July 26, 2016
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Astagraf XL

"The U.S. Food and Drug Administration today approved Liposorber LA-15 System to treat pediatric patients with primary focal segmental glomerulosclerosis (FSGS) either before transplant, or after renal (kidney) transplantation in which there is re"...

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Astagraf XL

CLINICAL PHARMACOLOGY

Mechanism Of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Pharmacokinetics

Table 7 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 7: Pharmacokinetic Parameters of ASTAGRAF XL (Given Once Daily) in Healthy Subjects and in Kidney Transplant Patients (Under Fasted Conditions)

Population ASTAGRAF XL Dosea Dayb Pharmacokinetic Parameters of ASTAGRAF XL
Cmax c (ng/mL) Tmax d (hr) AUC24c (ng•hr/mL) C24f (ng/mL)
Healthy Subjects (n=24) 4 mg Day 1 6.2 ± 2.1 2.0 [1.0-5.0] 74 ± 22 2.3 ± 0.8
4 mg Day 10 11.6 ± 3.4 2.0 [1.0-3.0] 155 ± 46 4.7 ± 1.5
Adult Kidney De novoe (n=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
Adult Kidney (6 months or greater post-transplant) (n=60) 5.2 mg/dayg Day 14g 16.1 ± 5.3 2.0 [1.0 -6.0] 222 ± 64 6.7 ± 1.9h
a Healthy adult subjects (actual administered dose of ASTAGRAF XL); Adult de novo kidney transplant patients (actual group mean dose of ASTAGRAF XL)
bDay of ASTAGRAF XL treatment and PK profiling
c Arithmetic means ± S.D.
dMedian [range]
e “De novo” refers to immunosuppression starting at the time of transplantation; data from PK substudy of Study 2
fTacrolimus trough concentration before the next dose
g Same daily dose of ASTAGRAF XL for 14-day period
hCorrelation coefficient of AUC24 to Cmin r = 0.88

In de novo adult kidney transplant patients, the tacrolimus systemic exposure, as assessed by AUC24, for ASTAGRAF XL 0.2 mg/kg once daily on Day 1 post-transplant was 18% (Ratio [SD]: 0.822 [1.647]) lower when compared with PROGRAF® (tacrolimus immediate-release) 0.2 mg/kg/day given twice daily. By Day 3 post-transplant, the AUC24 was similar between the two formulations. On Day 14 (steady state), the AUC24 for ASTAGRAF XL was 21% (Ratio [SD]: 1.207 [1.326]) higher than that of PROGRAF (tacrolimus immediate-release), 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].

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

Absorption

In healthy subjects, the administration of escalating ASTAGRAF XL doses ranging from 1.5 mg to 10 mg resulted in dose-proportional increases in tacrolimus AUC and C24h, and no change in elimination half-life.

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 tacrolimus immediate-release, 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

In a mass balance study of orally-administered radiolabeled tacrolimus to 6 healthy subjects, 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 38 ± 3 hours in 24 healthy subjects.

Specific Populations

Renal Impairment

Tacrolimus pharmacokinetics following a single administration of tacrolimus immediate-release 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 mean clearance of tacrolimus in patients with renal dysfunction given tacrolimus IV was similar to that in healthy subjects given tacrolimus IV and in healthy subjects given oral tacrolimus immediate-release [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Hepatic Impairment

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic impairment (mean Child-Pugh score: 6.2) following single oral administration of tacrolimus immediate-release. The mean clearance of tacrolimus in patients with mild hepatic impairment was not substantially different from that in healthy subjects. Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic impairment (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Race

The pharmacokinetics of tacrolimus was studied following single oral administration of tacrolimus immediate-release (5 mg) in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects [see DOSAGE AND ADMINISTRATION, Use In Specific Populations, and Clinical Studies]:

  • The 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 dosages 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

Because tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes and/or are known CYP3A substrates may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Figures 1 and 2 summarize the PK data from drug interaction studies of ASTAGRAF XL or tacrolimus immediate-release capsules. These studies assessed the effect of co-administered drugs on tacrolimus PK in healthy subjects. For the clinical recommendations, see DRUG INTERACTIONS.

Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus (when Given as ASTAGRAF XL)

Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus - Illustration

Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus (when Given as Immediate-Release Tacrolimus)

Effect of Co-administered Drugs on the Pharmacokinetics of Tacrolimus - Illustration

Clinical Studies

ASTAGRAF XL With Basiliximab Induction

Study 1 was a 12-month, randomized, open-label trial of ASTAGRAF XL (N=214) compared to active-control of tacrolimus (PROGRAF) immediate-release (N=212), conducted primarily in the U.S. in patients who were a recipient of a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. All patients received basiliximab induction and concomitant MMF and corticosteroids. The study population was 17 to 77 years of age, the mean age was 48 years; 64% were male and 36% were female; 73% were Caucasian, 22% were African-American, 2% were Asian, and 3% were categorized as other races. Living donors provided 49% of the organs and 51% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 19 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease. In the study, 97% of patients had no previous transplant and 3% had a previous transplant.

Study Medication

ASTAGRAF XL or Control [PROGRAF (tacrolimus) capsules]

The initial dose of ASTAGRAF XL was administered prior to reperfusion or within 48 hours after completion of the transplant procedure. The protocol defined initial post-operative daily doses were 0.15 to 0.20 mg per kg given as a single dose in the morning for ASTAGRAF XL and 0.075 to 0.10 mg per kg twice daily for control. The ASTAGRAF XL and control dosage was then adjusted on the basis of safety and efficacy and a target whole blood tacrolimus trough concentration range of 7 to 16 ng/mL for the first 90 days post-transplant and 5 to 15 ng/mL thereafter.

The average recorded starting tacrolimus daily dose, given any time up to day 2 post-transplant, was higher for ASTAGRAF XL than for control (0.14 mg per kg per day versus 0.10 mg per kg per day). Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average, 15% higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than for control.

Tacrolimus whole blood trough concentrations were monitored on Days 3, 7, 10, 14, 21, then Months 1, 2, 4, 6, 8, 10, and 12. Table 8 shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL. Approximately 80% of ASTAGRAF XL-treated patients maintained tacrolimus whole trough blood concentrations between 5 to 17 ng/mL during months 1 through 2 and between 4 to 12 ng/mL from months 3 through 12.

Table 8: Observed Tacrolimus Whole Blood Trough Concentrations in ASTAGRAF XL-Treated Kidney Transplant Patients in Study 1

Scheduled Visit Tacrolimus Whole Blood Trough Concentrations (ng/mL)*Median (10th to 90th Percentile)
Day 3 9.6 (4.9 to 20.2)
Day 7 9.1 (4.4 to 16.8)
Day 14 10.0 (5.7 to 16.9)
Month 1 10.5 (5.6 to 17.1)
Month 2 9.4 (6.1 to 14.2)
Month 6 7.7 (4.4 to 11.5)
Month 12 7.2 (3.8 to 10.4)
* Immunoassay was used in most laboratories

African-American patients required higher ASTAGRAF XL dosages to attain similar trough concentrations as Caucasian patients (see Table 9).

Table 9: ASTAGRAF XL Dosages 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 0.1 7.95 0.13 8.42
Month 12 0.09 7.53 0.12 7.33

MMF

The initial dose of MMF was 1 gram administered orally or intravenously prior to or within 48 hours of completion of the transplant procedure. Subsequent MMF was administered orally 1 gram twice daily or up to 1.5 grams twice daily in African-American patients. Dose-equivalent three times daily or four times daily dosing was permitted if MMF tolerability was a concern.

The MMF dosages administered by time period in ASTAGRAF XL-treated patients are shown in Table 10. The MMF dosage was reduced to less than 2 grams per day by month 12 in 56% of ASTAGRAF XL-treated patients. Approximately 57% of the MMF dose reductions were because of adverse reactions in the ASTAGRAF XL group [see ADVERSE REACTIONS].

Table 10: Proportion of Patients Who Received 2 grams (or less than or more than 2 grams) of MMF by Time Period in ASTAGRAF XL-treated Patients in Study 1

Time period (Days) Patients on MMF Time-averaged MMF dosagea
N Less than 2 grams per day 2 grams per day Greater than 2 grams per day
30-Jan 211 30% 64% 6%
31-90 208 38% 57% 5%
91-180 205 49% 48% 3%
181-365 201 51% 47% 3%
a Time-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period.

Basiliximab Induction

All patients were administered 2 doses of basiliximab induction therapy (20 mg intravenously) with the first dose on day 0 before skin closure and the second dose between days 3 and 5.

Steroids

All patients were administered an intravenous bolus of 500 to 1000 mg of methylprednisolone (or an equivalent steroid dose) on day 0 followed by oral administration of 200 mg methylprednisolone (or an equivalent dose of steroid) on day 1 and subsequent tapering to achieve a targeted mean prednisone dose of 5 to 10 mg/day after the first 3 months.

Efficacy Results

The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 11 for the intent-to-treat population, as well as the rates of the individual events.

Table 11: Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Kidney Transplant Patients in Study 1

  ASTAGRAF XL + MMF, steroids, basiliximab induction
(N=214)
PROGRAF + MMF,steroids, basiliximab induction
(N=212)
Efficacy Failure 30 (14.0%) 32 (15.1%)
Treatment Difference (95% CIa) -1.1% (-7.8%, +5.6%)
Efficacy Failure Endpoints
  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%)
a 95% confidence interval calculated using normal approximation

Glomerular Filtration Rate

The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population is shown in Table 12.

Table 12: Estimated Glomerular Filtration Rate (mL/min/1.73m²) by MDRD Formula at 12 Months Post-Transplant in Study 1

ASTAGRAF XL + MMF, steroids, basiliximab induction
(n=201)
PROGRAF + MMF,steroids, basiliximab induction
(n=202)
Month 1 Baseline Mean (SD) 56 (20) 56 (21)
Month 12 LOCFa    
Mean (Standard deviation) 58 (21) 56 (23)
Mean Difference XL minus PROGRAF (tacrolimus immediate-release)b +2.3 (-1.2, +5.8)  
a Last observation carried forward (LOCF); patients who died, lost the graft or were lost to follow-up are imputed as zeroes
bResults from analysis of covariance model with Month 1 Baseline as a covariate

Clinical Study Of ASTAGRAF XL Without Induction

Study 2 was a 12-month, randomized, double-blind trial of ASTAGRAF XL (N=331) compared to active control of tacrolimus (PROGRAF) immediate-release (N=336) in non-U.S. patients who received a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. This trial was designed to remain double-blind until the last patient enrolled had completed 24 weeks on study treatment. Patients with a high immunologic risk defined as a panel reactive antibody (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 patients of donor kidneys with cold ischemia time > 30 hours, or donor kidneys from a non heart-beating donor. The patient treatment assignments remained blinded for 12 months for 96% of the patients participating in the trial.

All patients received concomitant MMF and corticosteroids without 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 and 73% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 17 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease.

Study Medication

ASTAGRAF XL or Control [PROGRAF (tacrolimus) capsules]

The protocol specified initial pre-operative dose for both ASTAGRAF XL and control was 0.1 mg per kg given orally in one dose within 12 hours prior to reperfusion, given at any time of the day. The initial post-operative tacrolimus daily dose (0.2 mg per kg per day) was given orally in one dose, preferably in the morning for ASTAGRAF XL, and was given as 0.1 mg/kg twice daily for control. Subsequent doses of ASTAGRAF XL and control were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and according to whole blood tacrolimus trough concentration target ranges of 10 to 15 ng/mL for the first 28 days post-transplant, 5 to 15 ng/mL from Day 29 to Day 168, 5 to 10 ng/mL thereafter.

The actual tacrolimus doses on day 0 (0.1 mg per kg per day pre-operative) and day 1 (0.2 mg per kg per day post-operative) were comparable between ASTAGRAF XL and control. Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average, 25% higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than for control.

Tacrolimus whole blood trough concentrations were monitored on Days 1, 3, 7, 14 then Months 1, 2, 3, 6, 11, 12, and then every 3 months.

Table 13 shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL. Approximately 80% of ASTAGRAF XL-treated patients maintained tacrolimus whole trough blood concentrations between 6 to 20 ng/mL during months 1 through 2 and between 6 to 14 ng/mL from months 3 through 12.

Table 13: Observed Tacrolimus Whole Blood Trough Concentrations for ASTAGRAF XL Kidney Transplant Patients Evaluated in Study 2

Scheduled Visit Tacrolimus Whole Blood Trough Concentrations (ng/mL)*[Median (10th to 90th Percentile)]
Day 3 13.8 (6.5 to 25.5)
Day 7 10.1 (5.5 to 17.3)
Day 14 10.8 (6.7 to 17.9)
Month 1 12.0 (7.5 to 17.6)
Month 2 11.1 (6.6 to 17.3)
Month 6 9.2 (5.7 to 13.5)
Month 12 8.0 (5.1 to 13.8)
* Immunoassay was used in most laboratories

MMF

The initial dose of MMF was 1 gram orally twice daily starting pre-operatively and given for the first 14 days of the study. Thereafter the MMF dose was reduced to 0.5 grams twice daily to be maintained throughout the study.

The MMF dosages administered by time period in ASTAGRAF XL-treated patients are shown in Table 14. The MMF dosage was reduced to 0.5 grams twice daily starting after day 14 in the majority of patients.

Table 14: Distribution (%) of ASTAGRAF XL-treated Patients, by Average Daily Dosage of MMF received by Time Period in Study 2

Time period (Days) Patients on MMF Time-averaged MMF dosagea,b
N Less than 1 gram per day 1 gram to less than 2 grams per day 2 grams perday
30-Jan 331 1% 78% 21%
31-90 303 8% 87% 6%
91-180 281 12% 85% 3%
181-365 258 15% 83% 2%
a Time-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period.
bOne patient had a time-averaged dose during the first and last period of > 2 gm/day.

Steroids

An intravenous (IV) bolus of up to 1000 mg methylprednisolone (or equivalent) was administered perioperatively (Day 0) with a second IV bolus of 125 mg being administered 1 day after reperfusion (Day 1). On Day 2, oral prednisone was started at 20 mg per day. Thereafter the dose of oral prednisone (or equivalent) was tapered to a dose of 0 to 5 mg/day.

No Antibody Induction

Antibody induction therapy was not allowed.

Efficacy Results

The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 15 for the intent-to-treat population, as well as the rates of the individual events. About 1% of randomized patients were not transplanted and were not included in the ITT analysis.

Table 15: Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Kidney Transplant Patients in Study 2

  ASTAGRAF XL + MMF and steroids
(N=331)
PROGRAF + MMFand steroids
(N=336)
Efficacy Failure 93 (28.1%) 78 (23.2%)
  Treatment Difference (95% CIa) +4.9% (-1.7%, +11.5%)
Efficacy Failure Endpoints
  Biopsy Proven Acute Rejection 68 (20.5%) 54 (16.1%)
  Graft loss 28 (8.5%) 24 (7.1%)
  Death 10 (3%) 8 (2.4%)
  Lost to follow-up 4 (1.2%) 7 (2.1%)
a 95% confidence interval calculated using normal approximation

Glomerular Filtration Rate

The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population in Study 2 is shown in Table 16.

Table 16: Estimated Glomerular Filtration Rate (mL/min/1.73m²) by MDRD Formula at 12 Months Post-Kidney Transplant in Study 2

ASTAGRAF XL + MMF and steroids
(N=287)
PROGRAF + MMFand steroids
(N=300)
Month 1 Baseline Mean (SD) 51 (19) 52 (20)
Month 12 LOCFa    
  Mean (Standard deviation) 52 (20) 55 (19)
  Mean Difference XL minus PROGRAF (tacrolimus immediate-release)b -1.8 (-4.6, +0.8)  
a Last observation carried forward (LOCF); patients who died, lost the graft or were lost to follow-up are imputed as zeroes
bResults from analysis of covariance model with Month 1 Baseline as a covariate.

Last reviewed on RxList: 12/28/2015
This monograph has been modified to include the generic and brand name in many instances.

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