Tacrolimus Information
Tacrolimus () Description
Tacrolimus () capsules are available for oral administration containing the equivalent of 0.5 mg,1 mg or 5 mg of anhydrous Tacrolimus () . Inactive ingredients include croscarmellose sodium, lactose monohydrate and magnesium stearate.
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 [3-[3*[(1*,3*,4*)], 4*, 5*,8*,9,12*,14*,15*,16*,18*,19*,26a*]]-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 a molecular formula of CHNO•HO and a formula weight of 822.03. Tacrolimus () appears as white to off white powder. It is practically insoluble in water and soluble in methanol, ethanol, acetone, ethyl acetate, chloroform.
Tacrolimus () Clinical Pharmacology
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).
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 below).
a) not applicable
b) AUC
c) AUC
d) Corrected for individual bioavailability
e) Auc
f) not available
Due to intersubject variability in Tacrolimus () pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See ). 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 (C) 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) 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 C were decreased 37% and 77%, respectively; T was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C 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 was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean C 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 C(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 5-50 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.
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 C 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 ).
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.
a) corrected for bioavailability
b) 1 patient did not receive the PO dose
Renal Insufficiency
The mean clearance of Tacrolimus () in patients with renal dysfunction was similar to that in normal volunteers (see ).
Hepatic Insufficiency
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
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.
Tacrolimus () Clinical Studies
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.
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 () and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up () 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 ).
Table 1: Estimated Creatinine Clearance at 12 Months in Study 1
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
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) pair wise comparisons using Bonferroni corrections.
The protocol-specified target Tacrolimus () trough concentrations (C,Tac) were 3-7 ng/mL; however, the observed median C,Tac approximated 7 ng/mL throughout the 12 month study ().
Table 3: Tacrolimus () Whole Blood Trough Concentrations (Study 1)
a) Range of C, Tac that excludes lowest 10% and highest 10% of C, Tac
The protocol-specified target cyclosporine trough concentrations (C,CsA) for Group B were 50-100 ng/mL; however, the observed median C,CsA approximated 100 ng/mL throughout the 12 month study. The protocol-specified target C,CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C, 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
Table 4: MMF Dose Over Time in Tacrolimus () /MMF (Group C) (Study 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: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 2
a) 95% confidence interval calculated using Fisher's Exact Test
The protocol-specified target Tacrolimus () whole blood trough concentrations (C,Tac) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 ().
Table 6: Tacrolimus () Whole Blood Trough Concentrations (Study 2)
a) Range of C,Tac that excludes lowest 10% and highest 10% of C, Tac
The protocol-specified target cyclosporine whole blood concentrations (C,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C, 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
Table 7: MMF Dose Over Time in the Tacrolimus () /MMF group (Study 2)
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.
Tacrolimus () Indications And Usage
Tacrolimus () capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. It is recommended that Tacrolimus () capsules be used concomitantly with adrenal corticosteroids. In kidney transplant recipients, it is recommended that Tacrolimus () capsules be used in conjunction with azathiprine or mycophenolate moeftil (MMF).
Tacrolimus () Contraindications
Tacrolimus () capsules are 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).
Tacrolimus () Warnings
(See .)
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 ). 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
a) use of insulin for 30 or more consecutive days, with
Development of Post Transplant Diabetes Mellitus by Race and by Treatment Group during First Year Post Kidney Transplantation in the Phase III study
a
Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients
a) use of insulin for 30 or more consecutive days, with
b) Patients without pretransplant history of diabetes mellitus.
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 ). 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 () capsules (see ). 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.
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.
Tacrolimus () Precautions
For patients with renal insufficiency some evidence suggests that lower doses should be used (see and ).
The use of Tacrolimus () capsules 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 ).
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.
Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving Tacrolimus () capsules. They should be given complete dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Patients should be informed that changes in dosage should not be undertaken without first consulting their physician.
Patients should be informed that Tacrolimus () can cause diabetes mellitus and should be advised of the need to see their physician if they develop frequent urination, increased thirst or hunger.
As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Since Tacrolimus () is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of Tacrolimus () as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of Tacrolimus () or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.
a) This table is not all inclusive
b) In a study of 6 normal volunteers, a significant increase in Tacrolimus () oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of Tacrolimus () during ketoconazole administration was significantly decreased compared to Tacrolimus () alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of Tacrolimus () was not significantly changed by ketoconazole co-administration, although it was highly variable between patients.
c) Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of Tacrolimus () and thereby substantially increase Tacrolimus () whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.
a) This table is not all inclusive
St. John’s Wort () induces CYP3A4 and P-glycoprotein. Since Tacrolimus () is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving Tacrolimus () capsules could result in reduced Tacrolimus () levels.
In a single-dose crossover study in healthy volunteers, co-administration of Tacrolimus () and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean Tacrolimus () AUC and a 10% decrease in the mean Tacrolimus () C relative to Tacrolimus () administration alone.
In a study of 6 normal volunteers, a significant decrease in Tacrolimus () oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in Tacrolimus () clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration.
Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., nelfinavir, ritonavir) are administered concomitantly with Tacrolimus () . Based on a clinical study of 5 liver transplant recipients, co-administration of Tacrolimus () with nelfinavir increased blood concentrations of Tacrolimus () significantly and, as a result, a reduction in the Tacrolimus () dose by an average of 16-fold was needed to maintain mean trough Tacrolimus () blood concentrations of 9.7 ng/mL. Thus, frequent monitoring of Tacrolimus () blood concentrations and appropriate dosage adjustments are essential when nelfinavir is used concomitantly. Tacrolimus () may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (see ).
Following co-administration of Tacrolimus () and sirolimus (2 or 5 mg/day) in stable renal transplant patients, mean Tacrolimus () AUC and C decreased approximately by 30% relative to Tacrolimus () alone. Mean Tacrolimus () AUCand C following co-administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. The safety and efficacy of Tacrolimus () used in combination with sirolimus for the prevention of graft rejection has not been established and is not recommended.
Immunosuppressants may affect vaccination. Therefore, during treatment with Tacrolimus () , vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.
At a given MMF dose, mycophenolic acid (MPA) exposure is higher with Tacrolimus () co-administration than with cyclosporine co-administration due to the differences in the interruption of the enterohepatic recirculation of MPA. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Tacrolimus () in patients concomitantly receiving MMF or MPA.
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin’s lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in Tacrolimus () recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.
No evidence of genotoxicity was seen in bacterial ( and ) 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.
Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to Tacrolimus () dosage was found. The highest doses used in the mouse and rat studies were 0.8 – 2.5 times (mice) and 3.5 – 7.1 times (rats) the recommended clinical dose range of 0.1 – 0.2 mg/kg/day when corrected for body surface area.
No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus () , given orally at 1.0 mg/kg (0.7 – 1.4X the recommended clinical dose range of 0.1 – 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with 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 (2.3 – 4.6X the recommended clinical dose range based on body surface area correction), 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.
Category C:
In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus () at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 – 1X and 1.6 – 3.3X the recommended clinical dose range (0.1 – 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus () , at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus () , given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 – 1.4X and 2.3 – 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.
No reduction in male or female fertility was evident.
There are no adequate and well-controlled studies in pregnant women. Tacrolimus () is transferred across the placenta. The use of Tacrolimus () during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus () should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.
Tacrolimus () Adverse Reactions
The principal adverse reactions of Tacrolimus () are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of Tacrolimus () and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.
Hyperkalemia and hypomagnesemia have occurred in patients receiving Tacrolimus () therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see ).
The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving Tacrolimus () and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the Tacrolimus () group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month posttransplant information from the U.S. study and from the European study is presented below. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in ≥ 15% in Tacrolimus () patients (combined study results) are presented below for the two controlled trials in liver transplantation:
Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection below.
The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia.
Adverse events that occurred in ≥ 15% of kidney transplant patients treated with Tacrolimus () in conjunction with azathioprine are presented below.
Adverse events that occurred in ≥ 10% of kidney transplant patients treated with Tacrolimus () in conjunction with MMF in Study 1* are presented below:
* Study 1 was conducted entirely outside of the United States. Such studies often report a lower incidence of adverse events in comparison to US studies.
Adverse events that occurred in ≥15% of kidney transplant patients treated with Tacrolimus () in conjunction with MMF in Study 2 are presented below:
Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection shown below.
The following adverse events were reported in either liver or kidney transplant recipients who were treated with Tacrolimus () in clinical trials.
Nervous System (see
Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired
Special Senses
Abnormal vision, amblyopia, ear pain, otitis media, tinnitus
Gastrointestinal
Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting
Cardiovascular
Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, chest pain, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
Urogenital (see )
Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis
Metabolic/ Nutritional
Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain
Endocrine (see )
Cushing’s syndrome, diabetes mellitus
Hemic/Lymphatic
Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia
Miscellaneous
Abdomen enlarged, abdominal pain, abscess, accidental injury, allergic reaction, asthenia, back pain, cellulitis, chills, fall, feeling abnormal, fever, flu syndrome, generalized edema, hernia, mobility decreased, pain, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
Musculoskeletal
Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis
Respiratory
Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration
Skin
Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating.
Post Marketing Adverse Events
The following adverse events have been reported from worldwide marketing experience with Tacrolimus () . Because these events are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving Tacrolimus () therapy (see ).
Other events include:
Cardiovascular
Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation
Gastrointestinal
Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease
HemicLymphatic
Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura
MetabolicNutritional
Glycosuria, increased amylase including pancreatitis, weight decreased
Miscellaneous
Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction
Nervous System
Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope
Respiratory
Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure
Skin
Stevens-Johnson syndrome, toxic epidermal necrolysis
Special Senses
Blindness, blindness cortical, hearing loss including deafness, photophobia
Urogenital
Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder.
Tacrolimus () Overdosage
dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that Tacrolimus () is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52X the recommended human oral dose; in immature rats, 16X the recommended oral dose; and in adult rats, 16X the recommended human IV dose (all based on body surface area corrections).
Tacrolimus () Dosage And Administration
Array
Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations
a) Note: two divided doses, q12h
b) In a second smaller study, the initial dose of Tacrolimus () was 0.15-0.2 mg/kg/day and observed Tacrolimus () concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12 (see ).
It is recommended that patients initiate oral therapy with Tacrolimus () capsules if possible. If IV therapy is necessary, conversion from IV to oral Tacrolimus () capsules are recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Tacrolimus () capsules should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting oral dose of Tacrolimus () capsules are 0.10 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Co-administered grapefruit juice has been reported to increase Tacrolimus () blood trough concentrations in liver transplant patients. (See
Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Tacrolimus () capsules dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.
Dosage and typical Tacrolimus () whole blood trough concentrations are shown in the table above; blood concentration details are described in below.
The recommended starting oral dose of Tacrolimus () capsules (administered every 12 hours in two divided doses) is 0.2 mg/kg/day when used in combination with azathioprine or 0.1 mg/kg/day when used in combination with MMF and IL-2 receptor antagonist (see ). The initial dose of Tacrolimus () capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine ≤ 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical Tacrolimus () whole blood trough concentrations are shown in the table above; blood concentration details are described in below.
The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.
Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh ≥ 10) may require lower doses of Tacrolimus () capsules. Close monitoring of blood concentrations is warranted.
Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended IV and oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus () therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.
Monitoring of Tacrolimus () blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the posttransplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies.
Two methods have been used for the assay of Tacrolimus () , a microparticle enzyme immunoassay (MEIA) and ELISA. Both methods have the same monoclonal antibody for Tacrolimus () . Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.
Tacrolimus () How Supplied
Tacrolimus () capsules, 0.5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, dark yellow opaque cap imprinted with ‘0.5MG’ and dark yellow opaque body imprinted with ‘RDY 525’ using red ink and are supplied in unit dose packages of 100 (10 x 10).
Unit dose packages of 100 (10 x 10) NDC 68084-449-01
Tacrolimus () capsules, 1 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, white opaque cap imprinted with ‘1MG’ and white opaque body imprinted with ‘RDY 526’ using red ink and are supplied in unit dose packages of 100 (10 x 10).
Unit dose packages of 100 (10 x 10) NDC 68084-450-01
Tacrolimus () capsules, 5 mg are white to off white powder filled in hard gelatin capsule of size ‘4’, dark grayish red opaque cap imprinted with ‘5MG’ and dark grayish red opaque body imprinted with ‘RDY 527’ using white ink and are supplied in unit dose packages of 100 (10 x 10).
Unit dose packages of 100 (10 x 10) NDC 68084-451-01
Tacrolimus ()
Tacrolimus () Package Label.principal Display Panel Sectio - . Mg
Tacrolimus () Package Label.principal Display Panel Section - Mg
Tacrolimus () Package Label.principal Display Panel Section - Mg
