This information is not for clinical use. These highlights do not include all the information needed to use Astagraf Xl safely and effectively. Before taking Astagraf Xl please consult with your doctor. See full prescribing information for Astagraf Xl.

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

ASTAGRAF XL® is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients [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. (1, 8.4, 14.1, 14.2)

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Dosage And Administration

Month 1: 7-15 ng/mL Months 2-6: 5-15 ng/mL > 6 Months: 5-10 ng/mLFirst 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 reperfusionMonth 1: 10-15 ng/mL Months 2-6: 5-15 ng/mL > 6 Months: 5-10 ng/mLMonth 1: 10-20 ng/mL > Month 1: 5-15 ng/mL
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
With MMF and steroids, without basiliximab induction
PEDIATRIC
With basiliximab, MMF and steroids 0.3 mg/kg once daily, administered within 24 hours following reperfusion

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

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

Warning and Cautions

• Not Interchangeable with Other Tacrolimus Products-Medication Errors: Instruct patients or caregivers to recognize 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. (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. (5.13) 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 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 substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. 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. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. 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) [see Adverse Reactions (6.1, 6.2) and Drug Interactions (7.2)]. Monitor renal function and consider dosage reduction if nephrotoxicity occurs. 5.7 Neurotoxicity ASTAGRAF XL may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions (6.1, 6.2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of ASTAGRAF XL if neurotoxicity occurs. 5.8 Hyperkalemia Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ASTAGRAF XL. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment. 5.9 Hypertension Hypertension is a common adverse reaction of ASTAGRAF XL therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. Some antihypertensive drugs can increase the risk for hyperkalemia [see Warnings and Precautions (5.8)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL [see Drug Interactions (7.2)]. 5.10 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.11)]. Therefore, adjust ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations when coadministering ASTAGRAF XL with strong CYP3A inhibitors (e.g., including but not limited to telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including but not limited to rifampin, rifabutin) [see Dosage and Administration (2.4) and Drug Interactions (7.2)]. 5.11 QT Prolongation ASTAGRAF XL may prolong the QT/QTc interval and cause Torsade de Pointes. Avoid ASTAGRAF XL in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia). When coadministering ASTAGRAF XL with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in ASTAGRAF XL dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended [see Dosage and Administration (2.4) and Drug Interactions (7.2)]. 5.12 Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ASTAGRAF XL. Avoid the use of live attenuated vaccines during treatment with ASTAGRAF XL (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with ASTAGRAF XL. 5.13 Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of ASTAGRAF XL.

Adverse Reactions

The following clinically significant adverse drug reactions are discussed in greater detail in other sections of labeling: •Lymphoma and Other Malignancies [see Boxed Warning, Warnings and Precautions (5.1)] •Serious Infections [see Boxed Warnings , 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)] 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 1a 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 HbA1C ≥ 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 1a 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% HbA1C ≥ 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 1a 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. ASTAGRAF XL, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212 Diarrhea 45% 44% Constipation 40% 32% Nausea 36% 35% Peripheral Edema 36% 34% Tremor 35% 34% Anemia 33% 29% Hypertension 28% 30% Vomiting 25% 25% Hypomagnesemia 24% 27% Insomnia 24% 28% Hypophosphatemia 23% 28% Headache 22% 24% Hyperkalemia 20% 23% Increased Blood Creatinine 19% 23% Fatigue 16% 10% Leukopenia 16% 16% Hyperlipidemia 16% 17% Hyperglycemia 16% 18% Less Frequently Reported Adverse Reactions (< 15% in ASTAGRAF XL-treated patients) by System Organ Class The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with ASTAGRAF XL, MMF, and steroids (Studies 1 and 2): •Blood and Lymphatic System Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy •Cardiac Disorders: Atrial fibrillation, atrial flutter, tachycardia •Ear Disorders: Tinnitus •Eye Disorders: Vision blurred, conjunctivitis •Gastrointestinal Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease •General Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia •Hepatobiliary Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity •Infections and Infestations: Condyloma acuminatum, tinea versicolor •Injury: Fall •Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme •Metabolism and Nutrition Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis •Musculoskeletal and Connective Tissue Disorders: Arthralgia, osteopenia, osteoporosis •Neoplasms: Kaposi’s sarcoma •Nervous System Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy •Psychiatric Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare •Renal and Urinary Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy •Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough •Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash •Vascular Disorders: Deep vein thrombosis, flushing Pediatrics De Novo Pediatric Transplant Patients A study was conducted in 44 de novo pediatric transplant patients, (including 25 kidney transplant patients; 13 randomized to Astagraf XL and 12 randomized to Prograf), who were started on 0.3 mg/kg daily of tacrolimus product, given once daily for Astagraf XL and divided into two doses for Prograf. Two kidney transplant patients on Prograf discontinued the study (withdrawn consent, sapovirus enteritis). Thirteen (13) pediatric kidney transplant patients completed 52 weeks on ASTAGRAF XL. The most common adverse reactions were diarrhea [7/13 (54%)], increased blood creatinine [6/13 (46%)], hypertension [3/13 (23%)], cough [4/13 (31%)], and upper respiratory tract infection [4/13 (31%)]. Stable Pediatric Transplant Patients Another study was conducted in 81 stable pediatric allograft recipients (including 48 kidney transplant patients) 5 to 16 years of age converted 1:1 (mg:mg) from Prograf to ASTAGRAF XL. Seventy-six (76) pediatric patients completed at least one year of ASTAGRAF XL-based treatment. Treatment-related adverse reactions were reported in 35%, including 13% serious adverse reactions. The most frequent adverse reactions by system organ class were infections (55.7%), followed by gastrointestinal disorders (27.8%), skin and subcutaneous tissue disorders (21.5%), respiratory, thoracic and mediastinal disorders (20.3% each). The most common adverse reactions were diarrhea (13.9%), headache (13.9%) and cough (11.4%). 6.2 Postmarketing Experience The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to ASTAGRAF XL: •Blood and Lymphatic System Disorders: Agranulocytosis, disseminated intravascular coagulation, hemolytic uremic syndrome, pancytopenia, pure red cell aplasia [see Warnings and Precautions (5.13)], coagulopathy, thrombotic thrombocytopenic purpura, prolonged activated partial thromboplastin time, decreased blood fibrinogen •Cardiac Disorders: Cardiac arrest, myocardial infarction, ventricular fibrillation, congestive cardiac failure, hypertrophic cardiomyopathy, pericardial effusion, angina pectoris, supraventricular extrasystoles, supraventricular tachycardia, bradycardia, Torsade de Pointes, QT prolongation •Ear Disorders: Hearing loss •Eye Disorders: Blindness, optic atrophy, photophobia •Gastrointestinal Disorders: Gastrointestinal hemorrhage, gastrointestinal perforation, pancreatitis, peritonitis, stomach ulcer, intestinal obstruction, ascites, colitis, ileus, impaired gastric emptying, dysphagia •Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, cirrhosis, cholangitis, venoocclusive liver disease, bile duct stenosis, hepatic steatosis, jaundice •Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria •Immune System Disorders: Graft versus host disease (acute and chronic) •Investigations: Increased international normalized ratio •Metabolism and Nutrition Disorders: Hypoproteinemia •Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) •Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, hepatosplenic T-cell lymphoma, PTLD [see Warnings and Precautions (5.1)], leukemia, melanoma •Nervous System Disorders: Cerebral infarction, progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2)], posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.7)], coma, status epilepticus, quadriplegia, flaccid paralysis, hemiparesis, aphasia, syncope, carpal tunnel syndrome, nerve compression, mutism, dysarthria, somnolence •Psychiatric Disorders: Mental status changes •Renal and Urinary Disorders: Hemorrhagic cystitis, hematuria, urinary retention, urinary incontinence •Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease, pulmonary hypertension, lung infiltration, rhinitis allergic, hiccups •Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity •Vascular Disorders: Hemorrhage

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) •See Full Prescribing Information for clinically significant drug interactions. (7.1, 7.2) 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 coadministration than with cyclosporine coadministration 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 XLa a ASTAGRAF XL dosage adjustment recommendation based on observed effect of coadministered 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). Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juiceb 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 Inducersc: 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 Inhibitorsc: Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, schisandra sphenanthera extracts 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)]. 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)]. Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (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 concentrations. Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4)].

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/m2 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/m2 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/m2 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/m2 basis). At 1 mg/kg (1.6 times the maximum recommended clinical dose), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 times the maximum recommended clinical dose) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered. In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 times the maximum recommended clinical dose). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 times the maximum recommended clinical dose) [see Nonclinical Toxicology (13.1)]. 8.2 Lactation Risk Summary Controlled lactation studies have not been conducted in humans, however tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [see Pregnancy (8.1) and Nonclinical Toxicology (13.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ASTAGRAF XL and any potential adverse effects on the breastfed child from ASTAGRAF XL or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception ASTAGRAF XL can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with ASTAGRAF XL [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)]. Infertility Based on findings in animals, male and female fertility may be compromised by treatment with ASTAGRAF XL [see Nonclinical Toxicology (13.1)]. 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)]. 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. 8.6 Renal Impairment The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended [see Dosage and Administration ( 2.3 )]. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed. 8.8 Race African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration ( 2.3 ), Clinical Pharmacology (12.3), and Clinical Studies (14)]. African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.5)].