Tacrolimus

UDL Laboratories, Inc.
UDL Laboratories, Inc.

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING
• TACROLIMUS DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Mechanism of Action
  • Pharmacokinetics
• CLINICAL STUDIES
  • Liver Transplantation
  • Kidney Transplantation
• TACROLIMUS INDICATIONS AND USAGE
• TACROLIMUS CONTRAINDICATIONS
• WARNINGS
  • Post Transplant Diabetes Mellitus
  • Nephrotoxicity
  • Hyperkalemia
  • Neurotoxicity
  • Malignancy and Lymphoproliferative Disorders
  • Latent Viral Infections
  • Anaphylactic Reactions
• PRECAUTIONS
  • General
  • Renally and Hepatically Impaired Patients
  • Myocardial Hypertrophy
  • Information for Patients
  • Laboratory Tests
  • Drug Interactions
  • Drugs that May Alter Tacrolimus Concentrations
  • Other Drug Interactions
  • Carcinogenesis, Mutagenesis and Impairment of Fertility
  • Pregnancy
  • Nursing Mothers
  • Pediatric Patients
• TACROLIMUS ADVERSE REACTIONS
  • Liver Transplantation
  • Kidney Transplantation
  • Less Frequently Reported Adverse Reactions
  • Post-Marketing
• OVERDOSAGE
• TACROLIMUS DOSAGE AND ADMINISTRATION
  • Tacrolimus Capsules
  • Blood Concentration Monitoring
• HOW SUPPLIED:
• REFERENCE
• PRINCIPAL DISPLAY PANEL - 0.5 mg
• PRINCIPAL DISPLAY PANEL - 1 mg
• PRINCIPAL DISPLAY PANEL - 5 mg

FULL PRESCRIBING INFORMATION

TACROLIMUS DESCRIPTION

Tacrolimus capsules are available for oral administration as capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients in capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. In addition, the 0.5 mg capsules contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.

The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

Tacrolimus, previously known as FK506, is the active ingredient in tacrolimus capsules. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as (-)-(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-8-allyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl]-14,16-dimethyoxy-4,10,12,18-tetramethyl-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 C₄₄H₆₉NO₁₂•H₂O and a formula weight of 822.03. Tacrolimus appears as a white to off-white powder. It is insoluble in water, freely soluble in ethanol, very soluble in chloroform and soluble in methanol.

CLINICAL PHARMACOLOGY

Mechanism of Action

Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

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

Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant and liver transplant patients. (See table below.)

Population	N	Route (Dose)	Parameters
			Cmax (ng/mL)	Tmax (hr)	AUC (ng●hr/mL)	t½ (hr)	CI (L/hr/kg)	V (L/kg)
Healthy Volunteers	8	IV (0.025 mg/kg/ 4 hr)	not applicable	*	598AUC0-120 ± 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	243AUC0-72 ± 73	34.8 ± 11.4	0.041Corrected for individual bioavailability  ± 0.008	1.94§ ± 0.53
Kidney Transplant Patients	26	IV (0.02 mg/kg/12 hr)	*	*	294AUC0-inf ± 262	18.8 ± 16.7	0.083 ± 0.050	1.41 ± 0.66
		PO (0.2 mg/kg/day)	19.2 ± 10.3	3	203¶ ± 42	not available	#	#
		PO (0.3 mg/kg/day)	24.2 ± 15.8	1.5	288¶ ± 93	#	#	#
Liver Transplant Patients	17	IV (0.05 mg/kg/12 hr)	*	*	3,300¶ ± 2,130	11.7 ± 3.9	0.053 ± 0.017	0.85 ± 0.30
		PO (0.3 mg/kg/day)	68.5 ± 30	2.3 ± 1.5	519¶ ± 179	#	#	#

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION). Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17 ± 10% in adult kidney transplant patients (N = 26), 22 ± 6% in adult liver transplant patients (N = 17) and 18 ± 5% in healthy volunteers (N = 16).

A single-dose study conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose study in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (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 mg, 7 mg, and 10 mg.

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10 to 12 hours post-dose (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.

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_max 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 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_max (50 ± 19%), as compared to a fasted state.

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5 to 50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of eight 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 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 six healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus 0.172 ± 0.088 L/hr/kg.

Special Populations

Pediatric

Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to nine patients, mean AUC and C_max were 337 ± 167 ng·hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%.

Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations. (See DOSAGE AND ADMINISTRATION.)

Renal and Hepatic Insufficiency

The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in the following table.

Population (No. of Patients)	Dose	AUC0-t (ng·hr/mL)	t½ (hr)	V (L/kg)	CI (L/hr/kg)
Renal Impairment (n = 12)	0.02 mg/kg/4 hr IV	393 ± 123 (t = 60 hr)	26.3 ± 9.2	1.07 ± 0.20	0.038 ± 0.014
Mild Hepatic Impairment (n = 6)	0.02 mg/kg/4 hr IV	367 ± 107 (t = 72 hr)	60.6 ± 43.8 Range: 27.8 to 141	3.1 ± 1.6	0.042 ± 0.02
	7.7 mg PO	488 ± 320 (t = 72 hr)	66.1 ± 44.8 Range: 29.5 to 138	3.7 ± 4.7corrected for bioavailability	0.034 ± 0.019*
Severe Hepatic Impairment (n = 6, IV)	0.02 mg/kg/4 hr IV (n = 2)	762 ± 204 (t = 120 hr)	198 ± 158 Range: 81 to 436	3.9 ± 1	0.017 ± 0.013
	0.01 mg/kg/8 hr IV (n = 4)	289 ± 117 (t = 144 hr)
(n = 5, PO)one patient did not receive the PO dose	8 mg PO (n = 1)	658 (t = 120 hr)	119 ± 35 Range: 85 to 178	3.1 ± 3.4*	0.016 ± 0.011*
	5 mg PO (n = 4)	533 ± 156 (t = 144 hr)
	4 mg PO (n = 1)

Renal Insufficiency

Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (seven not on dialysis and five on dialysis, serum creatinine of 3.9 ± 1.6 and 12 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups.

The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (see previous table).

Hepatic Insufficiency

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in six patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration.

Race

A formal study to evaluate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted. However, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION.)

Gender

A formal study to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted; however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney and liver transplant patients indicated no gender-based differences.

CLINICAL STUDIES

Liver Transplantation

The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressive regimen. Both studies used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These studies were designed to evaluate whether the two regimens were therapeutically equivalent, with patient and graft survival at 12 months following transplantation as the primary endpoints. The tacrolimus-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive regimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used, while two 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 eight 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 one-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 one-year graft survival (CBIR and tacrolimus-based treatment groups combined) was 81% in the U.S. study and 73% in the European study. In both studies, the median time to convert from IV to oral tacrolimus dosing was 2 days.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

Kidney Transplantation

Tacrolimus/Azathioprine

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a Phase 3 randomized, multicenter, non-blinded, prospective study. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall one 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, 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 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%). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCL_cr) using the Cockcroft-Gault formula (Table 1) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 2) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen (see ADVERSE REACTIONS).

Table 1: Estimated Creatinine Clearance at 12 Months in Study 1

Group	eCLcr [mL/min] at Month 12All 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 imputed 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.
	N	MEAN	SD	MEDIAN	Treatment Difference with Group C (99.2% CIAdjusted for multiple (6) pairwise comparisons using Bonferroni corrections.)
(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	1,589	59.2	26.8	60.5
Key: CaA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, Siro = Sirolimus

Table 2: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 1

	A N = 390	B N = 399	C N = 401	D N = 399
Overall Failure	141 (36.2%)	126 (31.6%)	82 (20.4%)	185 (46.4%)
Components of efficacy failure
BPAR	113 (29%)	106 (26.6%)	60 (15%)	152 (38.1%)
Graft loss excluding death	28 (7.2%)	20 (5%)	12 (3%)	30 (7.5%)
Mortality	13 (3.3%)	7 (1.8%)	11 (2.7%)	12 (3%)
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% CIAdjusted for multiple (6) pairwise comparisons using Bonferroni corrections. )	15.8% (7.1%, 24.3%)	11.2% (2.7%, 19.5%)	-	26% (17.2%, 34.7%)
Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab and D = Siro/MMF/CS/Daclizumab

The protocol-specified target tacrolimus trough concentrations (C_trough, Tac) were 3 to 7 ng/mL; however, the observed median C_troughs, Tac approximated 7 ng/mL throughout the 12 month study (Table 3).

Table 3: Tacrolimus Whole Blood Trough Concentrations (Study 1)

Time	Median (P10 to P90Range of Ctrough , Tac that excludes lowest 10% and highest 10% of Ctrough, Tac) tacrolimus whole blood trough concentrations (ng/mL)
Day 30 (N = 366)	6.9 (4.4 to 11.3)
Day 90 (N = 351)	6.8 (4.1 to 10.7)
Day 180 (N = 355)	6.5 (4 to 9.6)
Day 365 (N = 346)	6.5 (3.8 to 10)

The protocol-specified target cyclosporine trough concentrations (C_trough, CsA) for Group B were 50 to 100 ng/mL; however, the observed median C_troughs, CsA approximated 100 ng/mL throughout the 12 month study. The protocol-specified target C_troughs, 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 C_troughs, 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 g BID, the MMF dose was reduced to < 2 g/day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 4); approximately 50% of these MMF dose reductions were due to adverse events. By comparison, the MMF dose was reduced to < 2 g/day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse events.

Table 4: MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)

Time period (Days)	Time-averaged MMF dose (g/day)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.
	< 2	2	> 2
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%
Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

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 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 overimmunosuppression (Table 5).

Table 5: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 2

	Tacrolimus/MMF (n = 212)	Cyclosporine/MMF (n = 212)
Overall Failure	32 (15.1%)	36 (17%)
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% CI95% confidence interval calculated using Fisher’s Exact Test )	-	1.9 (-5.2%, 9%)

The protocol-specified target tacrolimus whole blood trough concentrations (C_trough, Tac) in Study 2 were 7 to 16 ng/mL for the first 3 months and 5 to 15 ng/mL thereafter. The observed median C_troughs, Tac approximated 10 ng/mL during the first 3 months and 8 ng/mL from month 4 to month 12 (Table 6).

Table 6: Tacrolimus Whole Blood Trough Concentrations (Study 2)

Time	Median (P10 to P90Range of Ctrough , Tac that excludes lowest 10% and highest 10% of Ctrough, Tac) tacrolimus whole blood trough concentrations (ng/mL)
Day 30 (N = 174)	10.5 (6.3 to 16.8)
Day 60 (N = 179)	9.2 (5.9 to 15.3)
Day 120 (N = 176)	8.3 (4.6 to 13.3)
Day 180 (N = 171)	7.8 (5.5 to 13.2)
Day 365 (N = 178)	7.1 (4.2 to 12.4)

The protocol-specified target cyclosporine whole blood concentrations (C_trough, CsA) were 125 to 400 ng/mL for the first 3 months, and 100 to 300 ng/mL thereafter. The observed median C_troughs, CsA approximated 280 ng/mL during the first 3 months and 190 ng/mL from month 4 to month 12.

Patients in both groups started MMF at 1 g BID. The MMF dose was reduced to < 2 g/day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 7) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse events in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively.

Table 7: MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)

Time period (Days)	Time-averaged MMF dose (g/day)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.
	< 2	2	> 2
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%
Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

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 be used in conjunction with azathioprine or mycophenolate mofetil (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).

WARNINGS

(See boxed WARNING.)

Post Transplant Diabetes Mellitus

Insulin-dependent post transplant diabetes mellitus (PTDM) was reported in 20% of tacrolimus-treated kidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study (see Tables below). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM.

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in the Phase III Study

Status of PTDMuse of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.	Tacrolimus	CBIR
Patients without pretransplant history of diabetes mellitus.	151	151
New onset PTDM* , 1st Year	30/151 (20%)	6/151 (4%)
Still insulin dependent at one year in those without prior history of diabetes.	25/151 (17%)	5/151 (3%)
New onset PTDM* post one year	1	0
Patients with PTDM* at 2 years	16/151 (11%)	5/151 (3%)

Development of Post Transplant Diabetes Mellitus by Race and by Treatment Group During First Year Post Kidney Transplantation in the Phase III Study

Patient Race	Tacrolimus		CBIR
	No. of Patients at Risk	Patients Who Developed PTDM use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.	No. of Patients At Risk	Patients Who Developed PTDM*
Black	41	15 (37%)	36	3 (8%)
Hispanic	17	5 (29%)	18	1 (6%)
Caucasian	82	10 (12%)	87	1 (1%)
Other	11	0 (0%)	10	1 (10%)
Total	151	30 (20%)	151	6 (4%)

Insulin-dependent post transplant diabetes mellitus was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at one year post transplant, in the U.S. and European randomized studies, respectively (see Table below). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at One Year in Liver Transplant Recipients

Status of PTDM Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.	U.S. Study		European Study
	Tacrolimus	CBIR	Tacrolimus	CBIR
Patients at riskPatients without pretransplant history of diabetes mellitus.	239	236	239	249
New Onset PTDM*	42 (18%)	30 (13%)	26 (11%)	12 (5%)
Patients still on insulin at one year	23 (10%)	19 (8%)	18 (8%)	6 (2%)

Nephrotoxicity

Tacrolimus can cause nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials, respectively. More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, tacrolimus should not be used simultaneously with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Hyperkalemia

Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with tacrolimus in the U.S. and European randomized trials, respectively, and may require treatment (see ADVERSE REACTIONS). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during tacrolimus therapy (see PRECAUTIONS).

Neurotoxicity

Tacrolimus can cause neurotoxicity, particularly when used in high doses. Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in tacrolimus-treated kidney transplant patients (54%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving tacrolimus (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

Malignancy and Lymphoproliferative Disorders

As in patients receiving other immunosuppressants, patients receiving tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to tacrolimus following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

Latent Viral Infections

Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus. These infections may lead to serious, including fatal, outcomes.

Anaphylactic Reactions

A few patients receiving tacrolimus injection have experienced anaphylactic reactions. Although the exact cause of these reactions is not known, other drugs with castor oil derivatives in the formulation have been associated with anaphylaxis in a small percentage of patients. Because of this potential risk of anaphylaxis, tacrolimus injection should be reserved for patients who are unable to take tacrolimus capsules.

Patients receiving tacrolimus injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen.

PRECAUTIONS

General

Hypertension is a common adverse effect of tacrolimus therapy (see ADVERSE REACTIONS). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided. While calcium-channel blocking agents can be effective in treating tacrolimus-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions).

Renally and Hepatically Impaired Patients

For patients with renal insufficiency some evidence suggests that lower doses should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

The use of tacrolimus in liver transplant recipients experiencing post transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood levels of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients (see DOSAGE AND ADMINISTRATION).

Myocardial Hypertrophy

Myocardial hypertrophy has been reported in association with the administration of tacrolimus, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N = 10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N = 7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N = 3, age 37 to 53 years).

In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered.

Information for Patients

Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving tacrolimus. 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.

Laboratory Tests

Serum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metabolic and hematologic systems should be performed as clinically warranted.

Drug Interactions

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with the coadministration of tacrolimus and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to tacrolimus should receive the first tacrolimus dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels.

Drugs that May Alter Tacrolimus Concentrations

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.

This table is not all inclusive. Drugs That May Increase Tacrolimus Blood Concentrations

Calcium Channel Blockers	Antifungal Agents	Macrolide Antibiotics
diltiazem	clotrimazole	clarithromycin
nicardipine	fluconazole	erythromycin
nifedipine	itraconazole	troleandomycin
verapamil	ketoconazoleIn a study of six 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 coadministration, although it was highly variable between patients.
	voriconazole
Gastrointestinal Prokinetic Agents	Other Drugs
cisapride	bromocriptine
metoclopramide	chloramphenicol
	cimetidine
	cyclosporine
	danazol
	ethinyl estradiol
	methylprednisolone
	lansoprazoleLansoprazole (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.
	omeprazole
	protease inhibitors
	nefazodone
	magnesium-aluminum-hydroxide

This table is not all inclusive. Drugs That May Decrease Tacrolimus Blood Concentrations

Anticonvulsants	Antimicrobials
carbamazepine	rifabutin
phenobarbital	caspofungin
phenytoin	rifampin
Herbal Preparations	Other Drugs
St. John's Wort	sirolimus

St. John’s Wort (Hypericum perforatum) 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 could result in reduced tacrolimus levels.

In a single-dose crossover study in healthy volunteers, coadministration 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_max relative to tacrolimus administration alone.

In a study of six 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 five liver transplant recipients, coadministration 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 DOSAGE AND ADMINISTRATION).

Following coadministration of tacrolimus and sirolimus (2 or 5 mg/day) in stable renal transplant patients, mean tacrolimus AUC_0-12 and C_min decreased approximately by 30% relative to tacrolimus alone. Mean tacrolimus AUC_0-12 and C_min following coadministration 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.

Other Drug Interactions

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.¹

At a given MMF dose, mycophenolic acid (MPA) exposure is higher with tacrolimus coadministration than with cyclosporine coadministration 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.

Carcinogenesis, Mutagenesis and Impairment of Fertility

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 (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.

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 to 2.5 times (mice) and 3.5 to 7.1 times (rats) the recommended clinical dose range of 0.1 to 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 mg/kg (0.7 to 1.4X the recommended clinical dose range of 0.1 to 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 to 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.

Pregnancy

Teratogenic Effects. 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 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 to 1X and 1.6 to 3.3X the recommended clinical dose range (0.1 to 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 and 3.2 mg/kg (equivalent to 0.7 to 1.4X and 2.3 to 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.

Nursing Mothers

Since tacrolimus is excreted in human milk, nursing should be avoided.

Pediatric Patients

Experience with tacrolimus in pediatric kidney patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus. Two randomized active-controlled trials of tacrolimus in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).

TACROLIMUS ADVERSE REACTIONS

Liver Transplantation

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 WARNINGS).

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 post transplant 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 Less Frequently Reported Adverse Reactions below.

Kidney Transplantation

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

Study 1 was conducted entirely outside of the United States. Such studies often report a lower incidence of adverse events in comparison to U.S. 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 Less Frequently Reported Adverse Reactions shown below.

Less Frequently Reported Side Effects

The following adverse events were reported in either liver and/or kidney transplant recipients who were treated with tacrolimus in clinical trials.

Nervous System: (see WARNINGS): 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 WARNINGS): 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 PRECAUTIONS): 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

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 PRECAUTIONS: Myocardial Hypertrophy).

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, Torsades 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

Hemic/Lymphatic: Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Metabolic/Nutritional: 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.

OVERDOSAGE

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended 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 ADVERSE REACTIONS 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

NOTE: Anaphylactic reactions have occurred with injectables containing castor oil derivatives. See WARNINGS.

Tacrolimus Capsules

Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations

Patient Population	Recommended Initial Oral Dose Note: two divided doses, q12h	Typical Whole Blood Trough Concentrations
Adult kidney transplant patients      In combination with azathioprine	0.2 mg/kg/day	month 1 to 3: 7 to 20 ng/mL month 4 to 12: 5 to 15 ng/mL
In combination with MMF/IL-2      receptor antagonistIn a second smaller study, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 (see CLINICAL STUDIES).	0.1 mg/kg/day	month 1 to 12: 4 to 11 ng/mL
Adult liver transplant patients	0.10 to 0.15 mg/kg/day	month 1 to 12: 5 to 20 ng/mL
Pediatric liver transplant patients	0.15 to 0.20 mg/kg/day	month 1 to 12: 5 to 20 ng/mL

Liver Transplantation

It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. The initial dose of tacrolimus 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 to 12 hours after discontinuing the IV infusion. The recommended starting oral dose of tacrolimus capsules is 0.10 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Coadministered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations.)

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus 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 Blood Concentration Monitoring: Liver Transplantation below.

Kidney Transplantation

The recommended starting oral dose of tacrolimus (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 CLINICAL STUDIES). The initial dose of tacrolimus 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 Blood Concentration Monitoring: Kidney Transplantation 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.

Pediatric Patients

Pediatric liver transplantation patients without preexisting renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting IV dose of 0.03 to 0.05 mg/kg/day and a starting oral dose of 0.15 to 0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

Patients with Hepatic or Renal Dysfunction

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh ≥ 10) may require lower doses of tacrolimus. 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 postoperative oliguria.

Conversion from One Immunosuppressive Regimen to Another

Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Blood Concentration Monitoring

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 post transplant 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.

Liver Transplantation

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post transplant patients often are maintained at the low end of this target range.

Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post transplantation. After this early period, the median trough blood concentrations, measured at intervals from the second week to one year post transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

Kidney Transplantation

Data from a Phase 3 study of tacrolimus in conjunction with azathioprine indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx^® were most variable during the first week of dosing. 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 one year.

In a separate clinical trial of tacrolimus in conjunction with MMF and daclizumab, approximately 80% of patients maintained tacrolimus whole blood concentrations between 4 to 11 ng/mL through one year post transplant.

In another clinical trial of tacrolimus in conjunction with MMF and basiliximab, approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during month 1 to 3 and, then, between 5 to 12 ng/mL from month 4 through one year.

The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

HOW SUPPLIED:

Tacrolimus Capsules are available containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus.

The 0.5 mg capsule is a hard-shell gelatin capsule with a light orange opaque cap and a gray opaque body filled with white to off-white powder, axially printed with MYLAN over 2045 in black ink on both the cap and the body. They are available as follows:

NDC 51079-817-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).

The 1 mg capsule is a hard-shell gelatin capsule with a light blue opaque cap and a gray opaque body filled with white to off-white powder, axially printed with MYLAN over 2046 in black ink on both the cap and the body. They are available as follows:

NDC 51079-818-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).

The 5 mg capsule is a hard-shell gelatin capsule with a rubine red opaque cap and a gray opaque body filled with white to off-white powder, axially printed with MYLAN over 2047 in black ink on both the cap and the body. They are available as follows:

NDC 51079-028-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

REFERENCE

1. CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993; 42(RR-4):1-18.

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

Distributed by:
UDL Laboratories, Inc.
Rockford, IL 61103

S-10642
12/09

PRINCIPAL DISPLAY PANEL - 0.5 mg

NDC 51079-817-20

TACROLIMUS
CAPSULES
0.5 mg

100 Capsules (10 x 10)  

Each capsule contains:
Tacrolimus . . . . . . . . 0.5 mg

Usual Dosage: See accompanying
prescribing information.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

(Rx only)
S- 10643

Packaged and Distributed by:
UDL LABORATORIES, INC.
ROCKFORD, IL 61103

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

PRINCIPAL DISPLAY PANEL - 1 mg

NDC 51079-818-20

TACROLIMUS
CAPSULES
1 mg

100 Capsules (10 x 10)    

Each capsule contains:
Tacrolimus . . . . . . . . . 1 mg

Usual Dosage: See accompanying
prescribing information.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Protect from light.

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 

(Rx only)
S-10644

Packaged and Distributed by:
UDL LABORATORIES, INC.
ROCKFORD, IL 61103

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

PRINCIPAL DISPLAY PANEL - 5 mg

NDC 51079-028-20

TACROLIMUS
CAPSULES
5 mg

100 Capsules (10 x 10)   

Each capsule contains:
Tacrolimus . . . . . . . . . 5 mg

Usual Dosage: See accompanying
prescribing information.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

(Rx only)
S-10645

Packaged and Distributed by:
UDL LABORATORIES, INC.
ROCKFORD, IL 61103

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.