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2013年8月23日,美国推出Astagraf XL(他克莫司缓释胶囊，tacrolimus extended release capsules)，该药与霉酚酸酯(MMF)及皮质类醇联用、结合或无巴利昔单抗(basiliximab)诱导，用于预防成人肾移植受者中的器官排斥。
Give first dose prior to or within 48 hours after transplant completion; may delay therapy initiation until renal function has recovered ( 2.2). Give preoperative dose within 12 hours prior to reperfusion, and first post-operative dose within 12 hours after reperfusion but not less than 4 hours after pre-operative dose ( 2.1). Take once daily in the morning, preferably on an empty stomach; do not take with an alcoholic beverage or grapefruit juice; do not chew, divide or crush capsules ( 2.4, 7) • Monitoring of whole blood tacrolimus trough concentrations is recommended ( 2.5) DOSAGE FORMS AND STRENGTHS • Capsules: 0.5 mg, 1 mg, 5 mg ( 3) CONTRAINDICATIONS • ASTAGRAF XL is contraindicated in patients with hypersensitivity to tacrolimus ( 4). WARNINGS AND PRECAUTIONS • Medication errors have been reported including unintentional substitution between immediate-release tacrolimus and ASTAGRAF XL (extended-release) tacrolimus formulations ( 5.5) • New Onset Diabetes After Transplant: Monitor blood glucose ( 5.8) • Nephrotoxicity (acute and/or chronic): Monitor renal function; reduce the dose; use caution with other nephrotoxic drugs ( 5.9) • Neurotoxicity, Risk of Posterior Reversible Encephalopathy Syndrome (PRES): Monitor for neurologic abnormalities; reduce or discontinue immunosuppression ( 5.10) • Hyperkalemia: Monitor serum potassium levels; use caution with other agents that increase potassium ( 5.11) • Hypertension: May require antihypertensive therapy; monitor relevant drug-drug interactions ( 5.12) • Use with Sirolimus: Not recommended; increased risk of serious adverse reactions in liver and heart transplant recipients ( 5.13) • Use with Strong CYP3A Inhibitors and Inducers: Adjust tacrolimus dose and monitor trough concentrations and for occurrence of adverse reactions, including QT prolongation ( 5.14, 5.15, 7) • Immunizations: Avoid use of live vaccines ( 5.16) • Pure Red Cell Aplasia: Consider discontinuation ( 5.17) ADVERSE REACTIONS • The most common adverse reactions ( ≥ 30%) are: diarrhea, constipation, nausea, peripheral edema, tremor and anemia ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Mycophenolic Acid Products: Monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed ( 7.1) • CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.14, 7) • CYP3A Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use ( 5.14, 7) USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data may cause fetal harm ( 8.1) • Nursing Mothers: Discontinue drug or nursing ( 8.3) • Renal Impairment: If nephrotoxicity develops, reduce doses ( 2.2, 8.6) • Hepatic Impairment: Lower doses below the recommended starting dose may be required ( 2.3, 8.7) • Race: African-Americans may need higher doses ( 2.1, 8.8, 14) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 6/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Prophylaxis of Organ Rejection in Kidney Transplant ASTAGRAF XL is indicated for the prophylaxis of organ rejection in patients receiving a kidney transplant. It is recommended that ASTAGRAF XL be used concomitantly with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction [see Clinical Studies (14)]. Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL [see Dosage and Administration (2.5)]. 1.2 Limitations of Use • ASTAGRAF XL extended-release capsules are not interchangeable or substitutable with tacrolimus immediate-release capsules. • ASTAGRAF XL should not be used simultaneously with cyclosporine. 2 DOSAGE AND ADMINISTRATION 2.1 Dosage in Adult Kidney Transplant Recipients Initial dosage recommendations for adult patients after kidney transplantation are presented in Table 1. Dosing of ASTAGRAF XL should be titrated based on clinical assessments of rejection and tolerability, and to maintain trough concentration ranges as noted in Table 1. Frequent monitoring of tacrolimus trough concentrations is recommended in the early post-transplant period to ensure adequate drug exposure [see Dosage and Administration (2.5)]. ASTAGRAF XL extended-release capsules are not interchangeable or substitutable with tacrolimus immediate-release capsules. With Basiliximab Induction When used with basiliximab induction, MMF, and corticosteroids, the initial dose of ASTAGRAF XL should be administered prior to or within 48 hours of the completion of the transplant procedure, but may be delayed until renal function has recovered. Without Induction When used with MMF and corticosteroids, the pre-operative dose of ASTAGRAF XL should be given as one dose within 12 hours prior to reperfusion; the initial post-operative dose should be given not less than 4 hours after the pre-operative dose and within 12 hours after reperfusion. Table 1. Recommended Initial Oral Dose and Observed Whole Blood Trough Concentrations in Kidney Transplant Patients 10th - 90th percentile; see also Clinical Studies ( 14) for description of immunosuppressive regimens 2.2 Patients with Renal Impairment In kidney transplant patients with post-operative oliguria, the initial dose of ASTAGRAF XL should be administered no sooner than 6 hours and within 48 hours of transplantation, but may be delayed until renal function shows evidence of recovery. Frequent monitoring of renal function is recommended. ASTAGRAF XL dosage should be reduced if nephrotoxicity develops. 2.3 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 ASTAGRAF XL. Frequent monitoring of blood concentrations is warranted. 2.4 Administration Instructions ASTAGRAF XL is a once daily extended-release oral formulation of tacrolimus. Intravenous administration of tacrolimus should be reserved only for initiation in patients unable to take oral therapy. Prograf Injection is administered as a continuous IV infusion. Conversion from intravenous Prograf to oral ASTAGRAF XL is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving Prograf intravenous infusion, the first dose of oral ASTAGRAF XL therapy should be given 8-12 hours after discontinuing the Prograf IV infusion. To ensure consistent and maximum possible drug exposure, ASTAGRAF XL capsules should be taken consistently every morning, preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal [see Clinical Pharmacology (12.3)]. ASTAGRAF XL should be swallowed whole and should not be chewed, divided, or crushed. Patients should not eat grapefruit or drink grapefruit juice in combination with ASTAGRAF XL [see Drug Interactions (7.2)]. Patients should not take ASTAGRAF XL with an alcoholic beverage [see Drug Interactions (7.3)]. If a dose of ASTAGRAF XL is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, take by 10:00 PM). Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. It is not recommended to double the dose of ASTAGRAF XL to make up for the missed dose. 2.5 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 the 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 or 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) 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. 3 DOSAGE FORMS AND STRENGTHS • 0.5 mg hard gelatin capsule with a light yellow cap and orange body branded with red "647" on the capsule body and "0.5 mg" on the capsule cap. • 1 mg hard gelatin capsule with a white cap and orange body branded with red "677" on the capsule body and "1 mg" on the capsule cap. • 5 mg hard gelatin capsule with a grayish-red cap and orange body branded with red " 687" on the capsule body and "5 mg" on the capsule cap. 4 CONTRAINDICATIONS ASTAGRAF XL is contraindicated in patients with hypersensitivity to tacrolimus. 5 WARNINGS AND PRECAUTIONS 5.1 Management of Immunosuppression Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ASTAGRAF XL. 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 patients [see Boxed Warning]. 5.2 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including ASTAGRAF XL, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Boxed 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 ASTAGRAF XL, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Boxed Warning, Warnings and Precautions (5.6, 5.7)]. 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 Liver Transplant Recipients In a clinical trial of 471 liver transplant recipients randomized to ASTAGRAF XL or Prograf, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with ASTAGRAF XL compared to the 64 female patients (8%) treated with Prograf. Use of ASTAGRAF XL in liver transplantation is not recommended [see Boxed Warning]. 5.5 Medication Errors ASTAGRAF XL extended-release capsules are not interchangeable or substitutable with tacrolimus immediate-release capsules. Medication and dispensing errors, including inadvertent or unintentional substitution between twice daily immediate-release and ASTAGRAF XL (once daily extended-release) tacrolimus formulations have been observed in postmarketing surveillance of ASTAGRAF XL in countries where it is approved and marketed. This has led to serious adverse events, including graft rejection, or other adverse reactions, which could be a consequence of either under- or over-exposure to tacrolimus [see How Supplied (16)]. Note that ASTAGRAF XL is supplied in short, square bottles as well as in blister cartons containing 5 blister cards of 10 capsules on each card, and contains the statement "ONCE DAILY" on its label. 5.6 Polyoma Virus Infections Patients receiving immunosuppressants, including ASTAGRAF XL, 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 ASTAGRAF XL [see Adverse Reactions (6.2)]. PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft loss. Patient monitoring may help detect patients at risk for PVAN. Cases of PML have been reported in patients treated with ASTAGRAF XL. 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. 5.7 Cytomegalovirus (CMV) Infections Patients receiving immunosuppressants, including ASTAGRAF XL, 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 the 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. 5.8 New Onset Diabetes after Transplant ASTAGRAF XL was shown to cause new onset diabetes mellitus in clinical trials of kidney transplant patients [see Adverse Reactions (6.1)]. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk [see Use in Specific Populations (8.8)]. Blood glucose concentrations should be monitored frequently in patients using ASTAGRAF XL. 5.9 Nephrotoxicity ASTAGRAF XL, 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 ASTAGRAF XL 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. Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering ASTAGRAF XL 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 CYP3A 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 (7.4, 7.5, 7.6, 7.7)]. 5.10 Neurotoxicity ASTAGRAF XL 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 patients receiving tacrolimus [see Adverse Reactions (6.2)]. Other less severe neurotoxicities, include tremors, paresthesias, headache, and other changes in motor function, mental status, and sensory function have also been reported [see Adverse Reactions (6.1)]. Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. 5.11 Hyperkalemia Hyperkalemia has been reported with ASTAGRAF XL 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 ASTAGRAF XL therapy [see Adverse Reactions (6.1)]. 5.12 Hypertension Hypertension is a common adverse effect of ASTAGRAF XL 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 (5.11)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of ASTAGRAF XL [see Drug Interactions (7.6)]. 5.13 Use with Sirolimus The use of ASTAGRAF XL with sirolimus is not recommended in kidney transplant patients. Use of sirolimus with tacrolimus in studies of de novo liver transplant recipients was associated with an excess mortality, graft loss and hepatic artery thrombosis (HAT). Use of sirolimus with tacrolimus in heart transplant patients was associated with an increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus. 5.14 Use with CYP3A Inhibitors and Inducers When coadministering ASTAGRAF XL with strong CYP3A-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong CYP3A inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of ASTAGRAF XL and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended [see Drug Interactions (7)]. 5.15 QT Prolongation ASTAGRAF XL may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid ASTAGRAF XL in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When coadministering ASTAGRAF XL with other substrates and/or inhibitors of CYP3A that also have the potential to prolong the QT interval, a reduction in ASTAGRAF XL dose, frequent 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 [see Drug Interactions (7)]. 5.16 Immunizations The use of live vaccines should be avoided during treatment with ASTAGRAF XL; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.17 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 ASTAGRAF XL should be considered. 5.18 Gastrointestinal Perforation Gastrointestinal perforation has been reported in patients treated with tacrolimus; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation may be serious or life-threatening, appropriate medical/surgical management should be instituted promptly [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 Warnings and Precautions (5.2)] • Serious Infections [ see Warnings and Precautions (5.3)] • Polyoma Virus Infections [ see Warnings and Precautions (5.6)] • Cytomegalovirus (CMV) Infections [ see Warnings and Precautions (5.7)] • New Onset Diabetes after Transplant [ see Warnings and Precautions (5.8)] • Nephrotoxicity [ see Warnings and Precautions (5.9)] • Neurotoxicity [ see Warnings and Precautions (5.10)] • Hyperkalemia [ see Warnings and Precautions (5.11)] • Hypertension [ see Warnings and Precautions (5.12)] • Pure Red Cell Aplasia [ see Warnings and Precautions (5.17)] • Gastrointestinal Perforation [ see Warnings and Precautions (5.18)] 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 data described below reflect exposure to ASTAGRAF XL in 545 renal transplant recipients exposed to ASTAGRAF XL for periods up to two years [see Clinical Studies (14)]. The most frequent diseases leading to transplantation were glomerulonephritis, polycystic kidney disease, nephrosclerosis/hypertensive nephropathy, and diabetic nephropathy in both studies. Study 1: With Basiliximab Induction The proportion of patients who discontinued treatment due to adverse reactions was 9% in the ASTAGRAF XL arm and 11% in the Prograf control arm through 12 months of treatment. The most common adverse reactions leading to discontinuation in ASTAGRAF XL-treated patients were related to infections or renal/urinary disorders. The most common (≥ 30%) adverse reactions observed in the ASTAGRAF XL group were: diarrhea, constipation, nausea, peripheral edema, tremor and anemia. Study 2: Without Induction The proportion of patients who discontinued treatment due to adverse reactions was 13% in the ASTAGRAF XL arm and 11% in the Prograf control arm through 12 months of treatment. The most common adverse reactions leading to discontinuation in ASTAGRAF XL-treated patients were related to infections, graft dysfunction, renal vascular/ischemic conditions and diabetes. The most common (≥30%) adverse reaction observed in the ASTAGRAF XL group was anemia. Information on selected significant adverse reactions observed during Studies 1 and 2 are summarized below. New Onset Diabetes After Transplant (NODAT) New onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were > 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA1C ≥ 6.5%) is summarized in Table 2 below for Study 1 and Study 2 through one year post-transplant. Table 2. Composite NODAT Through 1 Year Post-Transplant in Studies 1 and 2 Infections Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with ASTAGRAF XL or the control in Studies 1 and 2 are shown in Table 3. Table 3. Overall Infections and Select Infections by Treatment Group in Studies 1 and 2 Through One Year Post-Transplant Studies 1 and 2 were not designed to support comparative claims for ASTAGRAF XL for the adverse reactions reported in this table. Glomerular Filtration Rate The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the ITT population in Studies 1 and 2 are shown in Table 4. Table 4. Estimated Glomerular Filtration Rate (mL/min/1.73m2) by MDRD Formula at 12 Months Post-Transplant Subject's last observation carried forward (LOCF) for missing data at Month 1; patients who died, lost the graft or were lost to follow-up are imputed as zeroes Tacrolimus XL-Prograf treatment mean difference results of analysis of covariance model with Month 1 Baseline as a covariate. Table 5. Adverse Events Occurring in ≥ 15% of ASTAGRAF XL-Treated Kidney Transplant Patients Through One Year Post Transplant in Studies 1 or 2* Studies 1 and 2 were not designed to support comparative claims for ASTAGRAF XL for the adverse reactions reported in this table. Less Frequently Reported Adverse Reactions (<15%) by System Organ Class The following adverse reactions were also reported in clinical studies of kidney transplant recipients who were treated with ASTAGRAF XL. Blood and Lymphatic System Disorders Coagulopathy, hemolytic anemia, leukocytosis, neutropenia, pancytopenia, thrombocytopenia, thrombotic microangiopathy Cardiac Disorders Angina pectoris, atrial fibrillation, atrial flutter, bradycardia, cardiac arrest, congestive cardiac failure, hypertrophic cardiomyopathy, myocardial ischemia, myocardial infarction, pericardial effusion, tachycardia, ventricular extrasystoles Ear Disorders Hearing loss, otitis (media and externa), tinnitus Eye Disorders Vision blurred, conjunctivitis Gastrointestinal Disorders Abdominal distension, abdominal pain, aphthous stomatitis, ascites, colitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, ileus, impaired gastric emptying, pancreatitis, stomach ulcer General Disorders and Administration Site Conditions Anasarca, asthenia, edema Hepatobiliary Disorders Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity Infections and Infestations Condyloma acuminatum, Epstein-Barr virus infection, tinea versicolor Injury, Poisoning and Procedural Complications Fall Investigations Abnormal electrocardiogram T wave, increased blood lactate dehydrogenase, increased blood urea, increased hematocrit, increased hepatic enzyme, increased international normalized ratio, weight fluctuation Metabolism and Nutrition Disorders Anorexia, dehydration, fluid overload, hypercalcemia, hyperphosphatemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypoproteinemia, metabolic acidosis Musculoskeletal and Connective Tissue Disorders Arthralgia, osteopenia, osteoporosis Neoplasms Bladder cancer, Kaposi’s sarcoma, non-melanoma skin cancer, papillary thyroid cancer Nervous System Disorders Aphasia, carpal tunnel syndrome, cerebral infarction, cerebral ischemia, convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy, somnolence, syncope Psychiatric Disorders Agitation, anxiety, confusional state, depression, hallucination, mental status changes, mood swings, nightmare Renal and Urinary Disorders Anuria, hematuria, oliguria, proteinuria, renal failure, renal graft dysfunction, renal tubular necrosis, toxic nephropathy, urinary incontinence, urinary retention Respiratory, Thoracic and Mediastinal Disorders Acute respiratory distress syndrome, allergic rhinitis, dyspnea, emphysema, hiccups, lung infiltration, pulmonary edema, productive cough, respiratory failure Skin and Subcutaneous Tissue Disorders Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash Vascular Disorders Deep vein thrombosis, flushing, hemorrhage, hypotension, orthostatic hypotension 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. Blood and Lymphatic System Disorders Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic uremic syndrome, prolonged activated partial thromboplastin time, pure red cell aplasia [see Warnings and Precautions (5.17)], thrombotic thrombocytopenic purpura Cardiac Disorders QT prolongation, supraventricular extrasystoles, supraventricular tachycardia, Torsade de Pointes, ventricular fibrillation Eye Disorders Blindness, photophobia, optic atrophy Gastrointestinal Disorders Dysphagia, gastrointestinal perforation [see Warnings and Precautions (5.18)], intestinal obstruction, peritonitis General Disorders Multi-organ failure Hepatobiliary Disorders Bile duct stenosis, cholangitis, cirrhosis, hepatic failure, hepatic necrosis, hepatic steatosis, jaundice, venoocclusive liver disease Immune disorders Graft versus host disease (acute and chronic) Musculoskeletal and Connective Tissue Disorders Myalgia, polyarthritis, rhabdomyolysis Neoplasms Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD [see Warnings and Precautions (5.2)]; leukemia, melanoma Nervous System Disorders Coma, dysarthria, flaccid paralysis, hemiparesis, mutism, nerve compression, posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.10)], progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.6)], quadriplegia, status epilepticus Renal and Urinary Disorders Hemorrhagic cystitis Respiratory, Thoracic and Mediastinal Disorders Interstitial lung disease, pulmonary hypertension Skin and Subcutaneous Tissue Disorders Hyperpigmentation, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria 7 DRUG INTERACTIONS 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 (5.14) and Clinical Pharmacology (12.3)]. Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when ASTAGRAF XL 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 (5.9) and (5.15)]. 7.1 Mycophenolic Acid Products With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with ASTAGRAF XL coadministration than with cyclosporine coadministration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should monitor for MPA associated adverse events and reduce the dose of concomitantly administered mycophenolic acid products, if needed. 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 in combination with ASTAGRAF XL [see Dosage and Administration (2.4)]. 7.3 Alcohol Consumption of alcohol with ASTAGRAF XL may increase the rate of release of tacrolimus and/or adversely alter the pharmacokinetic properties and the effectiveness and safety of ASTAGRAF XL. Therefore, alcoholic beverages should not be consumed with ASTAGRAF XL [see Dosage and Administration (2.4)]. 7.4 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 coadministered with telaprevir or with boceprevir. 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. 7.5 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. 7.6 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. 7.7 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. 7.8 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. 7.9 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 of phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when tacrolimus and phenytoin are administered concomitantly. 7.10 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 coadministered. 7.11 Gastric Acid Suppressors/Neutralizers Lansoprazole and omeprazole, the proton pump inhibitors (PPIs), as CYP2C19 and CYP3A4 substrates, share the same CYP3A4 system with tacrolimus for their hepatic elimination, and may potentially competitively 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 in which the PPIs metabolic pathway shifts from 2C19 to 3A4, as compared to those patients who are efficient CYP2C19 metabolizers. Cimetidine, a CYP2C19 and CYP3A4 inhibitor, may also inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. Coadministration with magnesium and aluminum hydroxide antacids increase 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. 7.12 Other Drugs Amiodarone, bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, 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 coadministered. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus given orally to pregnant rabbits at 0.5 times the maximum clinical dose and pregnant rats at 0.8 times the maximum clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. ASTAGRAF XL should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.5 and 1.6 times the maximum clinical dose based on body surface area, respectively) was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (2.6 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (0.8 and 2.6 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed. 8.3 Nursing Mothers Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from ASTAGRAF XL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of drug to the mother. 8.4 Pediatric Use The safety and efficacy of ASTAGRAF XL in pediatric kidney transplant patients < 16 years of age has not been established. 8.5 Geriatric Use Clinical studies of ASTAGRAF XL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 8.6 Renal Impairment The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, frequent monitoring of renal function is recommended; tacrolimus dosage should be reduced if indicated [see Warnings and Precautions (5.9), Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy subjects with normal hepatic function. Frequent monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Race The data from ASTAGRAF XL administration in kidney transplant patients indicate that African-American patients may require higher doses to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), Clinical Studies (14)]. 10 OVERDOSAGE Postmarketing cases of overdose with tacrolimus have been reported. Some of these cases were symptomatic with adverse reactions including nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and somnolence), gastrointestinal disturbances (nausea, vomiting, and diarrhea), abnormal renal function (increased blood urea nitrogen and elevated serum creatinine), urticaria, hypertension, peripheral edema, and infections. One fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus (extended-release) overdose. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage. In acute oral toxicity studies, mortality was observed at or above the following doses: in orally administered adult rats, 80-fold the recommended human dose for adults; in orally administered immature rats, 18-fold the maximum adult human dose. All doses are based on body surface area conversions (mg/m2). 11 DESCRIPTION ASTAGRAF XL is available for oral administration as hard gelatin capsules (tacrolimus extended-release capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include ethylcellulose NF, hypromellose USP, magnesium stearate NF and lactose monohydrate NF. The ingredients are directly proportional across all capsule strengths. The capsule shell contains gelatin NF, titanium dioxide USP, ferric oxide NF, and sodium lauryl sulfate. The capsule shell also has a trace of printing ink, Opacode S-1-15083 Red. Tacrolimus is the active ingredient in ASTAGRAF XL. 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 – methoxycyclo – hexyl) – 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:
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