Tacrolimus: Package Insert and Label Information (Page 6 of 10)

8.6 Use in Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Tacrolimus Capsules USP at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.7 Use in Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

The use of Tacrolimus Capsules USP in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations 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 (2.3) and Clinical Pharmacology (12.3)].

10 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. Acute overdosage was sometimes followed by adverse reactions consistent with those listed in Adverse Reactions (6) (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, 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 studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; (all based on body surface area corrections).

11 DESCRIPTION

Tacrolimus is available for oral administration as capsules (Tacrolimus Capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of tacrolimus USP. Inactive ingredients include anhydrous lactose, hypromellose 2910, 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.

Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus Capsules USP. 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 USP is:

Structural Formula
(click image for full-size original)

Tacrolimus USP has a molecular formula of C44 H69 NO12 •H2 O and a formula weight of 822.03. Tacrolimus appears as white to off white powder. It is soluble in acetone, chloroform, ethyl acetate and insoluble in water.

The Dissolution Test criteria of Tacrolimus Capsules USP as outlined below:

Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mg Complies with USP dissolution test 4

Tacrolimus Capsules USP comply with USP Organic Impurities test criteria as outlined below:

Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mg USP Procedure 1 and 2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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).

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.

12.3 Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 14).

Table 14. Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients

*
a) not applicable
a) not applicable
b) AUC0-120 ;
§
c) AUC0-72
d) Corrected for individual bioavailability
#
d) Corrected for individual bioavailability
Þ
a) not applicable
ß
a) not applicable
à
e) AUC0-inf ;
è
f) not available
ð
f) not available
ø
f) not available
ý
e) AUC0-inf ;
£
f) not available
¥
f) not available
Œ
f) not available
œ
a) not applicable
Ɖ
a) not applicable
A
e) AUC0-inf ;
B
e) AUC0-inf ;
C
f) not available
D
f) not available
E
f) not available
F
a) not applicable
G
a) not applicable
H
g) AUC0-t
I
f) not available
J
h) Determined after the first dose
K
i) Median [range]
L
j) AUC0-12
M
a) not applicable
N
f) not available
O
f) not available
P
h) Determined after the first dose
Q
i) Median [range]
R
j) AUC0-12
S
a) not applicable
T
f) not available
U
f) not available
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 ± 11.4 0.041 ±0.008 1.94# ± 0.53
Kidney Transplant Patients 26 IV (0.02 mg/kg/12 hr) Þ ß 294 e± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66
PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203à± 42 è ð ø
PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288ý± 93 £ ¥ Œ
Liver Transplant Patients 17 IV (0.05 mg/kg/12 hr) œ Ɖ 3300A± 2130 11.7 ± 3.9 0.053 ± 0.017 0.85 ± 0.30
PO (0.3 mg/kg/day) 68.5 ± 30.0 2.3 ± 1.5 519B± 179 C D E
Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) F G 954H± 334 23.6 ± 9.22 0.051 ± 0.015 I
11 PO (0.075 mg/kg/day)J 14.7 ± 7.79 2.1 [0.5-6.0]K 82.7L± 63.2 M N O
14 PO (0.15 mg/kg/day)P 24.5 ± 13.7 1.5 [0.4-4.0]Q 142R± 116 S T U

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)]. 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 trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial 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 doseproportional 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.

In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.

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 Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate 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 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, Tacrolimus Capsules USP 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.

Tacrolimus Capsules USP should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Dosage and Administration (2.5)].

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