TACROLIMUS

Tacrolimus Capsules, USP are available for oral administration as capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include anhydrous lactose NF DT, hypromellose USP, croscarmellose sodium NF, and magnesium stearate NF. The 0.5 mg capsule shell contains gelatin, titanium dioxide and yellow iron oxide, the 1 mg capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and red iron oxide. Non-volatile components of the ink are Shellac Glaze, Iron Oxide Red, and Simethicone USP. Tacrolimus USP, previously known as FK506, is the active ingredient in tacrolimus capsules, USP. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S [3R* [E (1S*, 3S* 4S*)], 4S*, 5R*, 8S*, 9E, 12R* 14R* 15S* 16R* 18S* 19S* 26aR*]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus has an empirical formula of C 44 H 69 NO 12 •H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. USP Dissolution Test 6 is used. USP Organic Impurities Procedure 2 is used. chemicalstructure

Tacrolimus is a calcineurin-inhibitor immunosuppressant indicated for • Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants ( 1.1 , 1.2 , 1.3 ) • Use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF) ( 1.1 , 1.2 , 1.3 ) • Limitations of Use ( 1.4 ): • Do not use simultaneously with cyclosporine • Intravenous use reserved for patients who can not tolerate capsules orally • Use with sirolimus is not recommended in liver and heart transplant; use with sirolimus in kidney transplant has not been established 1.1 Prophylaxis of Organ Rejection in Kidney Transplant Tacrolimus Capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that tacrolimus be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [ see Clinical Studies ( 14.1 )] . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus [ see Dosage and Administration ( 2.6 )]. 1.2 Prophylaxis of Organ Rejection in Liver Transplant Tacrolimus Capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that tacrolimus be used concomitantly with adrenal corticosteroids [ see Clinical Studies ( 14.2 )]. Therapeutic drug monitoring is recommended for all patients receiving tacrolimus[ see Dosage and Administration ( 2.6 )]. 1.3 Prophylaxis of Organ Rejection in Heart Transplant Tacrolimus Capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that tacrolimus capsules be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [ see Clinical Studies ( 14.3 )]. Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules [ see Dosage and Administration ( 2.6 )]. 1.4 Limitations of Use Tacrolimus Capsules should not be used simultaneously with cyclosporine [ see Dosage and Administration ( 2.5 )]. Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of tacrolimus with sirolimus has not been established in kidney transplant [ see Warnings and Precautions ( 5.12 )]. Intravenous use reserved for patients who cannot tolerate capsules orally.

Summary of Initial Oral Dosage Recommendation and Observed Whole Blood Trough Concentrations ( 2.1 , 2.2 ) Patient Population Recommended Tacrolimus Initial Oral Dosage (two divided doses every 12 hours) Observed Whole Blood Trough Concentrations Adult Kidney transplant patients In combination with azathioprine 0.2 mg/kg/day month 1-3: 7-20 ng/mL month 4-12: 5-15 ng/mL In combination with MMF/IL-2 receptor antagonist 0.1 mg/kg/day month 1-12: 4-11 ng/mL Adult Liver transplant 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL Pediatric Liver transplant 0.15-0.20 mg/kg/day month 1-12: 5-20 ng/mL Adult Heart transplant 0.075 mg/kg/day month 1-3: 10-20 ng/mL month ≥4: 5-15 ng/mL • Careful and frequent monitoring of tacrolimus trough concentrations is recommended; Black patients may require higher doses in order to achieve comparable trough concentrations ( 2.1 ) • Hepatic/Renal impaired patients should receive doses at the lowest value of the recommended initial oral dosing range ( 2.3 , 2.4 ) • Administer capsules consistently with or without food; do not drink grapefruit juice ( 2.5 , 7.2 ) 2.1 Dosage in Adult Kidney, Liver or Heart Transplant Patients The initial oral dosage recommendations for adult patients with kidney, liver or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation in the liver and heart transplant patients. In kidney transplant patients, the initial dose of tacrolimus may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details [ see Dosage and Administration ( 2.6 )] Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults Patient Population Recommended Tacrolimus Initial Oral Dosage Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients month 1-3: 7-20 ng/mL In combination with azathioprine 0.2 mg/kg/day month 4-12: 5-15 ng/mL In combination with MMF/IL-2 receptor antagonist a 0.1 mg/kg/day month 1-12: 4-11 ng/mL Adult liver transplant patients 0.10-0.15 mg/kg/day month 1-12: 5-20 ng/mL Adult heart transplant patients 0.075 mg/kg/day month 1-3: 10-20 ng/mL month ≥4: 5-15 ng/mL a) In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL during month 1-3 and 5-12 ng/mL during month 4-12 [ see Clinical Studies ( 14.1 )]. Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages 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 Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients Table 2. Table 1. Comparative Dose and Trough Concentrations Based on Race Time After Transplant Caucasian n=114 Black n=56 Dose (mg/kg) Trough Concentrations (ng/mL) Dose (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12.0 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 11.0 Initial Dose – Injection Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus, usually within 2-3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV 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. The recommended starting dose of tacrolimus injection is 0.03-0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation. Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as Tacrolimus injection [ see warnings and Precautions ( 5.11 )] 2.2 Dosage in Pediatric Liver Transplant Patients The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details [see Dosage and Administration (2.6)]. If necessary, pediatric patients may start on an IV dose of 0.03-0.05 mg/kg/day. Table 2. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population Recommended Tacrolimus Initial Oral DosageNote: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15-0.20 mg/kg/day Month 1-12: 5-20 ng/mL Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Experience in pediatric kidney and heart transplantation patients is limited. 2.3 Dosage Adjustment in Patients with Renal Impairment Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus 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 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. 2.4 Dosage Adjustment in 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. Close monitoring of blood concentrations is warranted. 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 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 ( 2.1 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 ) ]. 2.5 Administration Instructions It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3 [ see Dosage and Administration ( 2.1 , 2.2 )]; for blood concentration monitoring details in kidney transplant patients [ see Dosage and Administration ( 2.1 )]. It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [ see Clinical Pharmacology ( 12.3 )]. 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. In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. 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 2-3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. 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. Observed whole blood trough concentrations 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 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) 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; 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.

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). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6)]. Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil)( 4 )

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: • Lymphoma and Other Malignancies [ see Boxed Warning, Warnings and Precautions ( 5.2 )] • Serious Infections [ see Boxed Warning, Warnings and Precautions ( 5.3 )] • Polyoma Virus Infections [ see Boxed Warning, Warnings and Precautions ( 5.4 )] • CMV Infections [ see Boxed Warning, Warnings and Precautions ( 5.5 )] • New Onset Diabetes After Transplant [ see Warnings and Precautions ( 5.6 )] • Nephrotoxicity [ see Warnings and Precautions ( 5.7 )] • Neurotoxicity [ see Warnings and Precautions ( 5.8 )] • Hyperkalemia [ see Warnings and Precautions ( 5.9 )] • Hypertension [ see Warnings and Precautions ( 5.10 )] • Anaphylaxis with Tacrolimus Injection [ see Warnings and Precautions ( 5.11 )] • Myocardial Hypertrophy [ see Warnings and Precautions ( 5.15 )] • Pure Red Cell Aplasia [ see Warnings and Precautions ( 5.17 )] • Gastrointestinal Perforation [ see Warnings and Precautions ( 5.18 )] •Kidney Transplant: The most common adverse reactions ( ≥ 30%) were 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 ( 6.1 ) •Liver Transplant: The most common adverse reactions (≥ 40%) were tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia ( 6.1 ) •Heart Transplant: The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection and hyperlipemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajenat Pharmaceuticals LLC at 1-727-234-8872 or FDA at 1-800-FDA-1088 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. Kidney Transplant 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 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%), Black (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. Adverse reactions that occurred in ≥15% of kidney transplant patients treated with Tacrolimus in conjunction with azathioprine are presented below: Table 3. 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 Tremor 54% 34% Headache 44% 38% Insomnia 32% 30% Paresthesia 23% 16% Dizziness 19% 16% Gastrointestinal Diarrhea 44% 41% Nausea 38% 36% Constipation 35% 43% Vomiting 29% 23% Dyspepsia 28% 20% Cardiovascular Hypertension 50% 52% Chest Pain 19% 13% Urogenital Creatinine Increased 45% 42% Urinary Tract Infection 34% 35% Metabolic and Nutritional Hypophosphatemia 49% 53% Hypomagnesemia 34% 17% Hyperlipemia 31% 38% Hyperkalemia 31% 32% Diabetes Mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 22% 16% Edema 18% 19% Hemic and Lymphatic Anemia 30% 24% Leukopenia 15% 17% Miscellaneous Infection 45% 49% Peripheral Edema 36% 48% Asthenia 34% 30% Abdominal Pain 33% 31% Pain 32% 30% Fever 29% 29% Back Pain 24% 20% Respiratory System Dyspnea 22% 18% Cough Increased 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash 17% 12% Pruritus 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 4. 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%), Black (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: Table 5. 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 Diarrhea 44% 26% Nausea 39% 47% Constipation 36% 41% Vomiting 26% 25% Dyspepsia 18% 15% Injury, Poisoning, and Procedural Complications Post-Procedural Pain 29% 27% Incision Site Complication 28% 23% Graft Dysfunction 24% 18% Metabolism and Nutrition Disorders Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorders Tremor 34% 20% Headache 24% 25% Blood and Lymphatic System Disorders Anemia 30% 28% Leukopenia 16% 12% Miscellaneous Edema Peripheral 35% 46% Hypertension 32% 35% Insomnia 30% 21% Urinary Tract Infection 26% 22% Blood Creatinine Increased 23% 23% Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions . Liver Transplantation 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%), Black (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 ( ≥40%) 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. Table 6. 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 Headache 64% 60% 37% 26% Insomnia 64% 68% 32% 23% Tremor 56% 46% 48% 32% Paresthesia 40% 30% 17% 17% Gastrointestinal Diarrhea 72% 47% 37% 27% Nausea 46% 37% 32% 27% LFT Abnormal 36% 30% 6% 5% Anorexia 34% 24% 7% 5% Vomiting 27% 15% 14% 11% Constipation 24% 27% 23% 21% Cardiovascular Hypertension 47% 56% 38% 43% Urogenital Kidney Function Abnormal 40% 27% 36% 23% Creatinine Increased 39% 25% 24% 19% BUN Increased 30% 22% 12% 9% Oliguria 18% 15% 19% 12% Urinary Tract Infection 16% 18% 21% 19% Metabolic and Nutritional Hypomagnesemia 48% 45% 16% 9% Hyperglycemia 47% 38% 33% 22% Hyperkalemia 45% 26% 13% 9% Hypokalemia 29% 34% 13% 16% Hemic and Lymphatic Anemia 47% 38% 5% 1% Leukocytosis 32% 26% 8% 8% Thrombocytopenia 24% 20% 14% 19% Miscellaneous Pain 63% 57% 24% 22% Abdominal Pain 59% 54% 29% 22% Asthenia 52% 48% 11% 7% Fever 48% 56% 19% 22% Back Pain 30% 29% 17% 17% Ascites 27% 22% 7% 8% Peripheral Edema 26% 26% 12% 14% Respiratory System Pleural Effusion 30% 32% 36% 35% Dyspnea 29% 23% 5% 4% Atelectasis 28% 30% 5% 4% Skin and Appendages Pruritus 36% 20% 15% 7% Rash 24% 19% 10% 4% Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions . Heart Transplantation 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. Adverse reactions in heart transplant patients in the European trial are presented below: Table 8. Heart Transplantation: Adverse Reactions Occurring in ≥15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA Cyclosporine/AZA (n=157) (n=157) Cardiovascular System Hypertension 62% 69% Pericardial Effusion 15% 14% Body as a Whole CMV Infection 32% 30% Infection 24% 21% Metabolic and Nutritional Disorders Diabetes Mellitus 26% 16% Hyperglycemia 23% 17% Hyperlipemia 18% 27% Hemic and Lymphatic System Anemia 50% 36% Leukopenia 48% 39% Urogenital System Kidney Function Abnormal 56% 57% Urinary Tract Infection 16% 12% Respiratory System Bronchitis 17% 18% Nervous System Tremor 15% 6% In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e. 100 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 to 15 ng/mL) in74 to 86% of the patients in the Tacrolimus treatment arm. In the 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%), Black (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. New Onset Diabetes After Transplant Kidney Transplant New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA1C ≥ 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 9 [ see Clinical Studies ( 14.1 )]. Table 7. Incidence of New Onset Diabetes After Transplant at 1 Year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2) Parameter Treatment Group Tacrolimus/MMF (n = 212) Neoral/MMF (n = 212) NODAT 112/150 (75%) 93/152 (61%) Fasting Plasma Glucose ≥126 mg/dL 96/150 (64%) 80/152 (53%) HbA 1C ≥6% 59/150 (39%) 28/152 (18%) Insulin Use ≥30 days 9/150 (6%) 4/152 (3%) Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%) In early trials of Tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria 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 10 to 13. 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 10) 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 (Table 11) Table 8. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) Status of PTDM a Tacrolimus/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDMa, 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 PTDMa post 1 year 1 0 Patients with PTDMa at 2 years 16/151 (11%) 5/151 (3%) a) 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 9. 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 Patients Who Developed PTDM a Patient Race Tacrolimus Cyclosporine Black 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%) a) 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. Liver Transplant 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 12). 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 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients US Trial EuropeanTrial Status of PTDM a Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at riskb 239 236 239 249 New Onset PTDMa 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) a) 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. bPatients without pre-transplant history of diabetes mellitus. Heart Transplant 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 13). 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 Clinical Studies ( 6.1 )]. Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients Status of PTDM a US Trial European Trial Tacrolimus/MMF Cyclosporine/MMF Tacrolimus/AZA Cyclosporine/AZA Patients at riskb 75 83 132 138 New Onset PTDMa 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 yearc 7 (9%) 1 (1%) 24 (18%) 4 (3%) a) Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. bPatients without pre-transplant history of diabetes mellitus. c7-12 months for the U.S. trial. Less Frequently Reported Adverse Reactions (>3% and <15%) 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 [ see Warnings and Precautions ( 5.8 )] Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, haemorrhagic 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, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis Cardiovascular Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, 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 Acute kidney failure [ see Warnings and Precautions ( 5.7 )], 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 increase, weight gain Endocrine Cushing’s syndrome Hemic/Lymphatic Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased Miscellaneous Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Respiratory Asthma, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, 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. 6.2 Postmarketing Adverse Reactions 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 ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy [ see Warnings and Precautions ( 5.15 )]. Gastrointestinal Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal 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 Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia [ see Warnings and Precautions ( 5.17 )] Infections Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; -polyoma virus-associated nephropathy, (PVAN) including graft loss [ see Warnings and Precautions ( 5.4 )] 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) [ see Warnings and Precautions ( 5.8 )] , progressive multifocal leukoencephalopathy (PML) [ see Warnings and Precautions ( 5.4 )] , 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

Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [ see Warnings and Precautions ( 5.13 )] and Clinical Pharmacology ( 12.3 )].Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when tacrolimus is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation [ see Warnings and Precautions ( 5.7 ) and ( 5.14 )] • Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to tacrolimus; monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed ( 7.1 ) • Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use ( 7.2 , 7.3 ) • CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.13 , 7.3 , 7.4 , 7.5 , 7.6 ) • CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.13 , 7.7 , 7.8 , 7.9 ) 7.1 Mycophenolic Acid Products With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with tacrolimus co-administration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving MPA-containing products. 7.2 Grapefruit Juice Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with tacrolimus [ see Dosage and Administration ( 2.5 )]. 7.3 Protease Inhibitors Most protease inhibitors inhibit CYP3A enzymes and may increase tacrolimus whole blood concentrations. It is recommended to avoid concomitant use of tacrolimus with nelfinavir unless the benefits outweigh the risks [ see Clinical Pharmacology ( 12.3 )]. Whole blood concentrations of tacrolimus are markedly increased when co-administered with telaprevir or with boceprevir [ see Clinical Pharmacology ( 12.3 )]. Monitoring of tacrolimus whole blood concentrations and tacrolimus associated adverse reactions, and appropriate adjustments in the dosing regimen of tacrolimus are recommended when tacrolimus and protease inhibitors (e.g., ritonavir, telaprevir, boceprevir) are used concomitantly. 7.4 Antifungal Agents Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following antifungal drugs with tacrolimus is initiated or discontinued [ see Clinical Pharmacology ( 12.3 )]. Azoles: Voriconazole, posaconazole, itraconazole, ketoconazole, fluconazole and clotrimazole inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. When initiating therapy with voriconazole or posaconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be initially reduced to one-third of the original dose and the subsequent tacrolimus doses be adjusted based on the tacrolimus whole blood concentrations. Caspofungin is an inducer of CYP3A and decreases whole blood concentrations of tacrolimus. 7.5 Calcium Channel Blockers Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these calcium channel blocking drugs and tacrolimus are used concomitantly. 7.6 Antibacterials Erythromycin, clarithromycin, troleandomycin and chloramphenicol inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. 7.7 Antimycobacterials Rifampin [ see Clinical Pharmacology ( 12.3 )] and rifabutin are inducers of CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these antimycobacterial drugs and tacrolimus are used concomitantly. 7.8 Anticonvulsants Phenytoin, carbamazepine and phenobarbital induce CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. Concomitant administration of phenytoin with tacrolimus may also increase phenytoin plasma concentrations. Thus, frequent monitoring phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when tacrolimus and phenytoin are administered concomitantly. 7.9 St. John’s Wort (Hypericum perforatum) St. John’s Wort induces CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when St. John’s Wort and tacrolimus are co-administered. 7.10 Gastric Acid Suppressors/Neutralizers Lansoprazole and omeprazole, as CYP2C19 and CYP3A4 substrates, may potentially inhibit the CYP3A4 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. Cimetidine may also inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. Coadministration with magnesium and aluminum hydroxide antacids increases tacrolimus whole blood concentrations [ see Clinical Pharmacology ( 12.3 )]. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. 7.11 Others Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone, methylprednisolone and herbal products containing schisandra sphenanthera extracts may inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are co-administered.