ASTAGRAF XL

1 INDICATIONS AND USAGE ASTAGRAF XL ® is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact [see Use in Specific Populations ( 8.4 ) and Clinical Studies ( 14.1 ), ( 14.2 )]. ASTAGRAF XL is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact. ( 1 , 8.4 , 14.1 , 14.2 )

2 DOSAGE AND ADMINISTRATION • Capsules must be taken whole. ( 2.1 ) • Take consistently every morning at the same time on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal. ( 2.1 ) • Avoid eating grapefruit or drinking grapefruit juice or alcohol. ( 2.1 ) • African-American patients and patients with severe hepatic impairment may require dosing adjustments. ( 2.3 ) • Frequent monitoring of trough concentrations is recommended. ( 2.4 ) • For complete dosing information, see Full Prescribing Information. MMF = Mycophenolate mofetil Recommended ASTAGRAF XL Initial Dosage Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant • Month 1: 7‑15 ng/mL • Months 2-6: 5‑15 ng/mL • > 6 Months: 5‑10 ng/mL With MMF and steroids, without basiliximab induction • First dose (pre-operative): 0.1 mg/kg, within 12 hours prior to reperfusion • Subsequent doses (post-operative): 0.2 mg/kg once daily at least 4 hours after pre-operative dose and within 12 hours after reperfusion • Month 1: 10‑15 ng/mL • Months 2-6: 5‑15 ng/mL • > 6 Months: 5‑10 ng/mL PEDIATRIC With basiliximab, MMF and steroids 0.3 mg/kg once daily, administered within 24 hours following reperfusion • Month 1: 10‑20 ng/mL • > Month 1: 5‑15 ng/mL 2.1 Important Administration Instructions • ASTAGRAF XL should not be used without the supervision by a physician with experience in immunosuppressive therapy. • ASTAGRAF XL (tacrolimus extended-release capsules) is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision [see Warnings and Precautions ( 5.4 )]. • Advise patients to swallow ASTAGRAF XL capsules whole with liquid; patients must not chew, divide, or crush the capsules. • ASTAGRAF XL should be taken consistently every morning at the same time to ensure consistent and maximum possible drug exposure, on an empty stomach at least 1 hour before a meal, or at least 2 hours after a meal [see Clinical Pharmacology ( 12.3 )]. • If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken 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. Instruct the patient not to double the next dose. • Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking ASTAGRAF XL [see Drug Interactions ( 7.2 )]. • Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL [see Dosage and Administration ( 2.4 )]. 2.2 Dosage Recommendations for Kidney Transplant Patients Table 1 includes the recommended starting ASTAGRAF XL dosages and whole blood trough concentration ranges; the observed trough concentrations are shown in another section of the Full Prescribing Information [see Clinical Studies ( 14 )]. Titrate the ASTAGRAF XL dosage based on clinical assessments of rejection and tolerability, and to achieve target trough concentration ranges [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.6 , 5.7 , 5.10 , 5.11 )]. Table 1: Recommended Starting Daily Dosage Regimen of ASTAGRAF XL MMF = mycophenolate mofetil Recommended ASTAGRAF XL Initial Dosage * Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant • Month 1: 7-15 ng/mL • Months 2-6: 5-15 ng/mL • > 6 Months: 5-10 ng/mL With MMF …

5 WARNINGS AND PRECAUTIONS • Not Interchangeable with Other Tacrolimus Products-Medication Errors: Instruct patients or caregivers to recognize the appearance of ASTAGRAF XL capsules. ( 5.4 ) • New onset diabetes after transplant: Monitor blood glucose. ( 5.5 ) • Nephrotoxicity (acute and/or chronic): May occur due to ASTAGRAF XL, drug interactions, concomitant nephrotoxic drugs. Monitor renal function; consider dosage reduction. ( 5.6 ) • Neurotoxicity: Including risk of posterior reversible encephalopathy syndrome (PRES), monitor for neurologic abnormalities; reduce dosage or discontinue ASTAGRAF XL. ( 5.7 ) • Hyperkalemia: Risk may be increased with other agents associated with hyperkalemia; monitor serum potassium levels. ( 5.8 ) • Hypertension: May require antihypertensive therapy; monitor relevant drug interactions. ( 5.9 ) • QT prolongation: Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk. ( 5.11 ) • Immunizations: Avoid live vaccines. ( 5.12 ) • Pure red cell aplasia: Consider discontinuation of ASTAGRAF XL. ( 5.13 ) • Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.14 ) 5.1 Lymphoma and Other Malignancies Immunosuppressants, including ASTAGRAF XL, increase the risk of developing lymphomas and other malignancies, particularly of the skin . The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. The risk of PTLD appears greatest in patients who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment. 5.2 Serious Infections Immunosuppressants, including ASTAGRAF XL, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include: • Polyomavirus-associated nephropathy (especially due to BK virus infection) • JC virus-associated progressive multifocal leukoencephalopathy (PML) • Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease. Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions ( 6.1 , 6.2 )] . 5.3 Increased Mortality in Female Liver Transplant Patients In a clinical trial of 471 liver transplant patients randomized to ASTAGRAF XL or tacrolimus immediate-release product, 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 tacrolimus immediate-release product. ASTAGRAF XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant. 5.4 Not Interchangeable with Other Tacrolimus Products - Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and ASTAGRAF XL (tacrolimus extended-release capsules) were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus. ASTAGRAF XL is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Changes between tacrolimus immediate-re…

4 CONTRAINDICATIONS ASTAGRAF XL is contraindicated in patients with known hypersensitivity to tacrolimus [see Adverse Reactions ( 6.2 )] . Known hypersensitivity to tacrolimus. ( 4 )

7 DRUG INTERACTIONS • Risk of rejection with strong CYP3A inducers and risk of serious adverse reactions with strong CYP3A inhibitors: Adjust dose and monitor tacrolimus concentrations. ( 2.4 , 5.10 , 7.2 ) • Therapeutic drug monitoring and dose reduction for ASTAGRAF XL should be considered when ASTAGRAF XL is co-administered with cannabidiol ( 2.4 , 5.15 , 7.3 ). • See Full Prescribing Information for clinically significant drug interactions. ( 7.1 , 7.2 , 7.3 ) 7.1 Mycophenolic Acid When ASTAGRAF XL is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with ASTAGRAF XL co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed. 7.2 Effects of Other Drugs on ASTAGRAF XL Table 5 displays the effects of other drugs on ASTAGRAF XL. Table 5: Effects of Other Drugs/Substances on ASTAGRAF XL a Drug/Substance Class or Name Drug Interaction Effect Recommendations a ASTAGRAF XL dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology ( 12.3 )] , literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status. b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor. c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate). Grapefruit or grapefruit juice b May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.7 , 5.10 , 5.11 )]. Avoid grapefruit or grapefruit juice. Alcohol May increase the rate of tacrolimus release and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.7 , 5.10 , 5.11 )]. Avoid alcoholic beverages. Strong CYP3A Inducers c : Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions ( 5.10 )]. Increase ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Pharmacology ( 12.3 )]. Strong CYP3A Inhibitors c : Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see Warnings and Precautions ( 5.7 , 5.10 , 5.11 )]. Reduce ASTAGRAF XL dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Pharmacology ( 12.3 )]. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions ( 5.10 )] . Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and o…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ASTAGRAF XL during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ . Risk Summary Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress [see Human Data]. Advise pregnant women of the potential risk to the fetus. Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses [0.5 the maximum recommended clinical dose (0.2 mg/kg/day), on a mg/m 2 basis]. Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 the maximum recommended clinical dose, on a mg/m 2 basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 times the maximum recommended clinical dose, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data]. The background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death. Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported. Maternal Adverse Reactions ASTAGRAF XL may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.5 )] . ASTAGRAF XL may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.8 , 5.9 )] . Fetal/Neonatal Adverse Reactions Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking ASTAGRAF XL. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to ASTAGRAF XL. Data Human Data There are no adequate and well-controlled studies on the effects of tacrolimus in human pregnancy. Safety data from the TPRI and postmarke…

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are discussed in greater detail in other sections of labeling: • Lymphoma and Other Malignancies [see Warnings and Precautions ( 5.1 )] • Serious Infections [see Warnings and Precautions ( 5.2 )] • Increased Mortality in Female Liver Transplant Patients [see Warnings and Precautions ( 5.3 )] • New Onset Diabetes after Transplant [see Warnings and Precautions ( 5.5 )] • Nephrotoxicity due to ASTAGRAF XL and Drug Interactions [see Warnings and Precautions ( 5.6 )] • Neurotoxicity [see Warnings and Precautions ( 5.7 )] • Hyperkalemia [see Warnings and Precautions ( 5.8 )] • Hypertension [see Warnings and Precautions ( 5.9 )] • QT Prolongation [see Warnings and Precautions ( 5.11 )] • Pure Red Cell Aplasia [see Warnings and Precautions ( 5.13 )] • Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions ( 5.14 )] 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 . 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 patients were treated with ASTAGRAF XL (N=214) or tacrolimus immediate-release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S. patients (Study 1) [see Clinical Studies ( 14.1 )] . The types of adverse reactions seen in Study 1 were similar to the adverse reactions seen in Study 2 [non-U.S. trial in kidney transplant patients treated with ASTAGRAF XL (N=331) or tacrolimus immediate-release product (N=336) and concomitant immunosuppressants] [see Clinical Studies ( 14.2 )] . In Study 1, the proportion of patients who discontinued treatment due to adverse reactions was 9% and 11% in the ASTAGRAF XL and tacrolimus immediate-release treatment groups, respectively, 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. Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the ASTAGRAF XL or tacrolimus immediate-release product in Study 1 are shown in Table 2 . Table 2: Percentage of Patients with Infections in Study 1 a Through One Year Post-Kidney Transplant a Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release product for the adverse reactions reported in this table. ASTAGRAF XL, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 All Infections 69% 69% Respiratory Infections 34% 31% Urinary Tract Infections 16% 25% Cytomegalovirus Infections 10% 11% Bacterial Infections 8% 12% Gastroenteritis 7% 3% Polyomavirus Infections 3% 5% Serious Infections 22% 23% New Onset Diabetes After Transplant (NODAT) The incidence of 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 HbA 1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant [see Warnings and Precautions ( 5.5 )]. Table …