Astagraf XL tacrolimus extended-release capsules 1 mg Capsule, Coated, Extended Release, 30-count — NDC 0469-0677-73 (Billing 00469-0677-73)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin is 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).

12.3Pharmacokinetics 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 PK 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) a Healthy adult subjects (actual administered dose of ASTAGRAF XL); adult de novo kidney transplant patients (actual group mean dose of ASTAGRAF XL). b Day of ASTAGRAF XL treatment and PK profiling. c Arithmetic means ± S.D. d Median [range]. e “ De novo ” refers to immunosuppression starting at the time of transplantation; data from PK substudy of Study 2. f Tacrolimus trough concentration before the next dose. g Same daily dose of ASTAGRAF XL for 14-day period. h Correlation coefficient of AUC 24 to C min r = 0.88.

Population ASTAGRAF XL Dose a Day b PK Parameters of ASTAGRAF XL C max c (ng/mL) T max d (hr) AUC 24 c (ng•hr/mL) C 24 f (ng/mL) Healthy Subjects (N=24) 4 mg 4 mg Day 1 Day 10 6.2 ± 2.1 11.6 ± 3.4 2.0 [1.0-5.0] 2.0 [1.0-3.0] 74 ± 22 155 ± 46 2.3 ± 0.8 4.7 ±

1.5Adult Kidney De novo e (N=17) 0.20 mg/kg 0.19 mg/kg 0.18 mg/kg 0.18 mg/kg Day 1 Day 3 Day 7 Day 14 26.0 ± 13.7 31.0 ± 13.9 32.2 ± 10.2 32.7 ± 9.0 3.0 [2-24] 2.0 [0.5-2.0] 2.0 [1-6] 2.0 [1-4] 372 ± 202 437 ± 175 405 ± 117 412 ± 109 12.1 ± 7.2 13.5 ± 5.6 11.4 ± 4.0 11.2 ±

3.9Adult Kidney (6 months or greater post-transplant) (N=60) 5.2 mg/day g Day 14 g 16.1 ± 5.3 2.0 [1.0 - 6.0] 222 ± 64 6.7 ± 1.9 h In de novo adult kidney transplant patients, the tacrolimus systemic exposure, as assessed by AUC 24 , 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 AUC 24 was similar between the two formulations. On Day 14 (steady state), the AUC 24 for ASTAGRAF XL was 21% (Ratio [SD]: 1.207 [1.326]) higher than that of Prograf (tacrolimus immediate-release), at comparable trough concentrations (C 24 ).

Due to intersubject variability in tacrolimus PK, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration ( 2.3 , 2.4 )] . Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus PK. 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 C 24h , 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 greates… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin is 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).

12.3Pharmacokinetics 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 PK 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) a Healthy adult subjects (actual administered dose of ASTAGRAF XL); adult de novo kidney transplant patients (actual group mean dose of ASTAGRAF XL). b Day of ASTAGRAF XL treatment and PK profiling. c Arithmetic means ± S.D. d Median [range]. e “ De novo ” refers to immunosuppression starting at the time of transplantation; data from PK substudy of Study 2. f Tacrolimus trough concentration before the next dose. g Same daily dose of ASTAGRAF XL for 14-day period. h Correlation coefficient of AUC 24 to C min r = 0.88.

Population ASTAGRAF XL Dose a Day b PK Parameters of ASTAGRAF XL C max c (ng/mL) T max d (hr) AUC 24 c (ng•hr/mL) C 24 f (ng/mL) Healthy Subjects (N=24) 4 mg 4 mg Day 1 Day 10 6.2 ± 2.1 11.6 ± 3.4 2.0 [1.0-5.0] 2.0 [1.0-3.0] 74 ± 22 155 ± 46 2.3 ± 0.8 4.7 ±

1.5Adult Kidney De novo e (N=17) 0.20 mg/kg 0.19 mg/kg 0.18 mg/kg 0.18 mg/kg Day 1 Day 3 Day 7 Day 14 26.0 ± 13.7 31.0 ± 13.9 32.2 ± 10.2 32.7 ± 9.0 3.0 [2-24] 2.0 [0.5-2.0] 2.0 [1-6] 2.0 [1-4] 372 ± 202 437 ± 175 405 ± 117 412 ± 109 12.1 ± 7.2 13.5 ± 5.6 11.4 ± 4.0 11.2 ±

3.9Adult Kidney (6 months or greater post-transplant) (N=60) 5.2 mg/day g Day 14 g 16.1 ± 5.3 2.0 [1.0 - 6.0] 222 ± 64 6.7 ± 1.9 h In de novo adult kidney transplant patients, the tacrolimus systemic exposure, as assessed by AUC 24 , 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 AUC 24 was similar between the two formulations. On Day 14 (steady state), the AUC 24 for ASTAGRAF XL was 21% (Ratio [SD]: 1.207 [1.326]) higher than that of Prograf (tacrolimus immediate-release), at comparable trough concentrations (C 24 ).

Due to intersubject variability in tacrolimus PK, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration ( 2.3 , 2.4 )] . Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus PK. 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 C 24h , 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 C max , AUC t , and AUC inf of tacrolimus by approximately 25% compared with fasting values. Food delayed the median T max 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 AUC… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1ASTAGRAF 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 mycophenolate mofetil (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 Medications 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, and 21, then Months 1, 2, 4, 6, 8, 10, and 12.

Table 10 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 10: 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) Immunoassay was used in most laboratories. [Median (10 th to 90 th 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) African-American patients required higher ASTAGRAF XL dosages to attain similar trough concentrations as Caucasian patients (see Table 11 ).

Table 11: 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

7.78Month 1 0.14 11.11 0.17

10.92Month 6 0.10 7.95 0.13

8.42Month 12 0.09 7.53 0.12

7.33MMF 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… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 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 mg/kg/day (0.14 times the AUC at the maximum clinical dose of 0.2 mg/kg/day) [see Warnings and Precautions ( 5.1 )] .

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/m 2 /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 kidney 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. Mutagenesis 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.

Impairment of Fertility Tacrolimus subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day [1.6 times the maximum recommended clinical dose (0.2 mg/kg/day) on a mg/m 2 basis] or 3 mg/kg/day (2.4 times the maximum recommended clinical dose) resulted in a dose-related decrease in sperm count. Tacrolimus administered orally at 1.0 mg/kg (0.8 times the maximum clinical dose) 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- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 times the maximum 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.