FDA label fe52fe3c-0b0f-41ca-88ed-203591b62b7f

BOX WARNING – MALIGNANCIES AND SERIOUS INFECTIONS Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions ( 5.2 )]. Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions ( 5.3 , 5.4 , 5.5 )]. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions ( 5.1 )]. WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete box warning Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression ( 5.2 ) Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections ( 5.3 , 5.4 , 5.5 ) Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus ( 5.1 )

5 WARNINGS AND PRECAUTIONS Lymphoma and Other Malignancies: Risk of lymphomas, including post transplant lymphoproliferative disorder (PTLD); appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight ( 5.2 ) Serious infections: Increased risk of bacterial, viral, fungal and protozoal infections, including opportunistic infections: combination immunosuppression should be used with caution ( 5.3 ) Polyoma Virus Infections: Serious, sometimes fatal outcomes, including polyoma virus-associated nephropathy (PVAN), mostly due to BK virus, and JC virus-associated progressive multifocal leukoencephalopathy (PML); consider reducing immunosuppression ( 5.4 ) Cytomegalovirus (CMV) Infections: Increased risk of CMV viremia and disease; consider reducing immunosuppression ( 5.5 ) New Onset Diabetes After Transplant: Monitor blood glucose ( 5.6 ) Nephrotoxicity: Acute and/or chronic; reduce the dose; use caution with other nephrotoxic drugs ( 5.7 ) Neurotoxicity: Risk of Posterior Reversible Encephalopathy Syndrome, monitor for neurologic abnormalities; reduce or discontinue tacrolimus and other immunosuppressants ( 5.8 ) Hyperkalemia: Monitor serum potassium levels. Careful consideration should be given prior to use of other agents also associated with hyperkalemia ( 5.9 ) Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions ( 5.10 ) Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis ( 5.11 ) Use with Sirolimus: Not recommended in liver transplant due to increased risk of serious adverse reactions ( 5.12 ) Myocardial Hypertrophy: Consider dosage reduction or discontinuation ( 5.14 ) Immunizations: Use of live vaccines should be avoided ( 5.15 ) Pure Red Cell Aplasia: Discontinuation should be considered ( 5.16 ) 5.1 Management of Immunosuppression Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use tacrolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow up of the patient [see Box Warning ]. 5.2 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Box Warning ]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Post transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. 5.3 Serious Infections Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Box Warning and Warnings and Precautions ( 5.4 , 5.5 )]. These infections may lead to serious, including fatal, outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution. 5.4 Polyoma Virus Infections Patients receiving immunosuppressants, including tacrolimus, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus [see Adverse Reactions ( 6.2 )]. PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss [see Adverse Reactions ( 6.2 )]. Patient monitoring may help detect patients at risk for PVAN. Cases of PML have been reported in patients treated with tacrolimus. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft. 5.5 Cytomegalovirus (CMV) Infections Patients receiving immunosuppressants, including tacrolimus, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease. 5.6 New Onset Diabetes After Transplant Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney and liver, transplantation. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using tacrolimus [see Adverse Reactions ( 6.1 )]. 5.7 Nephrotoxicity Tacrolimus, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurin-inhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. 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. Based on reported adverse reactions terms related to decreased renal function, 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 [see Adverse Reactions ( 6.1 )]. 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, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A4 inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin) which will result in increased tacrolimus whole blood concentrations due to inhibition of tacrolimus metabolism [see Drug Interactions ( 7.3 , 7.4 , 7.5 , 7.6 )]. 5.8 Neurotoxicity Tacrolimus may cause a spectrum of neurotoxicities, particularly when used in high doses. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, and coma. Patients treated with tacrolimus have been reported to develop 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. Coma and delirium, in the absence of PRES, have also been associated with high plasma concentrations of tacrolimus. Seizures have occurred in adult and pediatric patients receiving tacrolimus [see Adverse Reactions ( 6.1 )]. Less severe neurotoxicities, include tremors, parathesias, headache, and other changes in motor function, mental status, and sensory function [see Adverse Reactions ( 6.1 )]. Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. 5.9 Hyperkalemia Hyperkalemia has been reported with tacrolimus use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy [see Adverse Reactions ( 6.1 )]. 5.10 Hypertension Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions ( 6.1 )]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions ( 5.9 )]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions ( 7.5 )]. 5.11 Anaphylactic Reactions with Tacrolimus Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. Tacrolimus injection should be reserved for patients who are unable to take tacrolimus capsules [see Indications and Usage ( 1.4 )]. 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. 5.12 Use with Sirolimus The safety and efficacy of tacrolimus with sirolimus has not been established in kidney transplant patients. Use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended [see Indications and Usage ( 1.4 )]. 5.13 Use with CYP3A4 Inhibitors and Inducers Including Those That Prolong QT Coadministration with strong CYP3A4-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions [see Drug Interactions ( 7 )] . When coadministering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation. 5.14 Myocardial Hypertrophy Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. 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 [see Adverse Reactions ( 6.2 )]. 5.15 Immunizations The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.16 Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of tacrolimus should be considered [see Adverse Reactions ( 6.2 )].

6 ADVERSE REACTIONS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Lymphoma and Other Malignancies [see Box Warning , Warnings and Precautions ( 5.2 )] Serious Infections [see Box Warning , Warnings and Precautions ( 5.3 )] Polyoma Virus Infections [see Box Warning , Warnings and Precautions ( 5.4 )] CMV Infections [see Box 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 ( 5.14 )] Pure Red Cell Aplasia [see Warnings and Precautions ( 5.16 )] 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, 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 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. 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 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 Tremor Headache Insomnia Paresthesia Dizziness Gastrointestinal Diarrhea Nausea Constipation Vomiting Dyspepsia Cardiovascular Hypertension Chest Pain Urogenital Creatinine Increased Urinary Tract Infection Metabolic and Nutritional Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema Hemic and Lymphatic Anemia Leukopenia Miscellaneous Infection Peripheral Edema Asthenia Abdominal Pain Pain Fever Back Pain Respiratory System Dyspnea Cough Increased Musculoskeletal Arthralgia Skin Rash Pruritus 54% 44% 32% 23% 19% 44% 38% 35% 29% 28% 50% 19% 45% 34% 49% 34% 31% 31% 24% 22% 22% 18% 30% 15% 45% 36% 34% 33% 32% 29% 24% 22% 18% 25% 17% 15% 34% 38% 30% 16% 16% 41% 36% 43% 23% 20% 52% 13% 42% 35% 53% 17% 38% 32% 9% 25% 16% 19% 24% 17% 49% 48% 30% 31% 30% 29% 20% 18% 15% 24% 12% 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) 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 Tacrolimus (Group C) (N=403) Cyclosporine (Group A) (N=384) Cyclosporine (Group B) (N=408) Diarrhea Urinary Tract Infection Anemia Hypertension Leucopenia Edema Peripheral Hyperlipidemia 25% 24% 17% 13% 13% 11% 10% 16% 28% 19% 14% 10% 12% 15% 13% 24% 17% 12% 10% 13% 13% 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 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 Diarrhea Nausea Constipation Vomiting Dyspepsia Injury, Poisoning, and Procedural Complications Post Procedural Pain Incision Site Complication Graft Dysfunction Metabolism and Nutrition Disorders Hypomagnesemia Hypophosphatemia Hyperkalemia Hyperglycemia Hyperlipidemia Hypokalemia Nervous System Disorders Tremor Headache Blood and Lymphatic System Disorders Anemia Leukopenia Miscellaneous Edema Peripheral Hypertension Insomnia Urinary Tract Infection Blood creatinine increased 44% 39% 36% 26% 18% 29% 28% 24% 28% 28% 26% 21% 18% 16% 34% 24% 30% 16% 35% 32% 30% 26% 23% 26% 47% 41% 25% 15% 27% 23% 18% 22% 21% 19% 15% 25% 18% 20% 25% 28% 12% 46% 35% 21% 22% 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 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 Headache Insomnia Tremor Paresthesia Gastrointestinal Diarrhea Nausea LFT Abnormal Anorexia Vomiting Constipation Cardiovascular Hypertension Urogenital Kidney Function Abnormal Creatinine Increased BUN Increased Oliguria Urinary Tract Infection Metabolic and Nutritional Hypomagnesemia Hyperglycemia Hyperkalemia Hypokalemia Hemic and Lymphatic Anemia Leukocytosis Thrombocytopenia Miscellaneous Pain Abdominal Pain Asthenia Fever Back Pain Ascites Peripheral Edema Respiratory System Pleural Effusion Dyspnea Atelectasis Skin and Appendages Pruritus Rash 64% 64% 56% 40% 72% 46% 36% 34% 27% 24% 47% 40% 39% 30% 18% 16% 48% 47% 45% 29% 47% 32% 24% 63% 59% 52% 48% 30% 27% 26% 30% 29% 28% 36% 24% 60% 68% 46% 30% 47% 37% 30% 24% 15% 27% 56% 27% 25% 22% 15% 18% 45% 38% 26% 34% 38% 26% 20% 57% 54% 48% 56% 29% 22% 26% 32% 23% 30% 20% 19% 37% 32% 48% 17% 37% 32% 6% 7% 14% 23% 38% 36% 24% 12% 19% 21% 16% 33% 13% 13% 5% 8% 14% 24% 29% 11% 19% 17% 7% 12% 36% 5% 5% 15% 10% 26% 23% 32% 17% 27% 27% 5% 5% 11% 21% 43% 23% 19% 9% 12% 19% 9% 22% 9% 16% 1% 8% 19% 22% 22% 7% 22% 17% 8% 14% 35% 4% 4% 7% 4% Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions . 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, 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 9 ) [see Clinical Studies ( 14.1 )]. Table 9. 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 12. 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 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) 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. Status of PTDM a Tacrolimus/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDM a , 1 st 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 a post 1 year 1 0 Patients with PTDM a at 2 years 16/151(11%) 5/151(3%) Table 11. 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 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. Patient Race Patients Who Developed PTDM a 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%) 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 12. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients a) Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. b) Patients without pre-transplant history of diabetes mellitus. Status of PTDM a US Trial European Trial Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at risk b 239 236 239 249 New Onset PTDM a 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) Less Frequently Reported Adverse Reactions (>3% and <15%) The following adverse reactions were reported in either liver and/or kidney 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 ( 5.14 )]. 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 Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia [see Warnings and Precautions ( 5.16 )] 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

<table ID="t4" width="100%"> <caption>Table 4. Kidney Transplantation: Adverse Reactions Occurring in &#x2265; 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) </caption> <col width="51.367%" align="left"/> <col width="20.967%" align="left"/> <col width="27.667%" align="left"/> <tbody> <tr> <td align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"/> <td align="left" valign="bottom" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Tacrolimus/AZA</content> <content styleCode="bold">(N=205)</content> </td> <td align="left" valign="bottom" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Cyclosporine/AZA</content> <content styleCode="bold">(N=207)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold underline">Nervous System</content> Tremor Headache Insomnia Paresthesia Dizziness <content styleCode="bold underline">Gastrointestinal</content> Diarrhea Nausea Constipation Vomiting Dyspepsia <content styleCode="bold underline">Cardiovascular</content> Hypertension Chest Pain <content styleCode="bold underline">Urogenital</content> Creatinine Increased Urinary Tract Infection <content styleCode="bold underline">Metabolic and Nutritional</content> Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema <content styleCode="bold underline">Hemic and Lymphatic</content> Anemia Leukopenia <content styleCode="bold underline">Miscellaneous</content> Infection Peripheral Edema Asthenia Abdominal Pain Pain Fever Back Pain <content styleCode="bold underline">Respiratory System</content> Dyspnea Cough Increased <content styleCode="bold underline">Musculoskeletal</content> Arthralgia <content styleCode="bold underline">Skin</content> Rash Pruritus </td> <td align="left" valign="top" styleCode="Botrule Rrule"> 54% 44% 32% 23% 19% 44% 38% 35% 29% 28% 50% 19% 45% 34% 49% 34% 31% 31% 24% 22% 22% 18% 30% 15% 45% 36% 34% 33% 32% 29% 24% 22% 18% 25% 17% 15% </td> <td align="left" valign="top" styleCode="Botrule Rrule"> 34% 38% 30% 16% 16% 41% 36% 43% 23% 20% 52% 13% 42% 35% 53% 17% 38% 32% 9% 25% 16% 19% 24% 17% 49% 48% 30% 31% 30% 29% 20% 18% 15% 24% 12% 7% </td> </tr> </tbody> </table>

<table ID="t5" width="100%"> <caption>Table 5. Kidney Transplantation: Adverse Reactions Occurring in &#x2265; 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1) </caption> <col width="41.025%" align="left"/> <col width="17.350%" align="left"/> <col width="17.675%" align="left"/> <col width="23.950%" align="left"/> <tfoot> <tr> <td colspan="4" align="left" valign="top" styleCode="Toprule Lrule Rrule"> <paragraph styleCode="footnote">Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab </paragraph> </td> </tr> <tr> <td colspan="4" align="left" valign="top" styleCode="Botrule Lrule Rrule"> <paragraph styleCode="footnote">CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="center" valign="middle" styleCode="Toprule Botrule Lrule Rrule"/> <td align="center" valign="middle" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Tacrolimus</content> <content styleCode="bold">(Group C)</content> <content styleCode="bold">(N=403)</content> </td> <td align="center" valign="middle" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(Group A)</content> <content styleCode="bold">(N=384)</content> </td> <td align="center" valign="middle" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Cyclosporine</content> <content styleCode="bold">(Group B)</content> <content styleCode="bold">(N=408)</content> </td> </tr> <tr> <td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Diarrhea Urinary Tract Infection Anemia Hypertension Leucopenia Edema Peripheral Hyperlipidemia </td> <td align="center" valign="middle" styleCode="Botrule Rrule">25% 24% 17% 13% 13% 11% 10% </td> <td align="center" valign="middle" styleCode="Botrule Rrule">16% 28% 19% 14% 10% 12% 15% </td> <td align="center" valign="middle" styleCode="Botrule Rrule">13% 24% 17% 12% 10% 13% 13% </td> </tr> </tbody> </table>

<table ID="t6" width="100%"> <caption>Table 6. Kidney Transplantation: Adverse Reactions Occurring in &#x2265; 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2) </caption> <col width="62.854%" align="left"/> <col width="16.639%" align="left"/> <col width="20.507%" align="left"/> <tbody> <tr> <td align="center" valign="middle" styleCode="Toprule Botrule Lrule Rrule"/> <td align="center" valign="middle" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Tacrolimus</content> <content styleCode="bold">/MMF</content> <content styleCode="bold">(N=212)</content> </td> <td align="center" valign="middle" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Cyclosporine/MMF</content> <content styleCode="bold">(N=212)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold underline">Gastrointestinal Disorders</content> Diarrhea Nausea Constipation Vomiting Dyspepsia <content styleCode="bold underline">Injury, Poisoning, and Procedural Complications</content> Post Procedural Pain Incision Site Complication Graft Dysfunction <content styleCode="bold underline">Metabolism and Nutrition Disorders</content> Hypomagnesemia Hypophosphatemia Hyperkalemia Hyperglycemia Hyperlipidemia Hypokalemia <content styleCode="bold underline">Nervous System Disorders</content> Tremor Headache <content styleCode="bold underline">Blood and Lymphatic System Disorders</content> Anemia Leukopenia <content styleCode="bold underline">Miscellaneous</content> Edema Peripheral Hypertension Insomnia Urinary Tract Infection Blood creatinine increased </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 44% 39% 36% 26% 18% 29% 28% 24% 28% 28% 26% 21% 18% 16% 34% 24% 30% 16% 35% 32% 30% 26% 23% </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 26% 47% 41% 25% 15% 27% 23% 18% 22% 21% 19% 15% 25% 18% 20% 25% 28% 12% 46% 35% 21% 22% 23% </td> </tr> </tbody> </table>