tacrolimus (tacrolimus 0.5 mg) Dailymed

1 Indications And Usage

Tacrolimus capsules are a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver, kidney or heart transplants, and pediatric patients receiving allogeneic liver transplants in combination with other immunosuppressants. (1.1)

1.1 Prophylaxis of Organ Rejection in Kidney, Liver, or Heart Transplant

Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult patients receiving allogeneic kidney transplant [see Clinical Studies (14.1)], liver transplant [see Clinical Studies (14.2)] and heart transplant [see Clinical Studies (14.3)], and pediatric patients receiving allogeneic liver transplants [see Clinical Studies (14.2)] in combination with other immunosuppressants.

Additional pediatric use and lung transplant information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2 Dosage And Administration

• •Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules). (2.1, 2.2)
• •Administer capsules consistently with or without food. (2.1)
• •Therapeutic drug monitoring is recommended. (2.1, 2.6)
• •Avoid eating grapefruit or drinking grapefruit juice. (2.1)
• •See dosage adjustments for African-American patients (2.2), hepatic and renal impaired. (2.4, 2.5) For complete dosing information, see the Full Prescribing Information

ADULT
Patient Population		Initial Oral Dosage	Whole Blood Trough Concentration Range
Kidney Transplant
With azathioprine	0.2 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL
With MMF/IL-2 receptor antagonist	0.1 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 12: 4 to 11 ng/mL
Liver Transplant
With corticosteroids only	0.1 to 0.15 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 12: 5 to 20 ng/mL
Heart Transplant
With azathioprine or MMF	0.075 mg/kg/day capsules, divided in two doses, every 12 hours		Month 1 to 3: 10 to 20 ng/mL Month ≥ 4: 5 to 15 ng/mL
PEDIATRIC
Patient Population		Initial Oral Dosage	Whole Blood Trough Concentration Range
Liver Transplant
	0.15 to 0.2 mg/kg/day capsules divided in two doses, every 12 hours		Month 1 to 12: 5 to 20 ng/mL

MMF= Mycophenolate mofetil

2.1 Important Administration Instructions

Tacrolimus capsules should not be used without supervision by a physician with experience in immunosuppressive therapy.

Tacrolimus capsules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision [see Warnings and Precautions (5.3)].

Intravenous Formulation - Administration Precautions due to Risk of Anaphylaxis

Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to oral tacrolimus is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions (5.9)].

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.

Oral Formulation (Capsules)

If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus capsules may be taken with or without food. However, since the presence of food affects the bioavailability of tacrolimus capsules, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology (12.3)].

General Administration Instructions

Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)].

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.

Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration (2.6)].

2.2 Dosage Recommendations for Adult Kidney, Liver, or Heart Transplant Patients Capsules and Injection

Capsules

If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of tacrolimus capsules should be administered no sooner than 6 hours after transplantation in the liver or heart transplant patients. In kidney transplant patients, the initial dose of tacrolimus capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered.

The initial oral tacrolimus capsules dosage recommendations for adult patients with kidney, liver, or heart transplants and whole blood trough concentration range are shown in Table 1. Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges uled in Table 1.

Table 1. Summary of Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults
With AzathioprineWith MMF/IL-2 receptor antagonist ^† With corticosteroids only With azathioprine or MMF

Patient Population	Tacrolimus Capsules* Initial Oral Dosage	Whole Blood Trough Concentration Range
Kidney Transplant
0.2 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL
0.1 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 12: 4 to 11 ng/mL
Liver Transplant
0.10 to 0.15 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 12: 5 to 20 ng/mL
Heart Transplant
0.075 mg/kg/day, divided in two doses, administered every 12 hours	Month 1 to 3: 10 to 20 ng/mL Month ≥ 4: 5 to 15 ng/mL

^* African-American patients may require higher doses compared to Caucasians (see Table 2).

^† In a second smaller trial, 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 (14.1)].

Dosage should be titrated based on clinical assessments of rejection and tolerability. Tacrolimus capsules dosages lower than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

The data in kidney transplant patients indicate that the African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2) [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].

Table 2. Comparative Dose and Trough Concentrations Based on Race

Time After Transplant	Caucasian N = 114		African-American N = 56
	Dose (mg/kg)	Trough Concentrations (ng/mL)	Dose (mg/kg)	Trough Concentrations (ng/mL)
Day 7	0.18	12	0.23	10.9
Month 1	0.17	12.8	0.26	12.9
Month 6	0.14	11.8	0.24	11.5
Month 12	0.13	10.1	0.19	11

Intravenous Injection

Tacrolimus injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of tacrolimus capsules should be given 8 to 12 hours after discontinuing the intravenous infusion.

The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney or liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous intravenous infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

The whole blood trough concentration range described in Table 1 pertains to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous intravenous infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions (5.9)].

2.3 Dosage Recommendations for Pediatric Liver Transplant Patients

Oral formulation (capsules)

Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges uled in Table 3.

Table 3. Summary of Initial Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Children

Patient Population	Initial Tacrolimus Capsules Dosing	Whole Blood Trough Concentration Range
Pediatric liver transplant patients *,†	0.15 to 0.2 mg/kg/day capsules divided in two doses, administered every 12 hours	Month 1 to 12: 5 to 20 ng/mL

^* See Clinical Studies (14.2), Liver Transplantation.

^† Dose at 0.1 mg/kg/day if antibody induction treatment is administered.

For conversion of pediatric patients from tacrolimus for oral suspension to tacrolimus capsules or from tacrolimus capsules to tacrolimus for oral suspension, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6)].

Intravenous Injection

If a patient is unable to receive an oral formulation, the patient may be started on tacrolimus injection. For pediatric liver transplant patients, the intravenous dose is 0.03 to 0.05 mg/kg/day.

Additional pediatric use and lung transplant information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.4 Dosage Modification for Patients with Renal Impairment

Due to its potential for nephrotoxicity, consider dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant, and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.5 Dosage Modification for Patients with Hepatic Impairment

Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥ 10) may require lower doses of tacrolimus capsules. Close monitoring of blood concentrations is warranted.

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 concentrations 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 (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

2.6 Therapeutic Drug 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. Whole blood trough concentration range can be found in Table 1.

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. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

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.

Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as the parent compound. Therefore, assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. 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) anticoagulant. Heparin anticoagulation 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; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20°C. One study showed drug recovery > 90% for samples stored at -20°C for 6 months, with reduced recovery observed after 6 months.

Additional pediatric use and lung transplant information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• •Lymphoma and Other Malignancies [see Warnings and Precautions (5.1)]
• •Serious Infections [see Warnings and Precautions (5.2)]
• •New Onset Diabetes After Transplant [see Warnings and Precautions (5.4)]
• •Nephrotoxicity [see Warnings and Precautions (5.5)]
• •Neurotoxicity [see Warnings and Precautions (5.6)]
• •Hyperkalemia [see Warnings and Precautions (5.7)]
• •Hypertension [see Warnings and Precautions (5.8)]
• •Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions (5.9)]
• •Myocardial Hypertrophy [see Warnings and Precautions (5.13)]
• •Pure Red Cell Aplasia [see Warnings and Precautions (5.15)]
• •Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.16)]

The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on tacrolimus and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below.

The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:
TremorHeadacheInsomniaParesthesiaDizzinessDiarrheaNauseaConstipationVomitingDyspepsiaHypertensionChest PainCreatinine IncreasedUrinary Tract InfectionHypophosphatemiaHypomagnesemiaHyperlipemiaHyperkalemiaDiabetes MellitusHypokalemiaHyperglycemiaEdemaAnemiaLeukopeniaInfectionPeripheral EdemaAstheniaAbdominal PainPainFeverBack PainDyspneaCough IncreasedArthralgiaRashPruritus

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

	Tacrolimus/AZA (N = 205)	Cyclosporine/AZA (N = 207)
Nervous System
54%	34%
44%	38%
32%	30%
23%	16%
19%	16%
Gastrointestinal
44%	41%
38%	36%
35%	43%
29%	23%
28%	20%
Cardiovascular
50%	52%
19%	13%
Urogenital
45%	42%
34%	35%
Metabolic and Nutritional
49%	53%
34%	17%
31%	38%
31%	32%
24%	9%
22%	25%
22%	16%
18%	19%
Hemic and Lymphatic
30%	24%
15%	17%
Miscellaneous
45%	49%
36%	48%
34%	30%
33%	31%
32%	30%
29%	29%
24%	20%
Respiratory System
22%	18%
18%	15%
Musculoskeletal
25%	24%
Skin
17%	12%
15%	7%

 

Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)

	Tacrolimus (Group C) (N = 403)	Cyclosporine (Group A) (N = 384)	Cyclosporine (Group B) (N = 408)
Diarrhea	25%	16%	13%
Urinary Tract Infection	24%	28%	24%
Anemia	17%	19%	17%
Hypertension	13%	14%	12%
Leukopenia	13%	10%	10%
Edema Peripheral	11%	12%	13%
Hyperlipidemia	10%	15%	13%
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab
CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

 

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:
DiarrheaNauseaConstipationVomitingDyspepsiaPost-Procedural PainIncision Site ComplicationGraft DysfunctionHypomagnesemiaHypophosphatemiaHyperkalemiaHyperglycemiaHyperlipidemiaHypokalemiaTremorHeadacheAnemiaLeukopeniaEdema PeripheralHypertensionInsomniaUrinary Tract InfectionBlood Creatinine Increased

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)

	Tacrolimus/MMF (N = 212)	Cyclosporine/MMF (N = 212)
Gastrointestinal Disorders
44%	26%
39%	47%
36%	41%
26%	25%
18%	15%
Injury, Poisoning, and Procedural Complications
29%	27%
28%	23%
24%	18%
Metabolism and Nutrition Disorders
28%	22%
28%	21%
26%	19%
21%	15%
18%	25%
16%	18%
Nervous System Disorders
34%	20%
24%	25%
Blood and Lymphatic System Disorders
30%	28%
16%	12%
Miscellaneous
35%	46%
32%	35%
30%	21%
26%	22%
23%	23%

Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥ 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥ 38%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials.
HeadacheInsomniaTremorParesthesiaDiarrheaNauseaLFT AbnormalAnorexiaVomitingConstipationHypertensionKidney Function AbnormalCreatinine IncreasedBUN IncreasedOliguriaUrinary Tract InfectionHypomagnesemiaHyperglycemiaHyperkalemiaHypokalemiaAnemiaLeukocytosisThrombocytopeniaPainAbdominal PainAstheniaFeverBack PainAscitesPeripheral EdemaPleural EffusionDyspneaAtelectasisPruritusRash

Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus

	U.S. TRIAL		EUROPEAN TRIAL
	Tacrolimus (N = 250)	Cyclosporine/AZA (N = 250)	Tacrolimus (N = 264)	Cyclosporine/AZA (N = 265)
Nervous System
64%	60%	37%	26%
64%	68%	32%	23%
56%	46%	48%	32%
40%	30%	17%	17%
Gastrointestinal
72%	47%	37%	27%
46%	37%	32%	27%
36%	30%	6%	5%
34%	24%	7%	5%
27%	15%	14%	11%
24%	27%	23%	21%
Cardiovascular
47%	56%	38%	43%
Urogenital
40%	27%	36%	23%
39%	25%	24%	19%
30%	22%	12%	9%
18%	15%	19%	12%
16%	18%	21%	19%
Metabolic and Nutritional
48%	45%	16%	9%
47%	38%	33%	22%
45%	26%	13%	9%
29%	34%	13%	16%
Hemic and Lymphatic
47%	38%	5%	1%
32%	26%	8%	8%
24%	20%	14%	19%
Miscellaneous
63%	57%	24%	22%
59%	54%	29%	22%
52%	48%	11%	7%
48%	56%	19%	22%
30%	29%	17%	17%
27%	22%	7%	8%
26%	26%	12%	14%
Respiratory System
30%	32%	36%	35%
29%	23%	5%	4%
28%	30%	5%	4%
Skin and Appendages
36%	20%	15%	7%
24%	19%	10%	4%

Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with tacrolimus (n = 157) or cyclosporine (n = 157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%).

The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

Adverse reactions in heart transplant patients in the European trial are presented below:
HypertensionPericardial EffusionCMV InfectionInfectionDiabetes MellitusHyperglycemiaHyperlipemiaAnemiaLeukopeniaKidney Function AbnormalUrinary Tract InfectionBronchitis Tremor

Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

	Tacrolimus/AZA (N = 157)	Cyclosporine/AZA (N = 157)
Cardiovascular System
62%	69%
15%	14%
Body as a Whole
32%	30%
24%	21%
Metabolic and Nutritional Disorders
26%	16%
23%	17%
18%	27%
Hemic and Lymphatic System
50%	36%
48%	39%
Urogenital System
56%	57%
16%	12%
Respiratory System
17%	18%
Nervous System
15%	6%

In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 ng/mL to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 ng/mL to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.

In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%).

Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin < 10 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs < 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium < 1.2 mEq/L (24%), platelet count < 75,000 cells/mcL (19%), and other opportunistic infections (15%).

Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.”

New Onset Diabetes After Transplant

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥ 126 mg/dL, HbA_1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1)].

Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)
Fasting Plasma Glucose ≥ 126 mg/dLHbA_1C ≥ 6%Insulin Use ≥ 30 daysOral Hypoglycemic Use

Parameter	Treatment Group
	Tacrolimus/MMF (N = 212)	NEORAL/MMF (N = 212)
NODAT	112/150 (75%)	93/152 (61%)
96/150 (64%)	80/152 (53%)
59/150 (39%)	28/152 (18%)
9/150 (6%)	4/152 (3%)
15/150 (10%)	5/152 (3%)

 

In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5-day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). 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. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).

Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)
Patients without pre-transplant history of diabetes mellitusNew onset PTDM^*, 1^st YearStill insulin-dependent at one year in those without prior history of diabetesNew onset PTDM^* post 1 yearPatients with PTDM^* at 2 years

Status of PTDM*	Tacrolimus /AZA	CsA/AZA
151	151
30/151 (20%)	6/151 (4%)
25/151 (17%)	5/151 (3%)
1	0
16/151 (11%)	5/151 (3%)

^*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.

Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial

Patient Race	Patients Who Developed PTDM*
	Tacrolimus	Cyclosporine
African-American	15/41 (37%)	3 (8%)
Hispanic	5/17 (29%)	1 (6%)
Caucasian	10/82 (12%)	1 (1%)
Other	0/11 (0%)	1 (10%)
Total	30/151 (20%)	6 (4%)

^*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.

Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

Status of PTDM*	US Trial		European Trial
	Tacrolimus	Cyclosporine	Tacrolimus	Cyclosporine
Patients at risk†	239	236	239	249
New Onset PTDM*	42 (18%)	30 (13%)	26 (11%)	12 (5%)
Patients still on insulin at 1 year	23 (10%)	19 (8%)	18 (8%)	6 (2%)

*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.

†Patients without pre-transplant history of diabetes mellitus.

Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels ≥126 mg/dL, was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients

Status of PTDM*	US Trial		European Trial
	Tacrolimus/MMF	Cyclosporine/MMF	Tacrolimus/AZA	Cyclosporine/AZA
Patients at risk†	75	83	132	138
New Onset PTDM*	10 (13%)	6 (7%)	29 (22%)	5 (4%)
Patients still on insulin at 1 year‡	7 (9%)	1 (1%)	24 (18%)	4 (3%)

^*Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

^†Patients without pre-transplant history of diabetes mellitus.

^‡7 to 12 months for the U.S. trial.

Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies

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

• •Nervous System: Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired
• •Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus
• •Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis
• •Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
• •Urogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, 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, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain
• •Endocrine: Cushing’s syndrome
• •Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased
• •Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
• •Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis
• •Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration
• •Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating

Additional pediatric use and lung transplant information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

6.2 Postmarketing Experience

The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

Other reactions include:

• •Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsades de pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy
• •Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease
• •Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy
• •Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy (PVAN) including graft loss
• •Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased
• •Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction
• •Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)
• •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, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia
• •Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome