Tacrolimus

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

1 INDICATIONS AND USAGE Tacrolimus extended-release capsules is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult patients who can swallow capsules intact [see Clinical Studies ( 14.1 ), ( 14.2 )] . Pediatric use information is approved for Astellas Pharma US, Inc.'s ASTAGRAF XL (tacrolimus extended-release capsules). However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. Tacrolimus extended-release capsules is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult patients who can swallow capsules intact. ( 1 , 14.1 , 14.2 )

2 DOSAGE AND ADMINISTRATION Capsules must be taken whole. ( 2.1 ) Take consistently every morning at the same time on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal. ( 2.1 ) Avoid eating grapefruit or drinking grapefruit juice or alcohol. ( 2.1 ) African-American patients and patients with severe hepatic impairment may require dosing adjustments. ( 2.3 ) Frequent monitoring of trough concentrations is recommended. ( 2.4 ) For complete dosing information, see Full Prescribing Information. MMF = Mycophenolate mofetil Recommended Tacrolimus Extended-Release Capsules Initial Dosage Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 mg/kg to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant Month 1: 7 ng/mL to 15 ng/mL Month 2 to Month 6: 5 ng/mL to 15 ng/mL More than 6 Months: 5 ng/mL to 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 ng/mL to 15 ng/mL Month 2 to Month 6: 5 ng/mL to 15 ng/mL More than 6 Months: 5 ng/mL to 10 ng/mL 2.1 Important Administration Instructions Tacrolimus extended-release capsules should not be used without the supervision by a physician with experience in immunosuppressive therapy. 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 tacrolimus extended-release capsules whole with liquid; patients must not chew, divide, or crush the capsules. Tacrolimus extended-release capsules 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 tacrolimus extended-release capsules [see Drug Interactions ( 7.2 )]. Therapeutic drug monitoring is recommended for all patients receiving tacrolimus extended-release capsules [see Dosage and Administration ( 2.4 )] . 2.2 Dosage Recommendations for Kidney Transplant Patients Table 1 includes the recommended starting tacrolimus extended-release capsules 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 tacrolimus extended-release capsules 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 Tacrolimus Extended-Release Capsules MMF = mycophenolate mofetil Recommended Tacrolimus Extended-Release Capsules Initial Dosage* Patient Population Initial Oral Dosage Whole Blood Trough Concentration Range ADULT With basiliximab, MMF and steroids 0.15 mg/kg to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant • Month 1: 7 ng/mL to 15 ng/mL • Month 2 to Month 6: 5 ng/mL to 15 ng/mL • More than 6 Months: 5 ng/mL to 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 ng/mL to 15 ng/mL • Month 2 to Month 6: 5 ng/mL to 15 ng/mL • More than 6 Months: 5 ng/mL to 10 ng/mL Pediatric use information is approved for Astellas Pharma US, Inc.'s ASTAGRAF XL (tacrolimus extended-release capsules). However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Dosage Modifications for African-American Patients, Patients with Hepatic Impairment, and Drug Interactions African-American patients, compared to Caucasian patients, may need to be titrated to higher tacrol

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 Tacrolimus Extended-Release Capsules 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 eVenus Pharmaceutical Laboratories, Inc. at 1-609-395-8625 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 tacrolimus extended-release capsules (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 tacrolimus extended-release capsules (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 tacrolimus extended-release capsules and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation in tacrolimus extended-release capsules-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 tacrolimus extended-release capsules or tacrolimus immediate-release product in Study 1 are shown in Table 2 . Table 2: Percentage of Patients with Infections in Study 1 Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table. Through One Year Post-Kidney Transplant Tacrolimus extended-release capsules, 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 more than 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA 1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant [see Warnings and Precautions ( 5.5 )] . Table 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1 Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release product for the adverse reactions reported in this table. Tacrolimus extended-release capsules, MMF, steroids, basiliximab induction N=162 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=151 Composite NODAT 36% 35% ≥ 2 Fasting Plasma Glucose Values ≥ 126 mg/dL ≥ 30 days apart 26% 23% HbA 1C ≥ 6.5% 19% 22% Oral hypoglycemic use ≥ 30 consecutive days 14% 9% Insulin use ≥ 30 consecutive days 6% 8% Hyperkalemia In Study 1 [see Clinical Studies ( 14.1 )] , 73 of 214 (34.1%) patients on tacrolimus extended-release capsules had a serum potassium leve

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 tacrolimus extended-release capsules should be considered when tacrolimus extended-release capsules is co-administered with cannabidiol. ( 2.4 , 5.15 , 7.3 ) See Full Prescribing Information for clinically significant drug interactions. ( 7.1 , 7.2 , 7.3 ) 7.1 Mycophenolic Acid When tacrolimus extended-release capsules is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus extended-release capsules co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed. 7.2 Effects of Other Drugs on Tacrolimus Extended-Release Capsules Table 5 displays the effects of other drugs on tacrolimus extended-release capsules. Table 5: Effects of Other Drugs/Substances on Tacrolimus Extended-Release Capsules Tacrolimus extended-release capsules 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. Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor. 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 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). : 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 tacrolimus extended-release capsules dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Pharmacology ( 12.3 )] . Strong CYP3A Inhibitors : 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 tacrolimus extended-release capsules dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.3 , 2.4 ) and Clinical Pharmacology ( 12.3 )] . Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions (5.10) ] . Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.7 , 5.10 , 5.11 )] . Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus extended-release capsules 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 tacroli