ASTAGRAF XL tacrolimus extended-release capsules 5 mg Capsule, Coated, Extended Release, 30-count
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Calcineurin Inhibitor Immunosuppressant class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Tacrolimus (Astagraf XL, Envarsus XR, Prograf) is used along with other medications to prevent rejection (attack of a transplanted organ by the immune system of a person receiving the organ) in people who have received a kidney transplant. Tacrolimus (Prograf) is also used along with other medications to prevent rejection in people who have received a liver, lung, or heart transplant. Tacrolimus is in a class of medications called immunosupressants. It works by decreasing the activity of the immune system to prevent it from attacking the transplanted organ.
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- Does it matter if I take tacrolimus with food or on an empty stomach?
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $27.772 | $833.17 / 30 capsules |
| Medicaid paysCMS SDUD · 12 mo | $25.72 | $771.60 / 30 capsules |
| Medicare drug plans payPart D · Q2 2026 | $30.33 | $909.99 / 30 capsules |
| Medicare Part B allowsASP · J7508 | $0.601 / J7508 unit | — |
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🧾 Billing & reimbursement
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Astagraf Xl 5 mgthis 00469-0687-73 | Astellas | 30 capsules | $27.772 | AB | FDA listed | — |
| Tacrolimus 5 mg 69238-2782-03 | Amneal | 10 capsules | — | AB | FDA listed | — |
| tacrolimus 5 mg 71432-2003-01 | Chengdu | 10 capsules | — | AB | FDA listed | — |
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⏳ Availability & generic status
The FDA lists approved generic versions of this medicine, but that does not always mean a pharmacy can get one today. Patent rules, launch agreements, supply and pricing can affect when generics actually arrive.
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🗺️ Medicaid utilization & spend
💊 Medicaid utilization by pack size
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
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📦 Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Status |
|---|---|---|---|---|---|
| 00469-0687-11 | 5 BLISTER PACK in 1 CARTON (0469-0687-11) / 10 CAPSULE, COATED, EXTENDED RELEASE in 1 BLISTER PACK | — | — | 2013-07-19 | Discontinued by firm |
| 00469-0687-73 You're viewing this | 1 BOTTLE in 1 CARTON (0469-0687-73) / 30 CAPSULE, COATED, EXTENDED RELEASE in 1 BOTTLE | $27.77 / ea | $833.17 | 2013-07-19 | Active |
In Medicaid, this is the most-dispensed pack of this product — about 100% of fills over the last four reported quarters. See all packs ↓
Pack size FAQ
What quantity is in NDC 00469-0687-73?
What NDC number is used to bill for this package of ASTAGRAF XL tacrolimus extended-release capsules 5 mg Capsule, Coated, Extended Release?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
📄 Full prescribing information FDA SPL
🚨 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 female liver transplant patients with ASTAGRAF XL. Not approved for use in liver transplantation. ( 5.3 )
🎯 Indications and Usage ▾
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 ▾
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
2.1Important 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 )].
2.2Dosage 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…
💊 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 Cautions ▾
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 )
5.1Lymphoma 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.
5.2Serious 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 )] .
5.3Increased 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.
5.4Not 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…
🤒 Adverse Reactions ▾
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 .
6.1Clinical 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…
🔄 Drug Interactions ▾
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 )
7.1Mycophenolic 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.
7.2Effects 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…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 )
8.1Pregnancy 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 The…
🤰 Pregnancy ▾
8.1Pregnancy 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…
🧒 Pediatric Use ▾
8.4Pediatric 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 ▾
8.5Geriatric 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 ▾
10 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.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism 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).
12.3Pharmacokinetics Table 7 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of ASTAGRAF XL in healthy subjects and in kidney transplant patients. Whole blood tacrolimus concentrations in these PK studies were measured using validated HPLC/MS/MS assays. Table 7: Pharmacokinetic Parameters of ASTAGRAF XL (Given Once Daily) in Healthy Subjects and in Kidney Transplant Patients (Under Fasted Conditions) a Healthy adult subjects (actual administered dose of ASTAGRAF XL); adult de novo kidney transplant patients (actual group mean dose of ASTAGRAF XL). b Day of ASTAGRAF XL treatment and PK profiling. c Arithmetic means ± S.D. d Median [range]. e “ De novo ” refers to immunosuppression starting at the time of transplantation; data from PK substudy of Study 2. f Tacrolimus trough concentration before the next dose. g Same daily dose of ASTAGRAF XL for 14-day period. h Correlation coefficient of AUC 24 to C min r = 0.88.
Population ASTAGRAF XL Dose a Day b PK Parameters of ASTAGRAF XL C max c (ng/mL) T max d (hr) AUC 24 c (ng•hr/mL) C 24 f (ng/mL) Healthy Subjects (N=24) 4 mg 4 mg Day 1 Day 10 6.2 ± 2.1 11.6 ± 3.4 2.0 [1.0-5.0] 2.0 [1.0-3.0] 74 ± 22 155 ± 46 2.3 ± 0.8 4.7 ±
1.5Adult Kidney De novo e (N=17) 0.20 mg/kg 0.19 mg/kg 0.18 mg/kg 0.18 mg/kg Day 1 Day 3 Day 7 Day 14 26.0 ± 13.7 31.0 ± 13.9 32.2 ± 10.2 32.7 ± 9.0 3.0 [2-24] 2.0 [0.5-2.0] 2.0 [1-6] 2.0 [1-4] 372 ± 202 437 ± 175 405 ± 117 412 ± 109 12.1 ± 7.2 13.5 ± 5.6 11.4 ± 4.0 11.2 ±
3.9Adult Kidney (6 months or greater post-transplant) (N=60) 5.2 mg/day g Day 14 g 16.1 ± 5.3 2.0 [1.0 - 6.0] 222 ± 64 6.7 ± 1.9 h In de novo adult kidney transplant patients, the tacrolimus systemic exposure, as assessed by AUC 24 , for ASTAGRAF XL 0.2 mg/kg once daily on Day 1 post-transplant was 18% (Ratio [SD]: 0.822 [1.647]) lower when compared with Prograf (tacrolimus immediate-release) 0.2 mg/kg/day given twice daily. By Day 3 post-transplant, the AUC 24 was similar between the two formulations. On Day 14 (steady state), the AUC 24 for ASTAGRAF XL was 21% (Ratio [SD]: 1.207 [1.326]) higher than that of Prograf (tacrolimus immediate-release), at comparable trough concentrations (C 24 ).
Due to intersubject variability in tacrolimus PK, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration ( 2.3 , 2.4 )] . Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus PK. Absorption In healthy subjects, the administration of escalating ASTAGRAF XL doses ranging from 1.5 mg to 10 mg resulted in dose-proportional increases in tacrolimus AUC and C 24h , and no change in elimination half-life.
Food Effects The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greates…
🧬 Mechanism of Action ▾
12.1Mechanism 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 / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING ASTAGRAF XL (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
📋 Description ▾
11 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
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
17.1Administration 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.
17.2Development 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 )] .
17.3Increased 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 )] .
17.4New 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 )] .
17.5Nephrotoxicity 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 )] .
17.6Neurotoxicity 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 )] .
17.7Hyperkalemia 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 )] .
17.8Hypertension 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.
17.9Thrombotic 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 Instr…
💬 Medication Guide ▾
MEDICATION GUIDE ASTAGRAF XL ® [as' tah graf ex el'] (tacrolimus) extended-release capsules Read this Medication Guide before you start taking ASTAGRAF XL and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
If you have any questions about ASTAGRAF XL, ask your healthcare provider or pharmacist. What is the most important information I should know about ASTAGRAF XL? ASTAGRAF XL can cause serious side effects, including: • Increased risk of cancer.
People who take ASTAGRAF XL have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma). • Increased risk of infection. ASTAGRAF XL is a medicine that affects your immune system. ASTAGRAF XL can lower the ability of your immune system to fight infections.
Serious infections can happen in people receiving ASTAGRAF XL that can cause death. Call your healthcare provider right away if you have symptoms of an infection such as: • fever • sweats or chills • cough or flu-like symptoms • muscle aches • warm, red, or painful areas on your skin • Increased risk of death in females who have had a liver transplant. You should not take ASTAGRAF XL if you have had a liver transplant without talking to your healthcare provider.
What is ASTAGRAF XL? • ASTAGRAF XL is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney transplant. • ASTAGRAF XL is an extended-release capsule and is not the same as tacrolimus immediate-release capsules, tacrolimus for oral suspension or tacrolimus extended-release tablets. Your healthcare provider should decide what medicine is right for you. Who should not take ASTAGRAF XL? • Do not take ASTAGRAF XL if you are allergic to tacrolimus or any of the ingredients in ASTAGRAF XL.
See the end of this leaflet for a complete list of ingredients in ASTAGRAF XL. What should I tell my healthcare provider before taking ASTAGRAF? Before you take ASTAGRAF XL tell your healthcare provider if you: • plan to receive any live vaccines.
Ask your healthcare provider if you are not sure if your vaccine is a live vaccine. • have or have had liver, kidney, or heart problems or any other medical conditions. • are pregnant or plan to become pregnant. ASTAGRAF XL may harm your unborn baby. o If you are able to become pregnant, you should use effective birth control before and during treatment with ASTAGRAF XL. Talk to your healthcare provider before starting treatment with ASTAGRAF XL about birth control methods that may be right for you. o Males who have female partners that are able to become pregnant should also use effective birth control before and during treatment with ASTAGRAF XL.
Talk to your healthcare provider before starting treatment with ASTAGRAF XL about birth control methods that may be right for you. o There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with ASTAGRAF XL. The purpose of this registry is to collect information about your health and of your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/ . • are breastfeeding or plan to breastfeed.
ASTAGRAF XL passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking ASTAGRAF XL. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements.
ASTAGRAF XL may affect the way other medicines work, and other medicines may affect how ASTAGRAF XL works. Especially tell your healthcare provider if you take: • sirolimus (RAPAMUNE): You should not take ASTAGRAF XL if you take sirolimus • cyclosporine (GENGRAF, NEORAL, and SANDIMMUNE) • medicines called aminoglycosides that are used to treat bacterial inf…