (see previous table). Prograf ( tacrolimus ) pharmacokinetics

were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The

mean clearance was substantially lower in patients with severe hepatic dysfunction,

irrespective of the route of administration.

Race

A formal study to evaluate the pharmacokinetic disposition of Prograf ( tacrolimus ) in Black transplant

patients has not been conducted. However, a retrospective comparison of Black and

Caucasian kidney transplant patients indicated that Black patients required higher Prograf ( tacrolimus )

doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION.)

Gender

A formal study to evaluate the effect of gender on Prograf ( tacrolimus ) pharmacokinetics has not been

conducted, however, there was no difference in dosing by gender in the kidney transplant

trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney

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 encephopathy, 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 Prograf ( 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 Prograftreated

kidney transplant patients without pretransplant history of diabetes mellitus in the

Phase III study (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

* 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 Prograf ( 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 wholeblood

concentrations of Prograf ( 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 Prograf ( 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 Prograf ( 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 Prograf ( 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 Prograf ( tacrolimus ). The 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

Prograf ( 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. As with other immunosuppressive agents, owing to the potential risk of malignant

skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing

protective clothing and using a sunscreen with a high protection factor.

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 Prograf ( tacrolimus ) Concentrations

Since Prograf ( tacrolimus ) is metabolized mainly by the CYP3A enzyme systems, substances known to

inhibit these enzymes may decrease the metabolism or increase bioavailability of Prograf ( tacrolimus )

as indicated by increased whole blood or plasma concentrations. Drugs known to induce

these enzyme systems may result in an increased metabolism of Prograf ( tacrolimus ) or decreased

bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring

of blood concentrations and appropriate dosage adjustments are essential when such drugs

are used concomitantly.

*Drugs That May Increase Prograf ( tacrolimus ) Blood Concentrations:

Calcium Antifungal Macrolide

Channel Blockers Agents Antibiotics

diltiazem clotrimazole clarithromycin

nicardipine fluconazole erythromycin

nifedipine itraconazole troleandomycin

verapamil ketoconazole

voriconazole

Gastrointestinal Other

Prokinetic Agents Drugs

cisapride bromocriptine

metoclopramide chloramphenicol

cimetidine

cyclosporine

danazol

ethinyl estradiol

methylprednisolone

omeprazole

protease inhibitors

nefazodone

magnesium-aluminum-hydroxide

In a study of 6 normal volunteers, a significant increase in Prograf ( tacrolimus ) oral bioavailability

(14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg).

The apparent oral clearance of Prograf ( tacrolimus ) during ketoconazole administration was

significantly decreased compared to Prograf ( tacrolimus ) alone (0.430±0.129 L/hr/kg vs. 0.148±0.043

L/hr/kg). Overall, IV clearance of Prograf ( tacrolimus ) was not significantly changed by ketoconazole

co-administration, although it was highly variable between patients.

*Drugs That May Decrease Prograf ( tacrolimus ) Blood Concentrations:

Anticonvulsants Antimicrobials

carbamazepine rifabutin

phenobarbital caspofungin

phenytoin rifampin

Herbal Preparations Other Drugs

St. John’s Wort sirolimus

*This table is not all inclusive.

St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since

Prograf ( 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 Prograf ( tacrolimus ) levels.

In a single-dose crossover study in healthy volunteers, co-administration of Prograf ( tacrolimus )

and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean Prograf ( tacrolimus ) AUC

and a 10% decrease in the mean Prograf ( tacrolimus ) Cmax relative to Prograf ( tacrolimus ) administration alone.

In a study of 6 normal volunteers, a significant decrease in Prograf ( tacrolimus ) oral bioavailability

(14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In

addition, there was a significant increase in Prograf ( tacrolimus ) clearance (0.036±0.008 L/hr/kg vs.

0.053±0.010 L/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., nelfinavir, ritonavir) are administered concomitantly with

Prograf ( tacrolimus ). Based on a clinical study of 5 liver transplant recipients, co-administration of

Prograf ( tacrolimus ) with nelfinavir increased blood concentrations of Prograf ( tacrolimus ) significantly and, as a

result, a reduction in the Prograf ( tacrolimus ) dose by an average of 16-fold was needed to maintain

mean trough Prograf ( tacrolimus ) blood concentrations of 9.7 ng/mL. Thus, frequent monitoring of

Prograf ( tacrolimus ) blood concentrations and appropriate dosage adjustment are essential when

nelfinavir is used concomitantly. Prograf ( 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 ADMINISTATION).

Following co-administration of Prograf ( tacrolimus ) and sirolimus (2 or 5 mg/day) in stable renal

transplant patients, mean Prograf ( tacrolimus ) AUC0-12 and Cmin decreased approximately by 30%

relative to Prograf ( tacrolimus ) alone. Mean Prograf ( tacrolimus ) AUC0-12 and Cmin following co-administration of

1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. The safety and

efficacy of Prograf ( tacrolimus ) used in combination with sirolimus for the prevention of graft rejection

has not been established and is not recommended.

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; Prograf ( 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

Prograf ( 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.

Prograf ( 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), Prograf ( 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. Prograf ( 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. Prograf ( 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. Prograf ( 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. Prograf ( tacrolimus ) is

transferred across the placenta. The use of Prograf ( 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 Prograf ( 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.

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 Prograf ( tacrolimus ) in living related donor liver transplantation. Pediatric

patients generally required higher doses of Prograf to maintain blood trough concentrations of

Prograf ( 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 Prograf ( 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 Prograf ( 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 Prograf ( 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. STUDY (%) EUROPEAN STUDY

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.