Dosage Form: capsule
Tacrolimus Capsules
Rx Only
WARNING
Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Tacrolimus capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
Tacrolimus Description
Tacrolimus Capsule is available for oral administration containing the equivalent of 0.5 mg, 1 mg or 5 mg of monohydrate Tacrolimus. Inactive ingredients include lactose monohydrate, hypromellose E5, croscarmellose sodium, and magnesium stearate. The 0.5 mg capsule shell contains gelatin, titanium dioxide, iron oxide yellow and sodium lauryl sulfate, the 1 mg capsule shell contains gelatin, titanium dioxide and sodium lauryl sulfate, and the 5 mg capsule shell contains gelatin, titanium dioxide, iron oxide red and sodium lauryl sulfate.
Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus capsules. 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.
Tacrolimus - Clinical Pharmacology
Mechanism of Action
Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.
In animals, Tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.
Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that Tacrolimus binds to an intracellular protein, FKBP-12. A complex of Tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).
Pharmacokinetics
Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of Tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, and liver transplant patients. (See table below.)
| Population | N | Route (Dose) | Parameters | |||||
| Cmax (ng/mL) | Tmax (hr) | AUC (ng.hr/mL) | t1/2 (hr) | CI (L/hr/kg) | V (L/kg) | |||
| HealthyVolunteers | 8 | IV (0.025 mg/kg/4hr) | a | a | 598b± 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 | 243c± 73 | 34.8±11.4 | 0.041d± 0.008 | 1.94d±0.53 | |
| KidneyTransplant Pts | 26 | IV (0.02 mg/kg/12 hr) | a | a | 294e± 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 | 203e± 42 | f | f | f | ||
| PO (0.3 mg/kg/day) | 24.2± 15.8 | 1.5 | 288e± 93 | f | f | f | ||
| LiverTransplant Pts | 17 | IV (0.05 mg/kg/12 hr) | a | a | 3300e± 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 | 519e± 179 | f | f | f | ||
a) not applicable
b) AUC0 to 120
c) AUC0 to 72
d) Corrected for individual bioavailability
e) Auc0 to inf;
f) not available
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), and 18±5% in healthy volunteers (N=16).
A single dose study conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose study 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 to 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.
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 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.
Distribution
The plasma protein binding of Tacrolimus is approximately 99% and is independent of concentration over a range of 5 to 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. study, 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 L/hr/kg in healthy volunteers, adult kidney transplant patients, and adult liver 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.
Special 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).
Renal and Hepatic Insufficiency
The mean pharmacokinetic parameters for Tacrolimus following single administrations to patients with renal and hepatic impairment are given in the following table.
| Population (No. of Patients) | Dose | AUC0 to 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 to 141 | 3.1 ± 1.6 | 0.042 ± 0.02 |
| 7.7 mgPO | 488 ± 320 (t=72 hr) | 66.1 ± 44.8 Range: 29.5 to 138 | 3.7 ± 4.7a | 0.034 ± 0.019a | |
| Severe Hepatic Impairment (n=6, IV) | 0.02 mg/kg/4hr IV (n=2) 0.01mg/kg/8hr IV (n=4) | 762 ± 204 (t=120 hr) 289±117 (t=144 hr) | 198 ± 158 Range:81to 436 | 3.9 ± 1.0 | 0.017 ± 0.013 |
| (n=5, PO)b | 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 to 178 | 3.1 ± 3.4a | 0.016 ± 0.011a |
a) corrected for bioavailability
b) 1 patient did not receive the PO dose
Renal Insufficiency: 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 (see previous table).
Hepatic Insufficiency: 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.
Race
A formal study to evaluate the pharmacokinetic disposition of Tacrolimus in Black transplant patients has not been conducted. However, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher Tacrolimus doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION.)
Gender
A formal study 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 and liver transplant patients indicated no gender-based differences.
Clinical Studies
Liver Transplantation
The safety and efficacy of Tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressive regimen. Both studies used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These studies were designed to evaluate whether the two regimens were therapeutically equivalent, with patient and graft survival at 12 months following transplantation as the primary endpoints. The Tacrolimus-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens.
In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the Tacrolimus-based immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive regimen (CBIR). In 10 of the 12 sites, the same CBIR 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 Tacrolimus-based immunosuppressive regimen and 275 to CBIR. In this study, each center used its local standard CBIR 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 Tacrolimus-based treatment groups were equivalent to those in the CBIR treatment groups in both studies. The overall 1-year patient survival (CBIR and Tacrolimus-based treatment groups combined) was 88% in the U.S. study and 78% in the European study. The overall 1-year graft survival (CBIR and Tacrolimus-based treatment groups combined) was 81% in the U.S. study and 73% in the European study. In both studies, the median time to convert from IV to oral Tacrolimus dosing was 2 days.
Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.
Kidney Transplantation
Tacrolimus/azathioprine
Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a Phase 3 randomized, multicenter, non-blinded, prospective study. 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 Tacrolimus-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 and was equivalent between treatment arms.
Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.
Tacrolimus/mycophenolate mofetil (MMF)
Tacrolimus-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 Tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine 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 study was conducted outside the United States; the study population was 93% Caucasian. In this study, mortality at 12 months in patients receiving Tacrolimus/MMF was similar (2.7%) compared to patients receiving cyclosporine/MMF (3.3% and 1.8%) or sirolimus/MMF (3.0%). Patients in the Tacrolimus group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 1) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 2) in comparison to each of the other three groups. Patients randomized to Tacrolimus/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 1: Estimated Creatinine Clearance at 12 Months in Study 1
| Group | eCLcr [mL/min] at Month 12 a | ||||
| N | MEAN | SD | MEDIAN | Treatment Difference with Group C (99.2% CI b) | |
| (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
a) 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) were inputed with 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). Weight was also imputed in the calculation of estimated GFR, if missing.
b) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
Table 2: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 1
| A N=390 | B N=399 | C N=401 | D N=399 | |
| Overall Failure Components of efficacy failure | 141 (36.2%) | 126 (31.6%) | 82 (20.4%) | 185 (46.4%) |
| 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 a) | 15.8% (7.1%, 24.3%) | 11.2% (2.7%, 19.5%) | - | 26.0% (17.2%, 34.7%) |
Group A=CsA/MMF/CS, B=CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab
a) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
The protocol-specified target Tacrolimus trough concentrations (Ctrough,Tac) were 3 to 7 ng/mL; however, the observed median Ctroughs,Tac approximated 7 ng/mL throughout the 12 month study (Table 3).
Table 3: Tacrolimus Whole Blood Trough Concentrations (Study 1)
| Time | Median (P10-P90 a) Tacrolimus whole blood trough concentrations(ng/mL) |
| Day 30 (N=366) | 6.9 (4.4 to 11.3) |
| Day 90 (N=351) | 6.8 (4.1 to 10.7) |
| Day 180(N=355) | 6.5 (4.0 to 9.6) |
| Day 365 (N=346) | 6.5 (3.8 to 10.0) |
a) 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 to 100 ng/mL; however, the observed median Ctroughs,CsA approximated 100 ng/mL throughout the 12 month study. The protocol-specified target Ctroughs,CsA for Group A were 150 to 300 ng/mL for the first 3 months and 100 to 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 1g BID, the MMF dose was reduced to <2 g/day in 63% of patients in the Tacrolimus treatment arm by month 12 (Table 4); approximately 50% of these MMF dose reductions were due to adverse events. By comparison, the MMF dose was reduced to <2 g/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 events.
Table 4: MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)
| Time period (Days) | Time-averaged MMF dose (g/day) a | ||
| <2.0 | 2.0 | >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% |
Time-averaged MMF dose = (total MMF dose)/(duration of treatment)
a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two g/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 Tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram BID, basiliximab induction, and corticosteroids. In this study, the rate for the combined endpoint of biopsy proven acute rejection, graft failure, death, and/or lost to follow-up at 12 months in the Tacrolimus/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 Tacrolimus/MMF (4.2%) compared to those receiving cyclosporine/MMF (2.4%), including cases attributed to over immunosuppression (Table 5).
Table 5: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 2
| Tacrolimus/MMF (n=212) | Cyclosporine/MMF (n=212) | |
| Overall Failure Components of efficacy failure | 32 (15.1%) | 36 (17.0%) |
| 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 Tacrolimus/MMF group (95% CIa) | - | 1.9% (-5.2%, 9.0%) |
a) 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 to16 ng/mL for the first three months and 5 to 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 6).
Table 6: Tacrolimus Whole Blood Trough Concentrations (Study 2)
| Time | Median (P10-P90a) Tacrolimus whole blood trough concentrations (ng/mL) |
| Day 30 (N=174) | 10.5 (6.3 to 16.8) |
| Day 60 (N=179) | 9.2 (5.9 to 15.3) |
| Day 120 (N=176) | 8.3 (4.6 to 13.3) |
| Day 180 (N=171) | 7.8 (5.5 to 13.2) |
| Day 365 (N=178) | 7.1 (4.2 to 12.4) |
a) 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 1g BID. The MMF dose was reduced to <2 g/day by month 12 in 62% of patients in the Tacrolimus/MMF group (Table 7) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse events in the Tacrolimus/MMF group and the cyclosporine/MMF group, respectively.
Table 7: MMF Dose Over Time in the Tacrolimus/MMF group (Study 2)
| Time period (Days) | Time-averaged MMF dose (g/day) a | ||
| <2.0 | 2.0 | >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% |
Time-averaged MMF dose=(total MMF dose)/(duration of treatment)
a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two g/day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
Indications and Usage for Tacrolimus
Tacrolimus Capsule is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, or kidney transplants. It is recommended that Tacrolimus be used concomitantly with adrenal corticosteroids. In kidney transplant recipients, it is recommended that Tacrolimus capsules be used in conjunction with azathioprine or mycophenolate mofetil (MMF).
Contraindications
Tacrolimus Capsule is contraindicated in patients with a hypersensitivity to Tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).
Warnings
(See boxed WARNING.)
Post-Transplant Diabetes Mellitus
Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of Tacrolimus-treated kidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study (See Tables Below). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM.
Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in the Phase III study
| Status of PTDMa | Tacrolimus | CBIR |
| Patients without pretransplant history of diabetes mellitus. | 151 | 151 |
| New onset PTDMa, 1st Year | 30/151 (20%) | 6/151 (4%) |
| Still insulin dependent at one year in those without prior history of diabetes. | 25/151 (17%) | 5/151 (3%) |
| New onset PTDMa post 1 year | 1 | 0 |
| Patients with PTDMa at 2 years | 16/151 (11%) | 5/151 (3%) |
a) use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.
Development of Post Transplant Diabetes Mellitus by Race and by Treatment Group during First Year Post Kidney Transplantation in the Phase III study
| Patient Race | Tacrolimus | CBIR | ||
| No. of Patients atRisk | Patients Who Developed PTDMa | No. of PatientsAt Risk | Patients Who Developed PTDMa | |
| Black | 41 | 15 (37%) | 36 | 3 (8%) |
| Hispanic | 17 | 5 (29%) | 18 | 1 (6%) |
| Caucasian | 82 | 10 (12%) | 87 | 1 (1%) |
| Other | 11 | 0 (0%) | 10 | 1 (10%) |
| Total | 151 | 30 (20%) | 151 | 6 (4%) |
a use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.
Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of Tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post transplant, in the U.S. and European randomized studies, respectively (See Table below). Hyperglycemia was associated with the use of Tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).
Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients
| Status of PTDMa | US Study | European Study | ||
| Tacrolimus | CBIR | Tacrolimus | CBIR | |
| Patients at riskb | 239 | 236 | 239 | 249 |
| New Onset PTDMa | 42 (18%) | 30 (13%) | 26 (11%) | 12 (5%) |
| Patients still on insulin at 1 year | 23 (10%) | 19 (8%) | 18 (8%) | 6 (2%) |
a) use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.
b) Patients without pretransplant history of diabetes mellitus.
Nephrotoxicity
Tacrolimus can cause nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Tacrolimus in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of Tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using Tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, Tacrolimus should not be used simultaneously with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated Tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.
Hyperkalemia
Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with Tacrolimus in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during Tacrolimus therapy (see PRECAUTIONS).
Neurotoxicity
Tacrolimus can cause neurotoxicity, particularly when used in high doses. Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in Tacrolimus-treated kidney transplant patients (54%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole-blood concentrations of Tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving Tacrolimus (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of Tacrolimus.
Patients treated with Tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.
Malignancy and Lymphoproliferative Disorders
As in patients receiving other immunosuppressants, patients receiving Tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to Tacrolimus following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.
Latent Viral Infections
Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving Tacrolimus. These infections may lead to serious, including fatal, outcomes.
Anaphylactic Reactions
A few patients receiving Tacrolimus injection have experienced anaphylactic reactions. Although the exact cause of these reactions is not known, other drugs with castor oil derivatives in the formulation have been associated with anaphylaxis in a small percentage of patients. Because of this potential risk of anaphylaxis, Tacrolimus injection should be reserved for patients who are unable to take Tacrolimus capsules.
Patients receiving Tacrolimus injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.
Precautions
General
Hypertension is a common adverse effect of Tacrolimus therapy (see ADVERSE REACTIONS). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since Tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating Tacrolimus-associated hypertension, care should be taken since interference with Tacrolimus metabolism may require a dosage reduction (see Drug Interactions).
Renally and Hepatically Impaired Patients
For patients with renal insufficiency some evidence suggests that lower doses should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
The use of Tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels 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).
Myocardial Hypertrophy
Myocardial hypertrophy has been reported in association with the administration of Tacrolimus, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean Tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years).
In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving Tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Tacrolimus should be considered.
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