Tacrolimus 1 mg Capsule, 100-count — NDC 82983-401-10 (Billing 82983-0401-10)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited.

This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression). Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

12.3Pharmacokinetics 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 12.

Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients Population N Route (Dose) Parameters C max (ng/mL) T max (hr) AUC (ng hr/mL) t 1/2 (hr) CI (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4hr) a a 598 b ± 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 c ± 73 34.8 ± 11.4 0.041 d ± 0.008 1.94d ±

0.53Kidney Transplant Patients 26 IV (0.02 mg/kg/12 hr) a a 294 e ± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ±

0.66PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203 e ± 42 f f f PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288 e ± 93 f f f Liver Transplant Patients 17 IV (0.05 mg/kg/12 hr) a a 3300 e ± 2130 11.7 ± 3.9 0.053 ± 0.017 0.85 ±

0.30PO (0.3 mg/kg/day) 68.5 ± 30 2.3 ± 1.5 519 e ± 179 f f f Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) a a 954 g ± 334 23.6 ± 9.22 0.051 ± 0.015 f 11 PO (0.075 mg/kg/day)h 14.7 ± 7.79 2.1 [0.5-6] i 82.7 j ± 63.2 a f f 14 PO (0.15 mg/kg/day) h 24.5 ± 13.7 1.5 [0.4-4] i 142j ± 116 a f f a) not applicable b) AUC 0-120 c) AUC 0-72 d) Corrected for individual bioavailability e) AUC 0-inf f) not applicable g) AUC 0-t h) Determined after the first dose i) Median [range] j) AUC 0-12 Due to intersubject variability in Tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [ see Dosage and Administration ( 2.6 )].Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe Tacrolimus pharmacokinetics.

Absorption Absorption of Tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of Tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), 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(C max ) 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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited.

This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression). Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

12.3Pharmacokinetics 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 12.

Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients Population N Route (Dose) Parameters C max (ng/mL) T max (hr) AUC (ng hr/mL) t 1/2 (hr) CI (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4hr) a a 598 b ± 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 c ± 73 34.8 ± 11.4 0.041 d ± 0.008 1.94d ±

0.53Kidney Transplant Patients 26 IV (0.02 mg/kg/12 hr) a a 294 e ± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ±

0.66PO (0.2 mg/kg/day) 19.2 ± 10.3 3.0 203 e ± 42 f f f PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288 e ± 93 f f f Liver Transplant Patients 17 IV (0.05 mg/kg/12 hr) a a 3300 e ± 2130 11.7 ± 3.9 0.053 ± 0.017 0.85 ±

0.30PO (0.3 mg/kg/day) 68.5 ± 30 2.3 ± 1.5 519 e ± 179 f f f Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) a a 954 g ± 334 23.6 ± 9.22 0.051 ± 0.015 f 11 PO (0.075 mg/kg/day)h 14.7 ± 7.79 2.1 [0.5-6] i 82.7 j ± 63.2 a f f 14 PO (0.15 mg/kg/day) h 24.5 ± 13.7 1.5 [0.4-4] i 142j ± 116 a f f a) not applicable b) AUC 0-120 c) AUC 0-72 d) Corrected for individual bioavailability e) AUC 0-inf f) not applicable g) AUC 0-t h) Determined after the first dose i) Median [range] j) AUC 0-12 Due to intersubject variability in Tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [ see Dosage and Administration ( 2.6 )].Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe Tacrolimus pharmacokinetics.

Absorption Absorption of Tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of Tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), 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(C max ) 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(C min ) 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; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C max was reduced… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Kidney Transplantation Tacrolimus/azathioprine (AZA)Tacrolimus-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 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.Data from this trial of Tacrolimus 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.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 (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 Tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%).

Patients in the Tacrolimus 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 tacrolim us/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 (6.1)].

Table 14. Estimated Creatinine Clearance at 12 Months (Study 1) eCLcr [mL/min] at Month 12 a Group N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CIb) (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

60.5Key: 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, 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. b)Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections. Table 15. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 1) Group AN=390 Group BN=399 Group CN=401 Group DN=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 dea… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 doses 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 ( 5.2 )].

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.