Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 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 Warnings and Precautions (5.1)].
A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% to 3%), equivalent to tacrolimus doses of 1.1 to 118 mg/kg/day or 3.3 to 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.
Impairment of Fertility
Tacrolimus, subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on a mg/m2 basis) or 3 mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in a dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) 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 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.
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 survivals were 96.1% and 89.6%, respectively.
Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7 to 20 ng/mL, and then between 5 to 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, multicenter trial (Study 1), 1,589 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 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) 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 (6.1)].
Table 20. Estimated Creatinine Clearance at 12 Months (Study 1)
|Group||eCLcr [mL/min] at Month 121|
|N||MEAN||SD||MEDIAN||Treatment Difference with Group C (99.2% CI 2 )|
|(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)|
|(D) Siro/MMF/CS/Daclizumab||399||56.2||27.4||57.3||-8.9 (-14.1, -3.9)|
|Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus|
1. 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 imputed 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.
2. Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)
|Group A N = 390||Group B N = 399||Group C N = 401||Group D N = 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 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% CI1)||15.8% (7.1%, 24.3%)||11.2% (2.7%, 19.5%)||–||26.0% (17.2%, 34.7%)|
|Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, and D = Siro/MMF/CS/Daclizumab|
1. 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 trial (Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4 to11 ng/mL through 1 year post-transplant.
Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1)
|Time||Median (P10 to P901 ) tacrolimus whole blood trough concentration range (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)|
1. 10 to 90th Percentile: 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 trial. 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 1 gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per 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 reactions.
Table 23. MMF Dose Over Time in Tacrolimus /MMF (Group C) (Study 1)
|Time period (Days)||Time-averaged MMF dose (grams per day)1|
|Less than 2.0||2.0||Greater than 2.0|
|0 to 30 (N=364)||37%||60%||2%|
|0 to 90 (N=373)||47%||51%||2%|
|0 to 180 (N=377)||56%||42%||2%|
|0 to 365 (N=380)||63%||36%||1%|
|Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)|
1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per 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, multicenter trial (Study 2), 424 kidney transplant patients received tacrolimus (N=212) or cyclosporine (N=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, 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%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression (Table 24).
Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)
|(N = 212)||(N = 212)|
|Overall Failure||32 (15.1%)||36 (17.0%)|
|Components of efficacy failure|
|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% CI1)||1.9% (-5.2%, 9.0%)|
1. 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 to 16 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 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.
Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2)
|Time||Median (P10 to P901) tacrolimus whole blood trough concentration range (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)|
1. 10 to 90th Percentile: 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 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1)].
Table 26. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)
|Time period (Days)||Time-averaged MMF dose (g/day)1|
|Less than 2.0||2.0||Greater than 2.0|
|0 to 30 (N=212)||25%||69%||6%|
|0 to 90 (N=212)||41%||53%||6%|
|0 to 180 (N=212)||52%||41%||7%|
|0 to 365 (N=212)||62%||34%||4%|
|Key: Time-averaged MMF dose=(total MMF dose)/(duration of treatment)|
1. Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time- averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods.
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