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Astagraf XL (Tacrolimus) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ASTAGRAF XL is available for oral administration as hard gelatin capsules (tacrolimus extended-release capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include ethylcellulose NF, hypromellose USP, magnesium stearate NF and lactose monohydrate NF. The ingredients are directly proportional across all capsule strengths. The capsule shell contains gelatin NF, titanium dioxide USP, ferric oxide NF, and sodium lauryl sulfate. The capsule shell also has a trace of printing ink, Opacode S-1-15083 Red.

Tacrolimus is the active ingredient in ASTAGRAF XL. 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 – methoxycyclo – hexyl) – 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).

Pharmacokinetics

Table 6 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of ASTAGRAF XL in healthy subjects and in kidney transplant patients. Whole blood tacrolimus concentrations in these pharmacokinetic studies were measured using validated HPLC/MS/MS assays.

Table 6. Pharmacokinetic Parameters of ASTAGRAF XL Once Daily in Healthy Subjects and in Kidney Transplant Patients (Under Fasted Conditions), and Statistical Comparison of PK Parameters with Prograf® Twice Daily

    Population    

N

ASTAGRAF XL Dose 1

    Day 2     

Pharmacokinetic Parameters of ASTAGRAF XL and ASTAGRAF XL:Prograf ratio (90% CI for ratio) 3

      Cmax 4       

(ng/mL)

       Tmax 5        

(hr)

    AUC24     

(ng•hr/mL)

        C24 6         

(ng/mL)

Healthy Subjects

24

4 mg

4 mg

Day 1

6.2 ± 2.1

2.0 [1.0-5.0]

74 ± 22

2.3 ± 0.8

Day 10

11.6 ± 3.4

2.0 [1.0-3.0]

155 ± 46

4.7 ± 1.5

Ratio

(90% CI)

Day 1

0.67

(0.59 - 0.75)

1.02

(0.91 - 1.13)

0.81

(0.72 - 0.92)

Day 10

0.74

(0.69 - 0.80)

0.93

(0.87-0.99)

0.87

(0.81 - 0.94)

Adult Kidney

De novo 7

17

0.20 mg/kg

Day 1

26.0 ± 13.7

3.0 [2-24]

372 ± 202

12.1 ± 7.2

0.19 mg/kg

Day 3

31.0 ± 13.9

2.0 [0.5-2.0]

437 ± 175

13.5 ± 5.6

0.18 mg/kg

Day 7

32.2 ± 10.2

2.0 [1-6]

405 ± 117

11.4 ± 4.0

0.18 mg/kg

Day 14

32.7 ± 9.0

2.0 [1-4]

412 ± 109

11.2 ± 3.9

Ratio

(90% CI)

Day 1

0.86

(0.63 - 1.19)

0.84

(0.63 - 1.12)

0.85

(0.59 - 1.17)

Day 3

0.93

(0.71 - 1.21)

1.05

(0.82 - 1.33)

1.04

(0.79 - 1.36)

Day 7

1.14

(0.95 - 1.38)

1.22

(1.02 - 1.46)

1.14

(0.90 - 1.44)

Day 14

1.27

(1.03 - 1.57)

1.21

(1.02 - 1.42)

0.99

(0.82 - 1.20)

Adult Kidney
(≥ 6 months post-transplant)

60

5.2 mg/day 8

Day 14

16.1 ± 5.3

2.0 [1.0 - 6.0]

222 ± 64

6.7 ± 1.9 9

1 Healthy adult subjects (actual administered dose of ASTAGRAF XL and Prograf); Adult de novo kidney transplant patients (actual group mean dose of ASTAGRAF XL, corresponding doses for Prograf on Days 1, 3, 7 and 14 were 0.20, 0.18, 0.16, and 0.17 mg/kg/day, respectively)
2 Day of ASTAGRAF XL treatment and PK profiling
3 Ratio of geometric least square means
4 Arithmetic means ± S.D.
5 Median [range]
6 Tacrolimus trough concentration before the next dose
7 PK substudy of Study 2
8 Same daily dose of ASTAGRAF XL for 14 day period
9 The correlation coefficient of AUC24 to Cmin r= 0.88

In de novo adult kidney transplant recipients, the tacrolimus systemic exposure, as assessed by AUC24, for ASTAGRAF XL once daily on Day 1 post-transplant was 16% lower when compared with Prograf twice daily. By Day 3 post-transplant, the AUC24 was similar between the two formulations. On Day 14, the AUC24 was 21% higher than Prograf, at comparable trough concentrations (C24).

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.5)].

Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption

Food Effects

The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 24 healthy subjects, administration of ASTAGRAF XL immediately following a high-fat meal (150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories) reduced the Cmax, AUCt, and AUCinf of tacrolimus by approximately 25% compared with fasting values. Food delayed the median Tmax from 2 hours in the fasted state to 4 hours in the fed state; however, the terminal half-life remained 36 hours regardless of dosing conditions. The time when a meal is consumed also affected tacrolimus bioavailability. In 24 healthy subjects, when ASTAGRAF XL was administered 1.5 hours after consumption of a high-fat breakfast, tacrolimus exposure was decreased approximately 35%. Administration of ASTAGRAF XL 1 hour prior to a high-fat breakfast reduced tacrolimus exposure by 10%. ASTAGRAF XL capsules should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.

Chronopharmacokinetic Effect

In 23 healthy subjects, a diurnal effect on the absorption of tacrolimus was observed. Evening dosing of ASTAGRAF XL reduced AUCinf by 35% relative to morning dosing. ASTAGRAF XL capsules should be taken consistently at the same time every morning.

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 in which tacrolimus was administered as Prograf, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

The desired pharmacological activity of tacrolimus is primarily due to the parent drug. 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, and 0.083 L/hr/kg in healthy subjects, and adult kidney 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 subjects, the mean recovery of radiolabel was 77.8 ± 12.7% with the feces accounting for 92.4 ± 1.0% of the total recovery. 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 the mean clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered orally (radiolabeled tacrolimus), the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. 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 the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

The elimination half-life of tacrolimus after oral administration of 4 mg ASTAGRAF XL daily for 10 days was 37.9 ± 3.4 hours in 24 healthy subjects.

Specific Populations

Renal and Hepatic Impairment

Renal Impairment

Tacrolimus pharmacokinetics following a single administration of Prograf injection (administered as a continuous IV infusion) 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 healthy subjects [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].

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 of Prograf. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in healthy subjects. 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 (2.3) and Use in Specific Populations (8.7)].

Race

African-American patients may require higher ASTAGRAF XL doses to attain similar trough concentrations as Caucasian patients [see Dosage and Administration (2.1), Use in Specific Populations (8.8), Clinical Studies (14)].

The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of Prograf in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects. 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 lower than in Caucasians (40.2±12.6 ng/mL) and Latino-Americans (36.2±15.8  ng/mL). 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 lower than in Caucasians (19±5.8%). There was no significant difference in mean terminal half-life among the three ethnic groups (range from approximately 25 to 30 hours).

Gender

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in total mg daily doses between male and female patients receiving ASTAGRAF XL in the kidney transplant trials. A retrospective comparison of pharmacokinetics in healthy subjects, and in kidney 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)].

Rifampin

In a study of 22 healthy male subjects, coadministration of a single 10 mg ASTAGRAF XL dose with rifampin (600 mg/day) for 12 days decreased mean AUCinf and Cmax of tacrolimus by 56% and 46%, respectively [see Drug Interactions (7.8)].

Ketoconazole

In a study of 24 healthy male subjects, coadministration of a 4 mg ASTAGRAF XL dose with ketoconazole (400 mg/day) for 9 days increased the mean AUCinf and Cmax of tacrolimus 7.5-fold and 4.6-fold, respectively [see Drug Interactions (7.5)].

Telaprevir

In a single dose study in 9 healthy subjects, coadministration of tacrolimus (0.5 mg single dose, as tacrolimus immediate-release) 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 (7.4)].

Boceprevir

In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose, as tacrolimus immediate-release) 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 (7.4)].

Nelfinavir

Based on a clinical study of 5 liver transplant recipients, coadministration of tacrolimus (as tacrolimus immediate-release) 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 tacrolimus and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.4)].

Magnesium-aluminum-hydroxide

In a single-dose crossover study in healthy subjects, coadministration of tacrolimus (as immediate-release) 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 (7.11)].

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, as tacrolimus immediate-release formulation) 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 (7.5)].

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, as immediate-release formulation) 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 (7.5)].

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, as immediate-release formulation) 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 (7.5)].

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 (0.49 times the AUC at the maximum clinical dose of 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.14 times the AUC at the maximum clinical dose of 0.2 mg/kg/day) [see  Boxed Warning , Warnings and Precautions (5.4)].

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; 2.4-fold the human exposure in stable adult renal transplant patients > 6 months post transplant). 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 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 times the maximum clinical dose 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 times the maximum clinical dose 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

The efficacy and safety of ASTAGRAF XL in de novo kidney transplantation were assessed in two randomized, multicenter, active-controlled trials (Study 1 and Study 2).

Study 1 -- Induction with Basiliximab

Study 1 was a randomized, open-label trial of ASTAGRAF XL (N=214) compared to Prograf (N=212), of 12 months duration conducted primarily in the US. Patients were stratified by donor type (living or deceased) and transplant history (primary or retransplant). All patients received basiliximab induction and concomitant treatment with MMF and corticosteroids. The population was 17 to 77 years of age, the mean age was 48 years; 64% of the study population was male; 73% were Caucasian, 22% were African-American, 2% were Asian, and 3% were categorized as other races. Living donors provided 49% of the organs. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease. Premature discontinuation from treatment at the end of one year occurred in 14% of ASTAGRAF XL patients and 16% of Prograf patients, primarily due to adverse reactions.

Study 2 -- No Induction

Study 2 was a randomized, double-blind trial, (designed to remain double-blind until the last patient enrolled had completed 24 weeks on study treatment) of ASTAGRAF XL (N = 331) compared to Prograf (N = 336), of 12 months duration conducted outside the US. The patient treatment assignments remained blinded for 12 months for 96% of the patients participating in the trial. Patients with a high immunologic risk defined as a PRA grade > 50% in the previous 6 months and/or with a previous graft survival of less than 12 months due to immunologic reasons were excluded, as were recipients of donor kidneys with cold ischemia time > 30 hours, or donor kidneys from a non heart-beating donor. All patients received concomitant treatment with MMF and corticosteroids without antibody induction. The population was 18 to 65 years of age; the mean age was 48 years; 63% of the study population was male; 82% were Caucasian, 5% were African-American, 2% were Asian, and 11% were categorized as other races. Living donors provided 27% of the organs. Premature discontinuation from treatment at the end of one year occurred in 24% of ASTAGRAF XL patients and 19% of Prograf patients, primarily due to adverse reactions.

Tacrolimus Dosing

In Study 1, the actual tacrolimus starting dose (given any time up to Day 2 post-transplant) of ASTAGRAF XL was higher than Prograf (0.15 mg/kg versus 0.1 mg/kg). In Study 2, the actual tacrolimus doses on Day 0 (0.1 mg/kg/day pre-operative) and Day 1 (0.2 mg/kg/day post-operative) were comparable between ASTAGRAF XL and Prograf. Thereafter, to achieve comparable mean tacrolimus trough concentrations (C24), higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than Prograf (on average, by 15% in Study 1 and by 25% in Study 2).

In Study 1, African-American patients required higher ASTAGRAF XL doses to attain similar trough concentrations as Caucasian patients (Table 7).

Table 7. ASTAGRAF XL Doses and Mean Whole Blood Trough Concentrations in African-American and Caucasian Kidney Transplant Patients in Study 1

Time After Transplant

Caucasian Patients

n=160

African-American Patients

n=41

Dose (mg/kg)

Mean Trough Concentration (ng/mL)

Dose (mg/kg)

Mean Trough Concentration (ng/mL)

Day 7

0.14

10.65

0.14

7.78

Month 1

0.14

11.11

0.17

10.92

Month 6

0.10

7.95

0.13

8.42

Month 12

0.09

7.53

0.12

7.33

Table 8 shows the observed tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL in Study 1 and Study 2. In Study 1, the protocol-specified target tacrolimus whole blood trough concentrations (Ctrough) were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter.

Approximately 80% of ASTAGRAF XL patients maintained tacrolimus whole trough blood concentrations between 5 to 17 ng/mL during Months 1 through 2 and, then, between 4 to 12 ng/mL from Months 3 through 12. In Study 2, the protocol-specified target tacrolimus whole blood trough concentrations (Ctrough) were 10-15 ng/mL during the first month, 5-15 ng/mL from Month 2 to Month 6, and 5-10 ng/mL thereafter. Approximately 80% of ASTAGRAF XL patients maintained tacrolimus whole trough blood concentrations between 6 to 20 ng/mL during Months 1 through 2 and, then between 6 to 14 ng/mL from Months 3 through 12.

Table 8. Observed Tacrolimus Whole Blood Trough Concentrations for ASTAGRAF XL Kidney Transplant Patients Evaluated in Studies 1 and 2

Scheduled Visit

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

Study 1

Study 2

Day 3

9.6 (4.9 - 20.2)

13.8 (6.5 - 25.5)

Day 7

9.1 (4.4 - 16.8)

10.1 (5.5 - 17.3)

Day 14

10.0 (5.7 - 16.9)

10.8 (6.7 - 17.9)

Month 1

10.5 (5.6 - 17.1)

12.0 (7.5 - 17.6)

Month 2

9.4 (6.1 - 14.2)

11.1 (6.6 - 17.3)

Month 6

7.7 (4.4 - 11.5)

9.2 (5.7 - 13.5)

Month 12

7.2 (3.8 - 10.4)

8.0 (5.1 - 13.8)

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

MMF Dosing

In Study 1, patients in each group started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by Month 12 in 56% of patients in the ASTAGRAF XL group (Table 9). Approximately 57% of the MMF dose reductions were because of adverse reactions in the ASTAGRAF XL group [see Adverse Reactions ()].

In Study 2, patients in each group received MMF at 1 gram twice daily starting preoperatively. In a majority of the patients, the MMF dose was reduced to 0.5 grams twice daily starting after day 14 (Table 9).

Table 9. Distribution of ASTAGRAF XL/MMF Patients (%) Based on Time-Averaged MMF Dose 1

Time period (Days)

Study 1

Study 2

Time-averaged MMF dose

Time-averaged MMF dose

Less than 2.0 (g/day)

2.0 (g/day)

Greater than 2.0 (g/day)

Less than 2.0 (g/day)

2.0 (g/day)

Greater than 2.0 (g/day)

1-30

30%

64%

6%

82%

17%

0%

1-90

42%

52%

7%

93%

7%

0%

1-180

52%

44%

4%

94%

6%

0%

1-365

56%

41%

3%

95%

5%

0%

1 Time-averaged MMF dose = (total MMF dose)/(duration of treatment). A time-averaged MMF dose of 2.0 grams per day means that the MMF dose was not reduced in those patients during the time period.

Efficacy Results

In Study 1, the efficacy failure rate including patients who developed biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, is shown in Table 10 for the intent to treat (ITT) population.

Table 10. Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months

ASTAGRAF XL/MMF

Tacrolimus Immediate- Release/MMF

(N=214)

(N=212)

Efficacy Failure

30 (14.0%)

32 (15.1%)

        Biopsy Proven Acute Rejection

22 (10.3%)

16 (7.5%)

        Graft Loss

5 (2.3%)

9 (4.2%)

        Death

3 (1.4%)

9 (4.2%)

        Lost to follow-up

3 (1.4%)

4 (1.9%)

Treatment Difference of efficacy failure compared to tacrolimus immediate-release/MMF group (95% CI 1)

-1.1% (-7.8%, +5.6%)

1 95% confidence interval calculated using normal approximation

In Study 2, the Efficacy Failure rate including patients who developed biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, is shown in Table 11 for the ITT population. About 1% of randomized patients were not transplanted and were not included in the ITT analysis.

Table 11. Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months

ASTAGRAF XL/MMF

Tacrolimus Immediate- Release/MMF

(N=331)

(N=336)

Efficacy Failure

93 (28%)

78 (23%)

        Biopsy Proven Acute Rejection

68 (21%)

54 (16%)

        Graft loss

28 (9%)

24 (7%)

        Death

10 (3%)

8 (2%)

        Lost to follow-up

4 (1%)

7 (2%)

Treatment Difference of efficacy failure compared to tacrolimus immediate-release/MMF group (95% CI 1)

+4.9% (-1.7%, +11.5%)

1 95% confidence interval calculated using normal approximation

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