Prograf

PROGRAF- tacrolimus anhydrous capsule, gelatin coated
Cardinal Health

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:

Structure

Tacrolimus has an empirical formula of C44 H69 NO12 •H2 O and a formula weight of 822.03. 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/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients. (See table below.)

*
not applicable
AUC0-120;
AUC0-72
§
Corrected for individual bioavailability
AUC0-inf ;
#
not available
Þ
AUC0-t ;
ß
Determined after the first dose
à
Median [range]
è
AUC0-12

Population

N

Route

(Dose)

Parameters

Cmax

(ng/mL)

Tmax

(hr)

AUC

(ng•hr/mL)

t1/2

(hr)

CI

(L/hr/kg)

V

(L/kg)

Healthy

Volunteers

8

IV

(0.025 mg/kg/4hr)

*

*

598

± 125

34.2

± 7.7

0.040

± 0.009

1.91

± 0.31

16

PO

(5 mg)

29.7

± 7.2

1.6

± 0.7

243

± 73

34.8

0.041 §

1.94§

Kidney

Transplant

Pts

26

IV

* *

294

± 262

18.8

0.083

1.41

PO

19.2

3.0

203

± 42

# # #

PO

24.2

± 15.8

1.5

288

# # #

Liver

Transplant

17

IV

*

*

3300

± 2130

11.7

0.053

± 0.017

0.85

PO

68.5

2.3

519

# # #

Heart

Transplant Patients

11

IV

* *

954Þ

23.6

0.051

#
11

PO

14.7+7.79 2.1 [0.5-6.0]à

82.7è

* # #
14

PO

24.5± 13.7 1.5 [0.4-4.0]à 142è±116 * # #

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.

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