Tacrolimus

INDICATIONS AND USAGE Tacrolimus capsules, USP are a calcineurin-inhibitor immunosuppressant indicated for: • Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants ( 1.1 , 1.2 , 1.3 ) • Use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF) ( 1.1 , 1.2 , 1.3 ) • Limitations of Use ( 1.4 ): • Do not use simultaneously with cyclosporine • Intravenous use reserved for patients who cannot tolerate capsules orally • Use with sirolimus is not recommended in liver and heart transplant; use with sirolimus in kidney transplant has not been established 1.1 Prophylaxis of Organ Rejection in Kidney Transplant Tacrolimus capsules, USP are indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidney transplants. It is recommended that tacrolimus capsules be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies (14.1) ] . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration (2.6) ]. 1.2 Prophylaxis of Organ Rejection in Liver Transplant Tacrolimus capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that tacrolimus capsules be used concomitantly with adrenal corticosteroids [see Clinical Studies (14.2) ] . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration (2.6) ] . 1.3 Prophylaxis of Organ Rejection in Heart Transplant Tacrolimus capsules are indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that tacrolimus capsules be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies (14.3) ] . Therapeutic drug monitoring is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration (2.6) ] . 1.4 Limitations of Use Tacrolimus capsules should not be used simultaneously with cyclosporine [see Dosage and Administration (2.5) ] . Tacrolimus injection should be reserved for patients unable to take tacrolimus capsules orally [see Warnings and Precautions (5.11) ]. Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of tacrolimus capsules with sirolimus has not been established in kidney transplant [see Warnings and Precautions (5.12) ].

DOSAGE AND ADMINISTRATION • Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules). ( 2.1 , 2.2 ) • Administer capsules consistently with or without food. ( 2.1 ) • Therapeutic drug monitoring is recommended. ( 2.1 , 2.6 ) • Avoid eating grapefruit or drinking grapefruit juice. ( 2.1 ) • See dosing adjustments for African-American patients ( 2.2 ), hepatic and renal impaired. ( 2.4 , 2.5 ) • For complete dosing information, see the Full Prescribing Information . ADULT Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concentration Range Kidney Transplant With azathioprine 0.2 mg/kg/day capsules, divided in two doses, every 12 hours Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL With MMF/IL-2 receptor antagonist 0.1 mg/kg/day capsules, divided in two doses, every 12 hours Month 1 to 12: 4 to 11 ng/mL Liver Transplant With corticosteroids only 0.1 to 0.15 mg/kg/day capsules, divided in two doses, every 12 hours Month 1 to 12: 5 to 20 ng/mL Heart Transplant With azathioprine or MMF MMF= Mycophenolate mofetil 0.075 mg/kg/day capsules, divided in two doses, every 12 hours Month 1 to 3: 10 to 20 ng/mL Month ≥ 4: 5 to 15 ng/mL PEDIATRIC Liver Transplant 0.15 to 0.2 mg/kg/day capsules divided in two doses, every 12 hours Month 1 to 12: 5 to 20 ng/mL 2.1 Important Administration Instructions Tacrolimus capsules should not be used without supervision by a physician with experience in immunosuppressive therapy. Tacrolimus capsules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. 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 (5.3)] . Intravenous Formulation - Administration Precautions due to Risk of Anaphylaxis Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to oral tacrolimus is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions (5.9)] . Patients receiving tacrolimus injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen. Oral Formulations (Capsules) If patients are able to initiate oral therapy, the recommended starting doses should be initiated. Tacrolimus capsules may be taken with or without food. However, since the presence of food affects the bioavailability of tacrolimus, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology (12.3)]. General Administration Instructions Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)] . Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Therapeutic drug monitoring (TDM) is recommended for all patients receiving tacrolimus capsules [see Dosage and Administration (2.6)] . 2.2 Dosage Recommendations for Adult Kidney, Liver, or Heart Transplant Patients - Capsules and Injection Capsules If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of tacrolimus capsules should be administered no sooner than 6 hours after transplantation in the liver or heart transplant patients. In kidney transplant patients, the initial dose of tacrolimus capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. The initial oral tacrolimus capsules dosage recommendations for adult patients with kidney, liver, or heart transplants and whole blood trough concentration range are shown in Table 1. Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges listed in Table 1. Table 1. Summary of Initial Oral Tacrolimus Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults Patient Population Tacrolimus Capsules African-American patients may require higher doses compared to Caucasians (see Table 2) Initial Oral Dosage Whole Blood Trough Concentration Range Kidney Transplant With Azathioprine 0.2 mg/kg/day, divided in two doses, administered every 12 hours Month 1 to 3: 7 to 20 ng/mL Month 4 to 12: 5 to 15 ng/mL With MMF/IL-2 receptor antagonist In a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 [ see Clinical Studies (14.1) ] 0.1 mg/kg/day, divided in two doses, administered every 12 hours Month 1 to 12: 4 to 11 ng/mL Liver Transplant With corticosteroids only 0.10 to 0.15 mg/kg/day, divided in two doses, administered every 12 hours Month 1 to 12: 5 to 20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day, divided in two doses, administered every 12 hours Month 1 to 3: 10 to 20 ng/mL Month ≥ 4: 5 to 15 ng/mL Dosage should be titrated based on clinical assessments of rejection and tolerability. Tacrolimus capsules dosages lower than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant. The data in kidney transplant patients indicate that the African-American patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2) [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3) ]. Table 2. Comparative Dose and Trough Concentrations Based on Race Time After Transplant Caucasian African-American N = 114 N = 56 Dose (mg/kg) Trough Concentrations (ng/mL) Dose (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12.0 0.23 10.9 Month 1 0.17 12.8 0.26 12.9 Month 6 0.14 11.8 0.24 11.5 Month 12 0.13 10.1 0.19 11.0 Intravenous Injection Tacrolimus injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of tacrolimus capsules should be given 8 to 12 hours after discontinuing the intravenous infusion. The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney or liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous intravenous infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation. The whole blood trough concentration range described in Table 1 pertains to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous intravenous infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy. Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [ see Warnings and Precautions (5.9) ]. 2.3 Dos

WARNINGS AND PRECAUTIONS Not Interchangeable with Other Tacrolimus Products-Medication Errors: Instruct patients or caregivers to recognize the appearance of tacrolimus extended-release capsules. ( 5.4 ) New onset diabetes after transplant: Monitor blood glucose. ( 5.5 ) Nephrotoxicity (acute and/or chronic): May occur due to tacrolimus extended-release capsules, 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 tacrolimus extended-release capsules. ( 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 tacrolimus extended-release capsules. ( 5.13 ) Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.14 ) 5.1 Lymphoma and Other Malignancies Immunosuppressants, including tacrolimus extended-release capsules, increase the risk of developing lymphomas and other malignancies, particularly of the skin . The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. The risk of PTLD appears greatest in patients who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment. 5.2 Serious Infections Immunosuppressants, including tacrolimus extended-release capsules, 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 tacrolimus extended-release capsules or tacrolimus immediate-release product, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with tacrolimus extended-release capsules compared to the 64 female patients (8%) treated with tacrolimus immediate-release product. Tacrolimus extended-release capsules 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 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. Tacrolimus extended-release capsules is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of tacrolimus extended-release 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 Tacrolimus extended-release capsules 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 Tacrolimus Extended-Release Capsules and Drug Interactions Tacrolimus extended-release capsules, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration. The risk for nephrotoxicity may increase when tacrolimus extended-release capsules is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use [see Adverse Reactions ( 6.1 , 6.2 ) and Drug Interactions ( 7.2 )]. 5.7 Neurotoxicity Tacrolimus extended-release capsules 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 tacrolimus extended-release capsules if neurotoxicity occurs. 5.8 Hyperkalemia Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including tacrolimus extended-release capsules. 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 tacrolimus extended-release capsules 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 tacrolimus extended-release capsules [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 u

CONTRAINDICATIONS • Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 ) Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions ( 6 ))] .

DRUG INTERACTIONS • Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to tacrolimus; monitor for MPA-related adverse reactions and adjust MMF or MPA dose as needed. (7.1) • Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use. (7.2) • CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. (5.11, 7.2) • CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. (5.11, 7.2) • Therapeutic drug monitoring and dose reduction for tacrolimus should be considered when tacrolimus is co-administered with cannabidiol (5.17, 7.3). 7.1 Mycophenolic Acid When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus 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 Table 15 displays the effects of other drugs on Tacrolimus Table 15. Effects of Other Drugs/Substances on Tacrolimus 1 1. Tacrolimus 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. 2. High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor. 3. 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 juice 2 May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)]. Avoid grapefruit or grapefruit juice. Strong CYP3A Inducers 3 : 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 (5.11)] . Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.2, 2.6) and Clinical Pharmacology (12.3)] . Strong CYP3A Inhibitors 3 : 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 (5.6, 5.11, 5.12)]. Reduce tacrolimus 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 (2.2, 2.6) 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 (5.11)]. 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 (5.6, 5.11, 5.12)]. Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6) 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 (5.6, 5.11, 5.12)]. Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6) and Clinical Pharmacology (12.3)] . Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)] . Caspofungin May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [see Dosage and Administration (2.2, 2.6)] . Direct Acting Antiviral (DAA) Therapy The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy and safety [see Dosage and Administration (2.2, 2.6)]. 7.3 Cannabidiol The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and tacrolimus are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of tacrolimus should be considered as needed when tacrolimus is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6) and Warnings and Precautions (5.17)]. Drug Interaction Studies Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)] . • Telaprevir: In a single-dose study in 9 healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized C max by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.2)] . • Boceprevir: In a single-dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus C max by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.2)] . • Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of tacrolimus and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.2)] . • Rifampin: In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 ± 6% vs. 7 ± 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036 ± 0.008 L/hr/kg vs. 0.053 ± 0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.2)] . • Magnesium and Aluminum-hydroxide: In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus a

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 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 tacrolimus extended-release capsules in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia. The incidence of adverse reactions that occurred in ≥ 15% of tacrolimus extended-release capsules-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 4 . Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1 Study 1 was not designed to support comparative claims of tacrolimus extended-release capsules compared to tacrolimus immediate-release for the adverse reactions reported in this table. Tacrolimus extended-release capsules, 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 (less than 15% in tacrolimus extended-release capsules-treated patients) by System Organ Class The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with tacrolimus extended-release capsules, 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, depress

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, after which 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). 12.3 Pharmacokinetics Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 17). Table 17. Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients * Not applicable † AUC0-inf ‡ Not available § AUC0-t ¶ Determined after the first dose # Median [range] Þ AUC0-12 Population N Route (Dose) Parameters Cmax (ng/mL) Tmax (hr) AUC (ng•hr/mL) t1/2 (hr) CL (L/hr/kg) V (L/kg) Healthy Volunteers 8 IV (0.025 mg/kg/4 hr) * * 652†± 156 34.2 ± 7.7 0.040 ± 0.009 1.91 ± 0.31 16 PO (5 mg) (capsules) 28.8 ± 8.9 1.5 ± 0.7 266†± 95 32.3 ± 8.8 ‡ ‡ Kidney Transplant Patients 26 IV (0.02 mg/kg/12 hr) * * 294†± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66 PO (0.2 mg/kg/day) 19.2 ± 10.3 3 203†± 42 ‡ ‡ ‡ PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288† ± 93 ‡ ‡ ‡ Liver Transplant Patients 17 IV (0.05 mg/kg/12 hr) * * 3300† ± 2130 11.7 ± 3.9 0.053 ± 0.017 0.85 ± 0.30 PO (0.3 mg/kg/day) 68.5 ± 30 2.3 ± 1.5 519† ± 179 ‡ ‡ ‡ Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) * * 954§ ± 334 23.6 ± 9.22 0.051 ± 0.015 ‡ 11 PO (0.075 mg/kg/day)¶ 14.7 ± 7.79 2.1 [0.5-6]# 82.7Þ ± 63.2 * ‡ ‡ 14 PO (0.15 mg/kg/day)¶ 24.5 ± 13.7 1.5 [0.4-4]# 142Þ ± 116 * ‡ ‡ Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics. Absorption Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), 23±9% in adult heart transplant patients (N=11) and 18±5% in healthy volunteers (N=16). A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10 to 12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state. If pediatric patients are converted between formulations, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained. Food Effects The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers. The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively. In healthy volunteers (N=16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. In 11 liver transplant patients, tacrolimus administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27±18%) and Cmax (50±19%), as compared to a fasted state. Tacrolimus capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Dosage and Administration (2.1)]. Distribution The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5 to 50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67). Elimination Metabolism Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A4 and CYP3A5). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. Excretion The mean clearance following IV administration of tacrolimus is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine. In a mass balance study of IV-administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8±12.7%. Fecal elimination accounted for 92.4±1% and the elimination half-life based on radioactivity was 48.1±15.9 hours whereas it was 43.5±11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029±0.015 L/hr/kg and clearance of tacrolimus was 0.029±0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9±30.7%. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1% and the elimination half-life based on radioactivity was 31.9±10.5 hours whereas it was 48.4±12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226±0.116 L/hr/kg and clearance of tacrolimus was 0.172±0.088 L/hr/kg. Specific Populations Pedi