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Prograf (Tacrolimus) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Prograf is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include lactose monohydrate NF, hypromellose USP, croscarmellose sodium NF, and magnesium stearate NF. The 0.5 mg capsule shell contains gelatin NF, titanium dioxide USP and ferric oxide NF, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains gelatin NF, titanium dioxide USP and ferric oxide NF.

Prograf is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus USP 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 822.03. 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 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.

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 (Table 14).

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

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)

1

598 2

± 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 3

± 73

34.8

± 11.4

0.041 4

± 0.008

1.94

± 0.53

Kidney

Transplant

Patients

26

IV

(0.02 mg/kg/12 hr)

294 5

± 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

203

± 42

6

PO

(0.3 mg/kg/day)

24.2

± 15.8

1.5

288

± 93

Liver

Transplant

Patients

17

IV

(0.05 mg/kg/12 hr)

3300

± 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

519

± 179

Heart

Transplant Patients

11

IV

(0.01 mg/kg/day as a continuous infusion)

954 7

± 334

23.6

± 9.22

0.051

± 0.015

11

PO

(0.075 mg/kg/day) 8

14.7 + 7.79

2.1 [0.5-6.0] 9

82.7 10

± 63.2

14

PO

(0.15 mg/kg/day)

24.5 ± 13.7

1.5 [0.4-4.0]

142 ± 116

1 not applicable
2 AUC0-120 
3 AUC0-72
4 Corrected for individual bioavailability
5 AUC0-inf
6 not available
7 AUC0-t
8 Determined after the first dose
9 Median [range]
10 AUC0-12

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), 23±9% in adult heart transplant patients (N=11) 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 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. 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, 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.

Prograf capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see Dosage and Administration].

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. trial, 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, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart 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.

Specific 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 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%.

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 ].

Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following IV infusion of a 0.06 (range 0.06 – 0.09) mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2±5.0 (range 3.4-25) hours and 0.12±0.04 (range 0.06-0.17) L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181±65 (range 81-300) ng·hr/mL and 30±11 (range 14-49) ng/mL, respectively. The absolute bioavailability was 19±14 (range 5.2-56) %.

Renal and Hepatic Impairment
The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in Table 15.

Table 15. Pharmacokinetic In Renal and Hepatic Impaired Patients

Population

(No. of Patients)

Dose

AUC0-t

(ng·hr/mL)

t1/2

(hr)

V

(L/kg)

CI

(L/hr/kg)

Renal

Impairment

(n=12)

0.02

mg/kg/4hr

IV

393±123

(t=60 hr)

26.3±9.2

1.07

±0.20

0.038

±0.014

Mild Hepatic

Impairment

(n=6)

0.02

mg/kg/4hr

IV

367±107

(t=72 hr)

60.6±43.8

Range: 27.8 – 141

3.1±1.6

0.042

±0.02

7.7 mg

PO

488±320

(t=72 hr)

66.1±44.8

Range: 29.5 – 138

3.7±4.7 1

0.034

±0.019

Severe

Hepatic

Impairment

(n=6, IV)

0.02 mg/kg/4hr

IV (n=2)

0.01 mg/kg/8hr

IV (n=4)

762±204

(t=120 hr)

289±117

(t=144 hr)

198±158

Range: 81-436

3.9±1.0

0.017

±0.013

(n=5, PO) 2

8 mg PO

(n=1)

5 mg PO

(n=4)

4 mg PO

(n=1)

658

(t=120 hr)

533±156 (t=144 hr)

119±35

Range: 85-178

3.1±3.4

0.016

±0.011

1 corrected for bioavailability
2 1 patient did not receive the PO dose

Renal Impairment: 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 (Table 15) [see Dosage and Administration and Use in Specific Populations].

Hepatic Impairment: 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 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 [see Dosage and Administration and Use in Specific Populations].

Race
The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of Prograf to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p<0.01). Mean AUC0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and Latino-Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration ].

Gender
A formal trial 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, liver and heart transplant patients indicated no gender-based differences.

Drug Interactions

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].

Telaprevir: In a single dose study in 9 healthy volunteers, coadministration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions ].

Boceprevir: In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions].

Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of Prograf and nelfinavir unless the benefits outweigh the risks [see Drug Interactions ].

Rifampin: 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±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions].

Magnesium-aluminum-hydroxide: In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see Drug Interactions ].

Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions].

Voriconazole (see complete prescribing information for VFEND®): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions ].

Posaconazole (see complete prescribing information for Noxafil®): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions].

Caspofungin (see complete prescribing information for CANCIDAS®): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS® 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions ].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Boxed Warning and Warnings and Precautions].

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals impairing their immune system’s ability to inhibit unrelated carcinogenesis.

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.

Tacrolimus given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range of 0.075 to 0.2 mg/kg/day based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and 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 (2.6 to 6.9 times the clinical dose range based on body surface area), 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.

CLINICAL STUDIES

Kidney Transplantation

Prograf/azathioprine (AZA)
Prograf-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. 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 1 year patient and graft survival was 96.1% and 89.6%, respectively.

Data from this trial of Prograf in conjunction with azathioprine indicate that during the first three months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

Prograf/mycophenolate mofetil (MMF)
Prograf-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received Prograf (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine (CsA) regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving Prograf/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the Prograf group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 16) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 17) in comparison to each of the other three groups. Patients randomized to Prograf/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions ].

Table 16. Estimated Creatinine Clearance at 12 Months (Study 1)

Group

eCLcr [mL/min] at Month 12 1

N

MEAN

SD

MEDIAN

Treatment Difference with Group C (99.2% CI 2 )

(A) CsA/MMF/CS

390

56.5

25.8

56.9

-8.6 (-13.7, -3.7)

(B) CsA/MMF/CS/Daclizumab

399

58.9

25.6

60.9

-6.2 (-11.2, -1.2)

(C) Tac/MMF/CS/Daclizumab

401

65.1

27.4

66.2

-

(D) Siro/MMF/CS/Daclizumab

399

56.2

27.4

57.3

-8.9 (-14.1, -3.9)

Total

1589

59.2

26.8

60.5

Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus

1 All death/graft loss (n=41, 27, 23 and 42 in Groups A, B, C and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7 and 9 in Groups A, B, C and D, respectively) were inputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.
2 Adjusted for multiple pairwise comparisons using Bonferroni corrections.

Table 17. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 1)
Key: Group A=CsA/MMF/CS, B=CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab

Group A

N=390

Group B

N=399

Group C

N=401

Group D

N=399

Overall Failure

141 (36.2%)

126 (31.6%)

82 (20.4%)

185 (46.4%)

Components of efficacy failure

       BPAR

113 (29.0%)

106 (26.6%)

60 (15.0%)

152 (38.1%)

       Graft loss excluding death

28 (7.2%)

20 (5.0%)

12 (3.0%)

30 (7.5%)

       Mortality

13 (3.3%)

7 (1.8%)

11 (2.7%)

12 (3.0%)

       Lost to follow-up

5 (1.3%)

7 (1.8%)

5 (1.3%)

6 (1.5%)

Treatment Difference of efficacy failure compared to Group C (99.2% CI 1)

15.8% (7.1%, 24.3%)

11.2% (2.7%, 19.5%)

-

26.0% (17.2%, 34.7%)

1 Adjusted for multiple pairwise comparisons using Bonferroni corrections.

The protocol-specified target tacrolimus trough concentrations (Ctrough,Tac) were 3-7 ng/mL; however, the observed median Ctroughs,Tac approximated 7 ng/mL throughout the 12 month trial (Table 18). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

Table 18. Tacrolimus Whole Blood Trough Concentrations (Study 1)

Time

Median (P10-P90 1 ) tacrolimus whole blood trough concentrations

(ng/mL)

Day 30 (N=366)

6.9 (4.4 – 11.3)

Day 90 (N=351)

6.8 (4.1 – 10.7)

Day 180 (N=355)

6.5 (4.0 – 9.6)

Day 365 (N=346)

6.5 (3.8 – 10.0)

1 10 to 90th Percentile: range of Ctrough, Tac that excludes lowest 10% and highest 10% of Ctrough,Tac

The protocol-specified target cyclosporine trough concentrations (Ctrough,CsA) for Group B were 50-100 ng/mL; however, the observed median Ctroughs,CsA approximated 100 ng/mL throughout the 12 month trial. The protocol-specified target Ctroughs,CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median Ctroughs, CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12.

While patients in all groups started MMF at 1gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 19); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.

Table 19. MMF Dose Over Time in Prograf/MMF (Group C) (Study 1)
Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

Time period (Days)

Time-averaged MMF dose (grams per day) 1

Less than 2.0

2.0

Greater than 2.0

0-30 (N=364)

37%

60%

2%

0-90 (N=373)

47%

51%

2%

0-180 (N=377)

56%

42%

2%

0-365 (N=380)

63%

36%

1%

1 Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.

In a second randomized, open-label, multi-center trial (Study 2), 424 kidney transplant patients received Prograf (N=212) or cyclosporine (N=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the Prograf/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving Prograf/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to overimmunosuppression (Table 20).

Table 20. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 2)

Prograf/MMF

Cyclosporine/MMF

(N=212)

(N=212)

Overall Failure

32 (15.1%)

36 (17.0%)

Components of efficacy failure

       BPAR

16 (7.5%)

29 (13.7%)

       Graft loss excluding death

6 (2.8%)

4 (1.9%)

       Mortality

9 (4.2%)

5 (2.4%)

       Lost to follow-up

4 (1.9%)

1 (0.5%)

Treatment Difference of efficacy failure compared to Prograf/MMF group (95% CI 1)

1.9% (-5.2%, 9.0%)

1 95% confidence interval calculated using Fisher's Exact Test

The protocol-specified target tacrolimus whole blood trough concentrations (Ctrough,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median Ctroughs,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 21). Approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

Table 21. Tacrolimus Whole Blood Trough Concentrations (Study 2)

Time

Median (P10-P90 1 ) tacrolimus whole blood trough concentrations

(ng/mL)

Day 30 (N=174)

10.5 (6.3 – 16.8)

Day 60 (N=179)

9.2 (5.9 – 15.3)

Day 120 (N=176)

8.3 (4.6 – 13.3)

Day 180 (N=171)

7.8 (5.5 – 13.2)

Day 365 (N=178)

7.1 (4.2 – 12.4)

1 10 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough, Tac

The protocol-specified target cyclosporine whole blood concentrations (Ctrough,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median Ctroughs, CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12.

Patients in both groups started MMF at 1gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the Prograf/MMF group (Table 22) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the Prograf/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions ].

Table 22. MMF Dose Over Time in the Prograf/MMF Group (Study 2)
Key: Time-averaged MMF dose=(total MMF dose)/(duration of treatment)

Time period (Days)

Time-averaged MMF dose (g/day) 1

Less than 2.0

2.0

Greater than 2.0

0-30 (N=212)

25%

69%

6%

0-90 (N=212)

41%

53%

6%

0-180 (N=212)

52%

41%

7%

0-365 (N=212)

62%

34%

4%

1 Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.

Liver Transplantation

The safety and efficacy of Prograf-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.

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 the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA 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 CsA/AZA. In this trial, each center used its local standard CsA/AZA 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 similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and Prograf-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and Prograf-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral Prograf dosing was 2 days.

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients often are maintained at the low end of this target range.

Data from the U.S. clinical trial show that 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.

Heart Transplantation

Two open-label, randomized, comparative trials evaluated the safety and efficacy of Prograf-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine in combination with Prograf or cyclosporine modified for 18 months. In a 3-arm trial conducted in the US, 331 patients received corticosteroids and Prograf plus sirolimus, Prograf plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.

In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the Prograf plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32 to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74 to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to18 ng/mL.

The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose Prograf; however, this regimen was associated with increased risk of wound healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions].

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