Astagraf Xl

Tacrolimus extended-release capsules · Capsule, Coated, Extended Release · Oral

Prescription (Rx) Calcineurin Inhibitor Immunosuppressant 1 recall

Boxed warning. WARNING: MALIGNANCIES AND SERIOUS INFECTIONS IN TRANSPLANT PATIENTS; AND INCREASED MORTALITY IN FEMALE LIVER TRANSPLANT PATIENTS
• Increased risk for developing serious infections and malignancies with ASTAGRAF XL ® or other immunosuppressants that may lead to hospitalization or death. [see Warnings and Precautions ( 5.1 , 5.2 )]
• Increased mortality in female liver transplant patients with ASTAGRAF XL. ASTAGRAF XL is not approved for use in liver transplantation. [see Warnings and Precautions ( 5.3 )] WARNING: MALIGNANCIES AND SERIOUS INFECTIONS IN TRANSPLANT PATIENTS; AND INCREASED MORTALITY IN FEMALE LIVER TRANSPLANT PATIENTS See full prescribing information for complete boxed warning.
• Increased risk for developing serious infections and malignancies with ASTAGRAF XL or other immunosuppressants that may lead to hospitalization or death. ( 5.1 , 5.2 )
• Increased mortality in…

Uses

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 )

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 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 2.3 Dosage Modifications for African-American Patients, Patients with Hepatic Impairment, and Drug Interactions African-American patients, compared to Caucasian patients, may need to be titrated to higher ASTAGRAF XL dosages to attain comparable trough concentrations [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] . Patients with severe hepatic impairment (Child-Pugh ≥ 10) may require a lower starting dosage of ASTAGRAF XL, due to the reduced clearance and prolonged half-life [see Clinical Pharmacology ( 12.3 )]. Dose adjustments of ASTAGRAF XL may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol [see Warnings and Precautions ( 5.10 , 5.15 ) and Drug Interactions ( 7.2 , 7.3 )]. 2.4 Therapeutic Drug Monitoring Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after a change in dosage, after a change in co-administration of CYP3A4 inducers and/or inhibitors or cannabidiol [see Drug Interactions ( 7.2 , 7.3 )] , or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ASTAGRAF XL dose. Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)].

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS ASTAGRAF XL CAPSULES:
• 0.5 mg: light yellow cap and orange body branded with red “ 647” on the capsule body and “0.5 mg” on the capsule cap.
• 1 mg: white cap and orange body branded with red “ 677” on the capsule body and “1 mg” on the capsule cap.
• 5 mg: grayish-red cap and orange body branded with red “ 687” on the capsule body and “5 mg” on the capsule cap. Capsules: 0.5 mg, 1 mg, 5 mg ( 3 ) Astellas logo Astellas logo Astellas logo

Contraindications

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

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-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of ASTAGRAF XL capsules [see Dosage Forms and Strengths ( 3 )] and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed. 5.5 New Onset Diabetes After Transplant ASTAGRAF XL caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately [see Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.8 )] . 5.6 Nephrotoxicity due to ASTAGRAF XL and Drug Interactions ASTAGRAF XL, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration. The risk for nephrotoxicity may increase when ASTAGRAF XL is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use [ see Adverse Reactions ( 6.1 , 6.2 ) and Drug Interactions ( 7.2 )] .

Side effects

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 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1 a ASTAGRAF XL, MMF, steroids, basiliximab induction N=162 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=151 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. Composite NODAT 36% 35% ≥ 2 Fasting Plasma Glucose Values ≥ 126 mg/dL ≥ 30 days apart 26% 23% HbA 1C ≥ 6.5% 19% 22% Oral hypoglycemic use ≥ 30 consecutive days 14% 9% Insulin use ≥ 30 consecutive days 6% 8% Hyperkalemia In Study 1 [see Clinical Studies ( 14.1 )] , 73 of 214 (34.1%) patients on ASTAGRAF XL had a serum potassium level greater than 5.4 up to 6.4 mEq/L, and 8 out of 214 (3.7%) patients had a serum potassium level greater than 6.4 mEq/L [see Warnings and Precautions ( 5.8 )] . Common Adverse Reactions The most common (≥ 30%) adverse reactions observed with ASTAGRAF XL in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia. The incidence of adverse reactions that occurred in ≥ 15% of ASTAGRAF XL-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 4 . Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1 a ASTAGRAF XL, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 a Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release for the adverse reactions reported in this table.

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 omeprazole 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 )]. Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Pharmacology ( 12.3 )]. Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide 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 )]. Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Pharmacology ( 12.3 )]. Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see Dosage and Administration ( 2.3 , 2.4 )]. Caspofungin May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see Dosage and Administration ( 2.3 , 2.4 )]. Direct Acting Antiviral (DAA) Therapy The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of ASTAGRAF XL is warranted to ensure continued efficacy and safety [see Dosage and Administration ( 2.3 , 2.4 )] . 7.3 Cannabidiol The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and ASTAGRAF XL are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity.

Use in specific populations

Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) 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 postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress. TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 6 . In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for kidney and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations. Table 6: TPRI-Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus Kidney Liver Pregnancy Outcomes Includes multiple births and terminations. 462 253 Miscarriage 24.5% 25% Live births 331 180 Pre-term delivery (< 37 weeks) 49% 42% Low birth weight (< 2500 g) 42% 30% Birth defects 8% Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. 5% Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.

Pregnancy

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 postmarketing surveillance suggest infants exposed to tacrolimus in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress. TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 6 . In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for kidney and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations. Table 6: TPRI-Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus Kidney Liver Pregnancy Outcomes Includes multiple births and terminations. 462 253 Miscarriage 24.5% 25% Live births 331 180 Pre-term delivery (< 37 weeks) 49% 42% Low birth weight (< 2500 g) 42% 30% Birth defects 8% Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. 5% Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients. Animal Data Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 times the maximum recommended clinical dose [0.2 mg/kg/day], on a mg/m 2 basis).

Pediatric use

8.4 Pediatric Use The safety and effectiveness of ASTAGRAF XL in de novo pediatric kidney transplant patients have been established. Use of ASTAGRAF XL in pediatric kidney transplant patients is based on adequate and well-controlled studies of ASTAGRAF XL in adult kidney transplant patients [see Clinical Studies ( 14.1 , 14.2 )] and supported by pharmacokinetic and safety data of ASTAGRAF XL in pediatric transplant patients 4 years of age and older who are able to swallow capsules intact and Prograf (tacrolimus) capsules in adult and pediatric transplant patients [see Clinical Pharmacology ( 12.3 )]. De Novo Pediatric Kidney Transplant Patients A pharmacokinetic and safety study included 25 de novo pediatric kidney transplant patients, 4 to 15 years of age, randomized to Prograf (N=12) or ASTAGRAF XL (N=13). Tacrolimus exposures for the two drug products were comparable on Days 7 and 28 [see Clinical Pharmacology ( 12.3 )]. Among the 13 pediatric kidney transplant patients who completed 52 weeks on ASTAGRAF XL, there were no graft loss, deaths or episodes of biopsy-proven acute rejection [see Dosage and Administration ( 2.2 ) and Adverse Reactions ( 6.1 )]. Stable Pediatric Kidney Transplant Patients Another pharmacokinetic and safety study included 48 stable pediatric kidney transplant patients, 5 to 16 years of age, who were converted from a Prograf-based regimen to ASTAGRAF XL. Tacrolimus systemic exposures for the two drug products were comparable [see Clinical Pharmacology ( 12.3 )]. Acute rejections were reported in 2/48 kidney pediatric patients that responded to subsequent treatment. There were no graft failures or deaths following use of ASTAGRAF XL during the 54-week follow up [see Adverse Reactions ( 6.1 )].

Geriatric use

8.5 Geriatric Use Clinical studies of ASTAGRAF XL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In Studies 1 and 2, 29 patients were 65 years of age and older, and 3 patients were 75 years of age and over [see Clinical Studies ( 14 )] . Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overdosage

Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:
• 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.

Description

Tacrolimus is the active ingredient in ASTAGRAF XL. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus is designated as [3 S – [3 R *[ E (1 S *, 3 S *, 4 S *)], 4 S *, 5 R *, 8 S *, 9 E , 12 R *, 14 R *, 15 S *, 16 R *, 18 S *, 19 S *, 26a R *]] – 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: Tacrolimus has an empirical formula of C 44 H 69 NO 12
• H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. 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. Tacrolimus structural formula

Mechanism of action

12.1 Mechanism of Action Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL‑2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

How supplied

(tacrolimus) extended-release capsules are supplied in short, square bottles (see Table 19 ). Table 19: Strengths of ASTAGRAF XL 0.5 mg Oblong capsule with a light yellow cap and orange body. Capsule is branded with red “ 647” on capsule body and “0.5 mg” on the capsule cap. The bottle packaging is branded with a brown stripe.
• 30-count in short, square bottles with a brown cap (NDC 0469-0647-73) 1 mg Oblong capsule with a white cap and orange body. Capsule is branded with red “ 677” on capsule body and “1 mg” on the capsule cap. The bottle packaging is branded with a blue stripe.
• 30-count in short, square bottles with a blue cap (NDC 0469-0677-73) 5 mg Oblong capsule with a grayish-red cap and orange body. Capsule is branded with red “ 687” on capsule body and “5 mg” on the capsule cap. The bottle packaging is branded with an orange stripe.
• 30-count in short, square bottles with an orange cap (NDC 0469-0687-73) Store and Dispense Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. astellas-logo-01 astellas-logo-02 astellas-logo-03

Patient information

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 17.1 Administration Advise patients or caregivers to:
• Inspect their ASTAGRAF XL medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for ASTAGRAF XL [see Warnings and Precautions ( 5.4 )].
• Take ASTAGRAF XL at the same time every day to achieve consistent blood concentrations.
• Take ASTAGRAF XL in the morning, on an empty stomach at least 1 hour before or at least 2 hours after breakfast, to achieve maximum possible blood concentrations of the drug.
• Swallow capsule whole with liquid. Do not chew, divide or crush capsule.
• Avoid alcoholic beverages, grapefruit, and grapefruit juice while on ASTAGRAF XL [see Dosage and Administration ( 2.1 ) and Drug Interactions ( 7.2 )].
• Take a missed dose of ASTAGRAF XL as soon as possible but not more than 14 hours after the scheduled time (i.e., for a missed 8 AM dose, take by 10 PM). Beyond the 14-hour timeframe, instruct the patient to wait until the usual scheduled time the following morning to take the next scheduled dose. Do not take 2 doses at the same time. 17.2 Development of Lymphoma and Other Malignancies Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions ( 5.1 )] . 17.3 Increased Risk of Infection Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas of the skin [see Boxed Warning and Warnings and Precautions ( 5.2 )] . 17.4 New Onset Diabetes after Transplant Inform patients that ASTAGRAF XL can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger [see Warnings and Precautions ( 5.5 )] . 17.5 Nephrotoxicity Inform patients that ASTAGRAF XL can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions ( 5.6 )] . 17.6 Neurotoxicity Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions ( 5.7 )] . 17.7 Hyperkalemia Inform patients that ASTAGRAF XL can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions ( 5.8 )] . 17.8 Hypertension Inform patients that ASTAGRAF XL can cause high blood pressure which may require treatment with anti-hypertensive therapy [see Warnings and Precautions ( 5.9 )] . Advise patients to monitor their blood pressure. 17.9 Thrombotic Microangiopathy Inform patients that ASTAGRAF XL can cause blood clotting problems. The risk of this occurring increases when patients take ASTAGRAF XL and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria [see Warnings and Precautions ( 5.14 )] . 17.10 Drug Interactions Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription and nonprescription medicines, herbal and dietary supplements. Some medications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage of ASTAGRAF XL. Advise patients to avoid grapefruit, grapefruit juice and alcoholic beverages [see Warnings and Precautions ( 5.10 , 5.15 ) and Drug Interactions ( 7 )] . 17.11 Pregnancy, Lactation and Infertility Inform women of childbearing potential that ASTAGRAF XL can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )]. Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations ( 8.1 )] . Based on animal studies, ASTAGRAF XL may affect fertility in males and females [see Nonclinical Toxicology ( 13.1 )]. 17.12 Immunizations Inform patients that ASTAGRAF XL can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions ( 5.12 )] . Product of Japan Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 ASTAGRAF XL ® is a registered trademark of Astellas Pharma Inc. Prograf ® is a registered trademark of Astellas Pharma Inc. 398977-AST

Label text from the FDA structured product label by Astellas Pharma US, Inc. (revised Jan 14, 2026). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Astagraf Xl NDC products (3)

NDCStrength & formLabelerType
0469-0647Tacrolimus .5 mg/1
Capsule, Coated, Extended Release		Astellas Pharma US, Inc.NDA
0469-0677Tacrolimus 1 mg/1
Capsule, Coated, Extended Release		Astellas Pharma US, Inc.NDA
0469-0687Tacrolimus 5 mg/1
Capsule, Coated, Extended Release		Astellas Pharma US, Inc.NDA

Astagraf Xl recalls

Frequently asked questions

What is Astagraf Xl used for?

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…

What are the side effects of Astagraf Xl?

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… See the full label for the complete list.

Who makes Astagraf Xl?

Astagraf Xl is listed by 1 labeler in the FDA NDC directory, including Astellas Pharma US, Inc..

Has Astagraf Xl been recalled?

The FDA enforcement database lists 1 recall for Astagraf Xl, most recently D-0210-2025 (class i): Failed Tablet/Capsule Specifications: Bottles shipped to the USA may contain empty capsules